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Increased circulating lactate concentration

MedGen UID:
332209
Concept ID:
C1836440
Finding
Synonym: Increased serum lactate
 
HPO: HP:0002151

Definition

Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35). [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVIncreased circulating lactate concentration

Conditions with this feature

Leigh syndrome
MedGen UID:
44095
Concept ID:
C0023264
Disease or Syndrome
Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation (summary by Lake et al., 2015). Genetic Heterogeneity of Leigh Syndrome Leigh syndrome may be a clinical presentation of a primary deficiency caused by genes in any of the mitochondrial respiratory chain complexes: complex I deficiency (see 252010), complex II deficiency (see 252011), complex III deficiency (see 124000), complex IV deficiency (cytochrome c oxidase; see 220110), and complex V deficiency (see 604273) (summary by Lake et al., 2015). Mutations in mitochondrial genes have also been identified in patients with Leigh syndrome: see MTTV (590105), MTTK (590060), MTTW (590095), and MTTL1 (590050). Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, 238331 and PDHA1, 300502). Deficiency of coenzyme Q10 (607426) can present as Leigh syndrome. Some forms of combined oxidative phosphorylation deficiency can present as Leigh syndrome (see, e.g., 617664).
Pyruvate carboxylase deficiency
MedGen UID:
18801
Concept ID:
C0034341
Disease or Syndrome
Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Three clinical types are recognized: Type A (infantile form), in which most affected children die in infancy or early childhood. Type B (severe neonatal form), in which affected infants have hepatomegaly, pyramidal tract signs, and abnormal movement and die within the first three months of life. Type C (intermittent/benign form), in which affected individuals have normal or mildly delayed neurologic development and episodic metabolic acidosis.
MERRF syndrome
MedGen UID:
56486
Concept ID:
C0162672
Disease or Syndrome
MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, occurring after normal early development. Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias such as Wolff-Parkinson-White syndrome, and peripheral neuropathy. Pigmentary retinopathy, optic neuropathy, diabetes mellitus, and lipomatosis have been observed.
Progressive sclerosing poliodystrophy
MedGen UID:
60012
Concept ID:
C0205710
Disease or Syndrome
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
Inborn glycerol kinase deficiency
MedGen UID:
82803
Concept ID:
C0268418
Disease or Syndrome
NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD.
Deficiency of hydroxymethylglutaryl-CoA lyase
MedGen UID:
78692
Concept ID:
C0268601
Disease or Syndrome
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988).
Acetyl-CoA: carboxylase deficiency
MedGen UID:
124338
Concept ID:
C0268603
Disease or Syndrome
Acetyl-CoA carboxylase-alpha deficiency (ACACAD) is an autosomal recessive disorder characterized by hypotonia and global developmental delay (summary by Shafieipour et al., 2023).
Lysinuric protein intolerance
MedGen UID:
75704
Concept ID:
C0268647
Disease or Syndrome
Lysinuric protein intolerance (LPI) typically presents after an infant is weaned from breast milk or formula; variable findings include recurrent vomiting and episodes of diarrhea, episodes of stupor and coma after a protein-rich meal, poor feeding, aversion to protein-rich food, failure to thrive, hepatosplenomegaly, and muscular hypotonia. Over time, findings include: poor growth, osteoporosis, involvement of the lungs (progressive interstitial changes, pulmonary alveolar proteinosis) and of the kidneys (progressive glomerular and proximal tubular disease), hematologic abnormalities (normochromic or hypochromic anemia, leukopenia, thrombocytopenia, erythroblastophagocytosis in the bone marrow aspirate), and a clinical presentation resembling the hemophagocytic lymphohistiocytosis/macrophagic activation syndrome. Hypercholesterolemia, hypertriglyceridemia, and acute pancreatitis can also be seen.
Acetyl-CoA acetyltransferase-2 deficiency
MedGen UID:
90995
Concept ID:
C0342735
Disease or Syndrome
Upshaw-Schulman syndrome
MedGen UID:
224783
Concept ID:
C1268935
Disease or Syndrome
Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome (USS), is a rare autosomal recessive thrombotic microangiopathy (TMA). Clinically, acute phases of TTP are defined by microangiopathic mechanical hemolytic anemia, severe thrombocytopenia, and visceral ischemia. Hereditary TTP makes up 5% of TTP cases and is caused mostly by biallelic mutation in the ADAMTS13 gene, or in very rare cases, by monoallelic ADAMTS13 mutation associated with a cluster of single-nucleotide polymorphisms (SNPs); most cases of all TTP (95%) are acquired via an autoimmune mechanism (see 188030). Hereditary TTP is more frequent among child-onset TTP compared with adult-onset TTP, and its clinical presentation is significantly different as a function of its age of onset. Child-onset TTP usually starts in the neonatal period with hematological features and severe jaundice. In contrast, almost all cases of adult-onset hereditary TTP are unmasked during the first pregnancy of a woman whose disease was silent during childhood (summary by Joly et al., 2018).
Deficiency of beta-ureidopropionase
MedGen UID:
226944
Concept ID:
C1291512
Disease or Syndrome
Beta-ureidopropionase deficiency is a rare autosomal recessive inborn error of metabolism due to a defect in pyrimidine degradation. Less than 10 patients have been reported, and the phenotype can range from severe neurologic involvement with mental retardation and seizures to normal neurologic development (Yaplito-Lee et al., 2008).
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
MedGen UID:
371919
Concept ID:
C1834846
Disease or Syndrome
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3
MedGen UID:
373087
Concept ID:
C1836439
Disease or Syndrome
Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Patients with C10ORF2-linked adPEO may have other clinical features including proximal muscle weakness, ataxia, peripheral neuropathy, cardiomyopathy, cataracts, depression, and endocrine abnormalities (summary by Fratter et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640). PEO caused by mutations in the POLG gene (174763) are associated with more complicated phenotypes than those forms caused by mutations in the SLC25A4 (103220) or C10ORF2 genes (Lamantea et al., 2002).
Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
MedGen UID:
322999
Concept ID:
C1836797
Disease or Syndrome
Combined oxidative phosphorylation deficiency is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (summary by Smits et al., 2011). Genetic Heterogeneity of Combined Oxidative Phosphorylation Deficiency See also COXPD2 (610498), caused by mutation in the MRPS16 gene (609204) on 10q22; COXPD3 (610505), caused by mutation in the TSFM gene (604723) on 12q14; COXPD4 (610678), caused by mutation in the TUFM gene (602389) on 16p11; COXPD5 (611719), caused by mutation in the MRPS22 gene (605810) on 3q23; COXPD6 (300816), caused by mutation in the AIFM1 gene (300169) on Xq26; COXPD7 (613559), caused by mutation in the MTRFR gene (613541) on 12q24; COXPD8 (614096), caused by mutation in the AARS2 gene (612035) on 6p21; COXPD9 (614582), caused by mutation in the MRPL3 gene (607118) on 3q22; COXPD10 (614702), caused by mutation in the MTO1 gene (614667) on 6q13; COXPD11 (614922), caused by mutation in the RMND1 gene (614917) on 6q25; COXPD12 (614924), caused by mutation in the EARS2 gene (612799) on 16p13; COXPD13 (614932), caused by mutation in the PNPT1 gene (610316) on 2p16; COXPD14 (614946), caused by mutation in the FARS2 gene (611592) on 6p25; COXPD15 (614947), caused by mutation in the MTFMT gene (611766) on 15q; COXPD16 (615395), caused by mutation in the MRPL44 gene (611849) on 2q36; COXPD17 (615440), caused by mutation in the ELAC2 gene (605367) on 17p11; COXPD18 (615578), caused by mutation in the SFXN4 gene (615564) on 10q26; COXPD19 (615595), caused by mutation in the LYRM4 gene (613311) on 6p25; COXPD20 (615917), caused by mutation in the VARS2 gene (612802) on 6p21; COXPD21 (615918), caused by mutation in the TARS2 gene (612805) on 1q21; COXPD22 (616045), caused by mutation in the ATP5A1 gene (164360) on 18q12; COXPD23 (616198), caused by mutation in the GTPBP3 (608536) gene on 19p13; COXPD24 (616239), caused by mutation in the NARS2 gene (612803) on 11q14; COXPD25 (616430), caused by mutation in the MARS2 gene (609728) on 2q33; COXPD26 (616539), caused by mutation in the TRMT5 gene (611023) on 14q23; COXPD27 (616672), caused by mutation in the CARS2 gene (612800) on 13q34; COXPD28 (616794), caused by mutation in the SLC25A26 gene (611037) on 3p14; COXPD29 (616811), caused by mutation in the TXN2 gene (609063) on 22q12; COXPD30 (616974), caused by mutation in the TRMT10C gene (615423) on 3q12; and COXPD31 (617228), caused by mutation in the MIPEP gene (602241) on 13q12; COXPD32 (617664), caused by mutation in the MRPS34 gene (611994) on 16q13; COXPD33 (617713), caused by mutation in the C1QBP gene (601269) on 17p13; and COXPD34 (617872), caused by mutation in the MRPS7 gene (611974) on 17q25; COXPD35 (617873), caused by mutation in the TRIT1 gene (617840) on 1p34; COXPD36 (617950), caused by mutation in the MRPS2 gene (611971) on 9q34; COXPD37 (618329), caused by mutation in the MICOS13 gene (616658) on 19p13; COXPD38 (618378), caused by mutation in the MRPS14 gene (611978) on 1q23; COXPD39 (618397), caused by mutation in the GFM2 gene (606544) on 5q13; COXPD40 (618835), caused by mutation in the QRSL1 gene (617209) on 6q21; COXPD41 (618838), caused by mutation in the GATB gene (603645) on 4q31; COXPD42 (618839), caused by mutation in the GATC gene (617210) on 12q24; COXPD43 (618851), caused by mutation in the TIMM22 gene (607251) on 17p13; COXPD44 (618855), caused by mutation in the FASTKD2 gene (612322) on 2q33; COXPD45 (618951), caused by mutation in the MRPL12 gene (602375) on 17q25; COXPD46 (618952), caused by mutation in the MRPS23 gene (611985) on 17q22; COXPD47 (618958), caused by mutation in the MRPS28 gene (611990) on 8q21; COXPD48 (619012), caused by mutation in the NSUN3 gene (617491) on 3q11; COXPD49 (619024), caused by mutation in the MIEF2 gene (615498) on 17p11; COXPD50 (619025), caused by mutation in the MRPS25 gene (611987) on 3p25; COXPD51 (619057), caused by mutation in the PTCD3 gene (614918) on 2p11; COXPD52 (619386), caused by mutation in the NFS1 gene (603485) on 20q11; COXPD53 (619423), caused by mutation in the C2ORF69 gene (619219) on 2q33; and COXPD54 (619737), caused by mutation in the PRORP gene (609947) on 14q13.; COXPD55 (619743), caused by mutation in the POLRMT gene (601778) on 19p13; COXPD56 (620139), caused by mutation in the TAMM41 gene (614948) on 3p25; COXPD57 (620167), caused by mutation in the CRLS1 gene (608188) on 20p12; COXPD58 (620451), caused by mutation in the TEFM gene (616422) on 17q11; and COXPD59 (620646), caused by mutation in the MRPL39 gene (611845) on 21q21.
Striatonigral degeneration, infantile, mitochondrial
MedGen UID:
374113
Concept ID:
C1839022
Disease or Syndrome
Leber optic atrophy and dystonia
MedGen UID:
333240
Concept ID:
C1839040
Disease or Syndrome
Pyruvate dehydrogenase E1-alpha deficiency
MedGen UID:
326486
Concept ID:
C1839413
Disease or Syndrome
Genetic defects in the pyruvate dehydrogenase complex are one of the most common causes of primary lactic acidosis in children. Most cases are caused by mutation in the E1-alpha subunit gene on the X chromosome. X-linked PDH deficiency is one of the few X-linked diseases in which a high proportion of heterozygous females manifest severe symptoms. The clinical spectrum of PDH deficiency is broad, ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis (Robinson et al., 1987; Brown et al., 1994). Genetic Heterogeneity of Pyruvate Dehydrogenase Complex Deficiency PDH deficiency can also be caused by mutation in other subunits of the PDH complex, including a form (PDHXD; 245349) caused by mutation in the component X gene (PDHX; 608769) on chromosome 11p13; a form (PDHBD; 614111) caused by mutation in the PDHB gene (179060) on chromosome 3p14; a form (PDHDD; 245348) caused by mutation in the DLAT gene (608770) on chromosome 11q23; a form (PDHPD; 608782) caused by mutation in the PDP1 gene (605993) on chromosome 8q22; and a form (PDHLD; 614462) caused by mutation in the LIAS gene (607031) on chromosome 4p14.
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
MedGen UID:
375302
Concept ID:
C1843851
Disease or Syndrome
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
Hypotonia-cystinuria syndrome
MedGen UID:
341133
Concept ID:
C1848030
Disease or Syndrome
A rare, genetic disorder of amino acid absorption and transport, characterized by generalized hypotonia at birth, neonatal/infantile failure to thrive (followed by hyperphagia and rapid weight gain in late childhood), cystinuria type 1, nephrolithiasis, growth retardation due to growth hormone deficiency, and minor facial dysmorphism. Dysmorphic features mainly include dolichocephaly and ptosis. Nephrolithiasis occurs at variable ages.
Hereditary myopathy with lactic acidosis due to ISCU deficiency
MedGen UID:
342573
Concept ID:
C1850718
Disease or Syndrome
Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive muscular disorder characterized by childhood onset of exercise intolerance with muscle tenderness, cramping, dyspnea, and palpitations. Biochemical features include lactic acidosis and, rarely, rhabdomyolysis. It is a chronic disorder with remission and exacerbation of the muscle phenotype (summary by Sanaker et al., 2010).
Mitochondrial myopathy-lactic acidosis-deafness syndrome
MedGen UID:
343245
Concept ID:
C1855033
Disease or Syndrome
A rare metabolic myopathy presenting during childhood, and characterized clinically by growth failure, severe muscle weakness, and moderate sensorineural deafness and biochemically by metabolic acidosis, elevated serum pyruvate concentration, hyperalaninemia and hyperalaninuria. There have been no further descriptions in the literature since 1973.
Intellectual disability, autosomal recessive 1
MedGen UID:
344468
Concept ID:
C1855304
Mental or Behavioral Dysfunction
Any autosomal recessive non-syndromic intellectual disability in which the cause of the disease is a mutation in the PRSS12 gene.
Glycogen storage disorder due to hepatic glycogen synthase deficiency
MedGen UID:
343430
Concept ID:
C1855861
Disease or Syndrome
Glycogen storage disease type 0 (also known as GSD 0) is a condition caused by the body's inability to form a complex sugar called glycogen, which is a major source of stored energy in the body. GSD 0 has two types: in muscle GSD 0, glycogen formation in the muscles is impaired, and in liver GSD 0, glycogen formation in the liver is impaired.\n\nIndividuals with liver GSD 0 usually show signs and symptoms of the disorder in infancy. People with this disorder develop low blood sugar (glucose), known as hypoglycemia, after going long periods of time without food (fasting). Signs of hypoglycemia become apparent when affected infants begin sleeping through the night and stop late-night feedings; these infants exhibit extreme tiredness (lethargy), pale skin (pallor), and nausea. During episodes of fasting, ketone levels in the blood may increase (ketosis). Ketones are molecules produced during the breakdown of fats, which occurs when stored sugars (such as glycogen) are unavailable. These short-term signs and symptoms of liver GSD 0 often improve when food is eaten and glucose levels in the body return to normal. The features of liver GSD 0 vary; they can be mild and go unnoticed for years, or they can include developmental delay and growth failure.\n\nThe signs and symptoms of muscle GSD 0 typically begin in early childhood. Affected individuals often experience muscle pain and weakness or episodes of fainting (syncope) following moderate physical activity, such as walking up stairs. The loss of consciousness that occurs with fainting typically lasts up to several hours. Some individuals with muscle GSD 0 have a disruption of the heart's normal rhythm (arrhythmia) known as long QT syndrome. In all affected individuals, muscle GSD 0 impairs the heart's ability to effectively pump blood and increases the risk of cardiac arrest and sudden death, particularly after physical activity. Sudden death from cardiac arrest can occur in childhood or adolescence in people with muscle GSD 0.
Progressive encephalopathy with leukodystrophy due to DECR deficiency
MedGen UID:
346552
Concept ID:
C1857252
Disease or Syndrome
2,4-Dienoyl-CoA reductase deficiency (DECRD) is a rare autosomal recessive inborn error of metabolism resulting in mitochondrial dysfunction due to impaired production of NADPH, which is an essential cofactor for several mitochondrial enzymes. Affected individuals have a variable phenotype: some may have severe neurologic symptoms and metabolic dysfunction beginning in early infancy, whereas others may present with more subtle features, such as childhood-onset optic atrophy or intermittent muscle weakness. The variable severity is putatively dependent on the effect of the mutation on the NADK2 enzyme. Biochemical analysis typically shows hyperlysinemia, due to defective activity of the mitochondrial NADP(H)-dependent enzyme AASS (605113), which is usually a benign finding. More severe cases have increased C10:2-carnitine levels, due to defective activity of the enzyme DECR (DECR1; 222745) (summary by Houten et al., 2014 and Pomerantz et al., 2018).
Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type
MedGen UID:
387801
Concept ID:
C1857355
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 5 (MC4DN5) is an autosomal recessive severe metabolic multisystemic disorder with onset in infancy. Features include delayed psychomotor development, impaired intellectual development with speech delay, mild dysmorphic facial features, hypotonia, ataxia, and seizures. There is increased serum lactate and episodic hypoglycemia. Some patients may have cardiomyopathy, abnormal breathing, or liver abnormalities, reflecting systemic involvement. Brain imaging shows lesions in the brainstem and basal ganglia, consistent with a diagnosis of Leigh syndrome (see 256000). Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Combined oxidative phosphorylation defect type 4
MedGen UID:
387884
Concept ID:
C1857682
Disease or Syndrome
A rare mitochondrial disorder due to a defect in mitochondrial protein synthesis with characteristics of neonatal onset of severe metabolic acidosis and respiratory distress, persistent lactic acidosis with episodes of metabolic crises, developmental regression, microcephaly, abnormal gaze fixation and pursuit, axial hypotonia with limb spasticity and reduced spontaneous movements. Neuroimaging studies reveal polymicrogyria, white matter abnormalities and multiple cystic brain lesions, including basal ganglia, and cerebral atrophy. Decreased activity of complex I and IV have been determined in muscle biopsy.
Sengers syndrome
MedGen UID:
395228
Concept ID:
C1859317
Disease or Syndrome
Sengers syndrome is an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4
MedGen UID:
350480
Concept ID:
C1864668
Disease or Syndrome
Progressive external ophthalmoplegia-4 is an autosomal dominant form of mitochondrial disease that variably affects skeletal muscle, the nervous system, the liver, and the gastrointestinal tract. Age at onset ranges from infancy to adulthood. The phenotype ranges from relatively mild, with adult-onset skeletal muscle weakness and weakness of the external eye muscles, to severe, with a multisystem disorder characterized by delayed psychomotor development, lactic acidosis, constipation, and liver involvement (summary by Young et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640).
Pyridoxal phosphate-responsive seizures
MedGen UID:
350498
Concept ID:
C1864723
Disease or Syndrome
Untreated pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency, characterized by a range of seizure types, is "classic" (i.e., seizure onset in the neonatal period) in about 90% of affected individuals and "late onset" (seizure onset after the neonatal period) in about 10%. In classic PNPO deficiency, seizures (including status epilepticus) often begin on the first day of life and typically before age two weeks. In both classic and late-onset untreated PNPO deficiency, seizure semiology varies from myoclonic to clonic or tonic seizures, and seizures are typically resistant to common anti-seizure medications. Independent of age of onset, seizures respond to life-long treatment with a B6 vitamer: pyridoxal 5'-phosphate (PLP) in about 60% of affected individuals and pyridoxine (PN) in about 40%. About 60% of individuals with PNPO deficiency have developmental impairment, affecting speech, cognition, and behavior; some individuals have neurologic impairment such as muscular hypotonia or dystonia. Severe neurodevelopmental impairment is more likely to occur in individuals with PNPO deficiency who experienced diagnostic delay and prolonged periods of uncontrolled seizures.
Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3
MedGen UID:
355842
Concept ID:
C1864840
Disease or Syndrome
Combined oxidative phosphorylation deficiency type 3 is an extremely rare clinically heterogenous disorder described in about 5 patients to date. Clinical signs included hypotonia, lactic acidosis, and hepatic insufficiency, with progressive encephalomyopathy or hypertrophic cardiomyopathy.
Combined oxidative phosphorylation defect type 2
MedGen UID:
400626
Concept ID:
C1864843
Disease or Syndrome
A rare mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by severe intrauterine growth retardation, neonatal limb edema and redundant skin on the neck (hydrops), developmental brain defects (corpus callosum agenesis, ventriculomegaly), brachydactyly, dysmorphic facial features with low set ears, severe intractable neonatal lactic acidosis with lethargy, hypotonia, absent spontaneous movements and fatal outcome. Markedly decreased activity of complex I, II + III and IV in muscle and liver have been determined.
Pontocerebellar hypoplasia type 6
MedGen UID:
370596
Concept ID:
C1969084
Congenital Abnormality
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Hypotonia with lactic acidemia and hyperammonemia
MedGen UID:
435972
Concept ID:
C2673642
Disease or Syndrome
This syndrome is characterized by severe hypotonia, lactic acidemia and congenital hyperammonemia. It has been described in three newborns born to consanguineous parents. Ultrasound examination during the 36th week of pregnancy revealed generalized edema. Hypertrophic cardiomyopathy and tubulopathy developed within the first week of life and the infants died within the first month. The activities of enzymes in the mitochondrial respiratory chain were reduced in the muscles of the patients. Mutations were identified in the MRPS22 gene on chromosome 3q23, encoding a mitochondrial ribosomal protein
Hypomyelinating leukodystrophy 4
MedGen UID:
383026
Concept ID:
C2677109
Disease or Syndrome
Any leukodystrophy in which the cause of the disease is a mutation in the HSPD1 gene.
Autosomal recessive ataxia due to ubiquinone deficiency
MedGen UID:
436985
Concept ID:
C2677589
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
MedGen UID:
413170
Concept ID:
C2749864
Disease or Syndrome
SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized by onset of the following features in infancy or childhood (median age of onset 2 months; range of onset birth to 6 years): psychomotor retardation, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, postnatal growth retardation, and feeding difficulties. Other less frequent features include distinctive facial features, contractures, kyphoscoliosis, gastroesophageal reflux, ptosis, choreoathetosis, ophthalmoplegia, and epilepsy (infantile spasms or generalized convulsions). The median survival is 20 years; approximately 30% of affected individuals succumb during childhood. Affected individuals may have hyperintensities in the basal ganglia, cerebral atrophy, and leukoencephalopathy on head MRI. Elevation of methylmalonic acid (MMA) in the urine and plasma is found in a vast majority of affected individuals, although at levels that are far below those typically seen in individuals with classic methylmalonic aciduria.
Glycogen storage disease IXc
MedGen UID:
442778
Concept ID:
C2751643
Disease or Syndrome
Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis.
Developmental and epileptic encephalopathy, 39
MedGen UID:
414492
Concept ID:
C2751855
Disease or Syndrome
Developmental and epileptic encephalopathy-39 with leukodystrophy (DEE39) is an autosomal recessive neurologic syndrome characterized clinically by global developmental delay apparent in early infancy, early-onset seizures, hypotonia with poor motor function, and hypomyelination on brain imaging. Other features include absent speech and inability to walk; spasticity and hyperreflexia has also been reported. Although there is significant hypomyelination on brain imaging, the disorder was not classified as a primary leukodystrophy. The myelination defect was thought to stem from primary neuronal dysfunction due to impaired mitochondrial transport activity (summary by Wibom et al., 2009 and Falk et al., 2014). However, serial brain imaging in a patient with DEE39 by Kavanaugh et al. (2019) suggested that the mechanism of disease is consistent with a leukoaxonopathy type of leukodystrophy. For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Oxoglutaricaciduria
MedGen UID:
414553
Concept ID:
C2752074
Disease or Syndrome
Oxoglutarate dehydrogenase deficiency (OGDHD) is an autosomal recessive disorder associated with features of infantile- and pediatric-onset basal ganglia-associated movement disorders, hypotonia, developmental delays, ataxia, and seizures (summary by Yap et al., 2021).
Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency
MedGen UID:
419152
Concept ID:
C2931743
Disease or Syndrome
Lactate dehydrogenase deficiency is a condition that affects how the body breaks down sugar to use as energy in cells, primarily muscle cells.\n\nThere are two types of this condition: lactate dehydrogenase-A deficiency (sometimes called glycogen storage disease XI) and lactate dehydrogenase-B deficiency.\n\nPeople with lactate dehydrogenase-A deficiency experience fatigue, muscle pain, and cramps during exercise (exercise intolerance). In some people with lactate dehydrogenase-A deficiency, high-intensity exercise or other strenuous activity leads to the breakdown of muscle tissue (rhabdomyolysis). The destruction of muscle tissue releases a protein called myoglobin, which is processed by the kidneys and released in the urine (myoglobinuria). Myoglobin causes the urine to be red or brown. This protein can also damage the kidneys, in some cases leading to life-threatening kidney failure. Some people with lactate dehydrogenase-A deficiency develop skin rashes. The severity of the signs and symptoms among individuals with lactate dehydrogenase-A deficiency varies greatly.\n\nPeople with lactate dehydrogenase-B deficiency typically do not have any signs or symptoms of the condition. They do not have difficulty with physical activity or any specific physical features related to the condition. Affected individuals are usually discovered only when routine blood tests reveal reduced lactate dehydrogenase activity.
Combined oxidative phosphorylation defect type 7
MedGen UID:
462151
Concept ID:
C3150801
Disease or Syndrome
A rare mitochondrial disease due to a defect in mitochondrial protein synthesis with a variable phenotype that includes onset in infancy or early childhood of failure to thrive and psychomotor regression (after initial normal development), as well as ocular manifestations (such as ptosis, nystagmus, optic atrophy, ophthalmoplegia and reduced vision). Additional manifestations include bulbar paresis with facial weakness, hypotonia, difficulty chewing, dysphagia, mild dysarthria, ataxia, global muscle atrophy, and areflexia. It has a relatively slow disease progression with patients often living into the third decade of life.
Myopathy, lactic acidosis, and sideroblastic anemia 2
MedGen UID:
462152
Concept ID:
C3150802
Disease or Syndrome
Myopathy, lactic acidosis, and sideroblastic anemia-2 (MLASA2) is an autosomal recessive disorder of the mitochondrial respiratory chain. The disorder shows marked phenotypic variability: some patients have a severe multisystem disorder from infancy, including cardiomyopathy and respiratory insufficiency resulting in early death, whereas others present in the second or third decade of life with sideroblastic anemia and mild muscle weakness (summary by Riley et al., 2013). For a discussion of genetic heterogeneity of MLASA, see MLASA1 (600462).
Hyperuricemia, pulmonary hypertension, renal failure, alkalosis syndrome
MedGen UID:
462559
Concept ID:
C3151209
Disease or Syndrome
HUPRA syndrome is a severe autosomal recessive multisystem disorder characterized by onset in infancy of progressive renal failure leading to electrolyte imbalances, metabolic alkalosis, pulmonary hypertension, hypotonia, and delayed development. Affected individuals are born prematurely (summary by Belostotsky et al., 2011).
Severe X-linked mitochondrial encephalomyopathy
MedGen UID:
463103
Concept ID:
C3151753
Disease or Syndrome
Combined oxidative phosphorylation deficiency-6 (COXPD6) is an X-linked recessive severe encephalomyopathic disorder with onset in utero or in infancy. Affected patients have hypotonia and severely impaired psychomotor development associated with variably decreased enzymatic activity of mitochondrial respiratory complexes in skeletal muscle or fibroblasts. More variable features may include sensorimotor neuropathy, seizures, severe muscle weakness, abnormal signals in the basal ganglia, hypertrophic cardiomyopathy, deafness, swallowing difficulties, and respiratory insufficiency. Death in childhood may occur (summary by Berger et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Mitochondrial myopathy with reversible cytochrome C oxidase deficiency
MedGen UID:
463248
Concept ID:
C3151898
Disease or Syndrome
Infantile mitochondrial myopathy due to reversible COX deficiency is a rare mitochondrial disorder characterized by onset in infancy of severe hypotonia and generalized muscle weakness associated with lactic acidosis, but is distinguished from other mitochondrial disorders in that affected individuals recover spontaneously after 1 year of age (summary by Mimaki et al., 2010). See also transient infantile liver failure (LFIT; 613070), which is a similar disorder.
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1
MedGen UID:
477906
Concept ID:
C3276276
Disease or Syndrome
A distinct group of inborn defects of complex V (ATP synthase) is represented by the enzyme deficiency due to nuclear genome mutations characterized by a selective inhibition of ATP synthase biogenesis. Biochemically, the patients show a generalized decrease in the content of ATP synthase complex which is less than 30% of normal. Most cases present with neonatal-onset hypotonia, lactic acidosis, hyperammonemia, hypertrophic cardiomyopathy, and 3-methylglutaconic aciduria. Many patients die within a few months or years (summary by Mayr et al., 2010). Genetic Heterogeneity of Mitochondrial Complex V Deficiency Other nuclear types of mitochondrial complex V deficiency include MC5DN2 (614052), caused by mutation in the TMEM70 gene (612418) on chromosome 8q21; MC5DN3 (614053), caused by mutation in the ATP5E gene (ATP5F1E; 606153) on chromosome 20q13; MC5DN4A (620358) and MC5DN4B (615228), both caused by mutation in the ATP5A1 gene (ATP5F1A; 164360) on chromosome 18q; MC5DN5 (618120), caused by mutation in the ATP5D gene (ATP5F1D; 603150) on chromosome 19p13; MC5DN6 (618683), caused by mutation in the USMG5 gene (ATP5MD; 615204) on chromosome 10q24; and MC5DN7 (620359), caused by mutation in the ATP5PO gene (600828) on chromosome 21q22. Mutations in the mitochondrial-encoded MTATP6 (516060) and MTATP8 (516070) genes can also cause mitochondrial complex V deficiency (see, e.g., 500015).
Multiple mitochondrial dysfunctions syndrome 1
MedGen UID:
478062
Concept ID:
C3276432
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome is a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death (summary by Seyda et al., 2001). Genetic Heterogeneity of Multiple Mitochondrial Dysfunctions Syndrome See also MMDS2 (614299), caused by mutation in the BOLA3 gene (613183) on chromosome 2p13; MMDS3 (615330), caused by mutation in the IBA57 gene (615316) on chromosome 1q42; MMDS4 (616370), caused by mutation in the ISCA2 gene (615317) on chromosome 14q24; MMDS5 (617613), caused by mutation in the ISCA1 gene (611006) on chromosome 9q21; MMDS6 (617954), caused by mutation in the PMPCB gene (603131) on chromosome 7q22; and MMDS7 (620423), caused by mutation in the GCSH gene (238330) on chromosome 16q23.
Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins
MedGen UID:
480294
Concept ID:
C3278664
Disease or Syndrome
Acute infantile liver failure resulting from TRMU mutation is a transient disorder of hepatic function. In addition to elevated liver enzymes, jaundice, vomiting, coagulopathy, and hyperbilirubinemia, the presence of increased serum lactate is consistent with a defect in mitochondrial respiratory function. With supportive care, patients who survive the initial acute episode can recover and show normal development (Zeharia et al., 2009). See also transient infantile mitochondrial myopathy (MMIT; 500009), which is a similar disorder. A more severe, permanent disorder with some overlapping features is associated with mitochondrial DNA depletion (251880). See ILFS1 (615438) for information on syndromic infantile liver failure.
Mitochondrial complex V (ATP synthase) deficiency nuclear type 2
MedGen UID:
481329
Concept ID:
C3279699
Disease or Syndrome
Mitochondrial encephalo-cardio-myopathy due to <i>TMEM70</i> mutation is characterized by early neonatal onset of hypotonia, hypetrophic cardiomyopathy and apneic spells within hours after birth accompanied by lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria.
Methylmalonate semialdehyde dehydrogenase deficiency
MedGen UID:
481470
Concept ID:
C3279840
Disease or Syndrome
Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (summary by Marcadier et al., 2013).
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1
MedGen UID:
482290
Concept ID:
C3280660
Disease or Syndrome
Encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by Sheffer et al., 2016; Fahrner et al., 2016). Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission See also EMPF2 (617086), caused by mutation in the MFF gene (614785) on chromosome 2q36.
Childhood encephalopathy due to thiamine pyrophosphokinase deficiency
MedGen UID:
482496
Concept ID:
C3280866
Disease or Syndrome
Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (Mayr et al., 2011). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).
Lipoic acid synthetase deficiency
MedGen UID:
482517
Concept ID:
C3280887
Disease or Syndrome
Hyperglycinemia, lactic acidosis, and seizures (HGCLAS) is a severe autosomal recessive disorder characterized by onset of hypotonia and seizures associated with increased serum glycine and lactate in the first days of life. Affected individuals develop an encephalopathy or severely delayed psychomotor development, which may result in death in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including HGCLAS, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014).
Mitochondrial complex III deficiency nuclear type 1
MedGen UID:
762097
Concept ID:
C3541471
Disease or Syndrome
Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (de Lonlay et al., 2001; De Meirleir et al., 2003). Genetic Heterogeneity of Mitochondrial Complex III Deficiency Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (615157), caused by mutation in the TTC19 gene (613814) on chromosome 17p12; MC3DN3 (615158), caused by mutation in the UQCRB gene (191330) on chromosome 8q; MC3DN4 (615159), caused by mutation in the UQCRQ gene (612080) on chromosome 5q31; MC3DN5 (615160), caused by mutation in the UQCRC2 gene (191329) on chromosome 16p12; MC3DN6 (615453), caused by mutation in the CYC1 gene (123980) on chromosome 8q24; MC3DN7 (615824), caused by mutation in the UQCC2 gene (614461) on chromosome 6p21; MC3DN8 (615838), caused by mutation in the LYRM7 gene (615831) on chromosome 5q23; MC3DN9 (616111), caused by mutation in the UQCC3 gene (616097) on chromosome 11q12; and MC3DN10 (618775), caused by mutation in the UQCRFS1 gene (191327) on chromosome 19q12. See also MTYCB (516020) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene.
Deafness-encephaloneuropathy-obesity-valvulopathy syndrome
MedGen UID:
766268
Concept ID:
C3553354
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Coenzyme Q10 deficiency, primary, 3
MedGen UID:
766272
Concept ID:
C3553358
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome
MedGen UID:
766288
Concept ID:
C3553374
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Mitochondrial pyruvate carrier deficiency
MedGen UID:
766521
Concept ID:
C3553607
Disease or Syndrome
Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation (summary by Bricker et al., 2012).
Mitochondrial complex III deficiency nuclear type 3
MedGen UID:
767520
Concept ID:
C3554606
Disease or Syndrome
Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and the muscles used for movement (skeletal muscles). Signs and symptoms of mitochondrial complex III deficiency usually begin in infancy but can appear later.\n\nThe severity of mitochondrial complex III deficiency varies widely among affected individuals. People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise intolerance). More severely affected individuals have problems with multiple body systems, such as liver disease that can lead to liver failure, kidney abnormalities (tubulopathy), and brain dysfunction (encephalopathy). Encephalopathy can cause delayed development of mental and motor skills (psychomotor delay), movement problems, weak muscle tone (hypotonia), and difficulty with communication. Some affected individuals have a form of heart disease called cardiomyopathy, which can lead to heart failure. \n\nMost people with mitochondrial complex III deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis). Some affected individuals also have buildup of molecules called ketones (ketoacidosis) or high blood glucose levels (hyperglycemia). Abnormally high levels of these chemicals in the body can be life-threatening.\n\nMitochondrial complex III deficiency can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood.
Mitochondrial complex III deficiency nuclear type 4
MedGen UID:
767521
Concept ID:
C3554607
Disease or Syndrome
Mitochondrial complex III deficiency can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood.\n\nMost people with mitochondrial complex III deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis). Some affected individuals also have buildup of molecules called ketones (ketoacidosis) or high blood glucose levels (hyperglycemia). Abnormally high levels of these chemicals in the body can be life-threatening.\n\nThe severity of mitochondrial complex III deficiency varies widely among affected individuals. People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise intolerance). More severely affected individuals have problems with multiple body systems, such as liver disease that can lead to liver failure, kidney abnormalities (tubulopathy), and brain dysfunction (encephalopathy). Encephalopathy can cause delayed development of mental and motor skills (psychomotor delay), movement problems, weak muscle tone (hypotonia), and difficulty with communication. Some affected individuals have a form of heart disease called cardiomyopathy, which can lead to heart failure. \n\nMitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and the muscles used for movement (skeletal muscles). Signs and symptoms of mitochondrial complex III deficiency usually begin in infancy but can appear later.
Mitochondrial complex III deficiency nuclear type 5
MedGen UID:
767522
Concept ID:
C3554608
Disease or Syndrome
Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and the muscles used for movement (skeletal muscles). Signs and symptoms of mitochondrial complex III deficiency usually begin in infancy but can appear later.\n\nThe severity of mitochondrial complex III deficiency varies widely among affected individuals. People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise intolerance). More severely affected individuals have problems with multiple body systems, such as liver disease that can lead to liver failure, kidney abnormalities (tubulopathy), and brain dysfunction (encephalopathy). Encephalopathy can cause delayed development of mental and motor skills (psychomotor delay), movement problems, weak muscle tone (hypotonia), and difficulty with communication. Some affected individuals have a form of heart disease called cardiomyopathy, which can lead to heart failure. \n\nMost people with mitochondrial complex III deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis). Some affected individuals also have buildup of molecules called ketones (ketoacidosis) or high blood glucose levels (hyperglycemia). Abnormally high levels of these chemicals in the body can be life-threatening.\n\nMitochondrial complex III deficiency can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood.
Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency
MedGen UID:
815669
Concept ID:
C3809339
Disease or Syndrome
Combined oxidative phosphorylation deficiency-16 (COXPD16) is an autosomal recessive multisystem disorder with hypertrophic cardiomyopathy as a major feature.
Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive
MedGen UID:
815773
Concept ID:
C3809443
Disease or Syndrome
Mitochondrial DNA depletion syndrome-12B is an autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance, and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy shows ragged-red fibers, mtDNA depletion, and accumulation of abnormal mitochondria (summary by Echaniz-Laguna et al., 2012). For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).
Mitochondrial complex III deficiency nuclear type 6
MedGen UID:
815883
Concept ID:
C3809553
Disease or Syndrome
Mitochondrial complex III deficiency nuclear type 6 (MC3DN6) is an autosomal recessive disorder caused by mitochondrial dysfunction. It is characterized by onset in early childhood of episodic acute lactic acidosis, ketoacidosis, and insulin-responsive hyperglycemia, usually associated with infection. Laboratory studies show decreased activity of mitochondrial complex III. Psychomotor development is normal (summary by Gaignard et al., 2013). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Mitochondrial DNA depletion syndrome 13
MedGen UID:
815922
Concept ID:
C3809592
Disease or Syndrome
FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
Growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome
MedGen UID:
816331
Concept ID:
C3810001
Disease or Syndrome
Combined oxidative phosphorylation deficiency-18 (COXPD18) is an autosomal recessive disorder of mitochondrial function characterized by intrauterine growth retardation, hypotonia, visual impairment, speech delay, and lactic acidosis associated with decreased mitochondrial respiratory chain activity. Affected patients may also show hematologic abnormalities, mainly macrocytic anemia (summary by Hildick-Smith et al., 2013). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
MedGen UID:
816734
Concept ID:
C3810404
Disease or Syndrome
Most children with carbonic anhydrase VA (CA-VA) deficiency reported to date have presented between day 2 of life and early childhood (up to age 20 months) with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma). Given that fewer than 20 affected individuals have been reported to date, the ranges of initial presentations and long-term prognoses are not completely understood. As of 2021 the oldest known affected individual is an adolescent. Almost all affected individuals reported to date have shown normal psychomotor development and no further episodes of metabolic crisis; however, a few have shown mild learning difficulties or delayed motor skills.
Pontocerebellar hypoplasia type 9
MedGen UID:
862791
Concept ID:
C4014354
Disease or Syndrome
Pontocerebellar hypoplasia type 9 (PCH9) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination (summary by Akizu et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Mitochondrial complex III deficiency nuclear type 7
MedGen UID:
862845
Concept ID:
C4014408
Disease or Syndrome
Any mitochondrial complex III deficiency in which the cause of the disease is a mutation in the UQCC2 gene.
Mitochondrial complex III deficiency nuclear type 8
MedGen UID:
862877
Concept ID:
C4014440
Disease or Syndrome
Mitochondrial complex III deficiency, nuclear type 8, is an autosomal recessive disorder characterized by progressive neurodegeneration with onset in childhood. Affected individuals may have normal or delayed early development, and often have episodic acute neurologic decompensation and regression associated with febrile illnesses. The developmental regression results in variable intellectual disability and motor deficits, such as hypotonia, axial hypertonia, and spasticity; some patients may lose the ability to walk independently. Laboratory studies show increased serum lactate and isolated deficiency of mitochondrial complex III in skeletal muscle and fibroblasts. Brain imaging shows a characteristic pattern of multifocal small cystic lesions in the periventricular and deep cerebral white matter (summary by Dallabona et al., 2016). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Mitochondrial complex III deficiency nuclear type 9
MedGen UID:
863690
Concept ID:
C4015253
Disease or Syndrome
Any mitochondrial complex III deficiency in which the cause of the disease is a mutation in the UQCC3 gene.
Perrault syndrome 5
MedGen UID:
863744
Concept ID:
C4015307
Disease or Syndrome
Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.
Autosomal dominant mitochondrial myopathy with exercise intolerance
MedGen UID:
863950
Concept ID:
C4015513
Disease or Syndrome
CHCHD10-related disorders are characterized by a spectrum of adult-onset neurologic phenotypes that can include: Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance. Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons. Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs. Late-onset spinal motor neuronopathy (SMA, Jokela type): weakness, cramps, and/or fasciculations; areflexia. Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities. Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder. Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown.
Combined oxidative phosphorylation defect type 24
MedGen UID:
864080
Concept ID:
C4015643
Disease or Syndrome
Combined oxidative phosphorylation deficiency-24 (COXPD24) is an autosomal recessive mitochondrial disorder with wide phenotypic variability. Most patients present in infancy with delayed neurodevelopment, refractory seizures, hypotonia, and hearing impairment due to auditory neuropathy. Less common features may include cortical blindness, renal dysfunction, and/or liver involvement, suggestive of Alpers syndrome (MTDPS4A; 203700). Patients with the severe phenotype tend to have brain abnormalities on imaging, including cerebral atrophy and hyperintensities in the basal ganglia and brainstem, consistent with Leigh syndrome. Laboratory values may be normal or show increased lactate and evidence of mitochondrial respiratory chain defects, particularly in muscle. Some patients achieve little developmental milestones and may die in infancy or early childhood. However, some patients have a less severe phenotype manifest only by myopathy (summary by Sofou et al., 2015, Vanlander et al., 2015, and Mizuguchi et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
MedGen UID:
873604
Concept ID:
C4040739
Disease or Syndrome
The phenotypic spectrum of SERAC1 deficiency comprises MEGD(H)EL syndrome (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome), juvenile-onset complicated hereditary spastic paraplegia (in 1 consanguineous family), and adult-onset generalized dystonia (in 1 adult male). MEGD(H)EL syndrome is characterized in neonates by hypoglycemia and a sepsis-like clinical picture for which no infectious agent can be found. During the first year of life feeding problems, failure to thrive, and/or truncal hypotonia become evident; many infants experience (transient) liver involvement ranging from undulating transaminases to prolonged hyperbilirubinemia and near-fatal liver failure. By age two years progressive deafness, dystonia, and spasticity prevent further psychomotor development and/or result in loss of acquired skills. Affected children are completely dependent on care for all activities of daily living; speech is absent.
Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)
MedGen UID:
903789
Concept ID:
C4225163
Disease or Syndrome
Any mitochondrial DNA depletion syndrome in which the cause of the disease is a mutation in the OPA1 gene.
Spasticity-ataxia-gait anomalies syndrome
MedGen UID:
905660
Concept ID:
C4225178
Disease or Syndrome
Childhood-onset spasticity with hyperglycinemia is an autosomal recessive disorder characterized by onset of slowly progressive spasticity that results in impaired gait in the first decade of life. Imaging of the central nervous system shows leukodystrophy and/or lesions in the upper spinal cord. More variable features include visual defects and mild learning disabilities. Serum glycine is increased, but CSF glycine is only mildly increased or normal; serum lactate is normal. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including SPAHGC, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014).
Charcot-Marie-Tooth disease type 4K
MedGen UID:
895560
Concept ID:
C4225246
Disease or Syndrome
Charcot-Marie-Tooth disease type 4K is an autosomal recessive demyelinating peripheral neuropathy characterized by onset in the first decade of distal muscle weakness and atrophy associated with impaired distal sensation. Both upper and lower limbs are affected. Affected individuals may also have nystagmus and late-onset cerebellar ataxia. Laboratory studies show increased serum lactate and isolated mitochondrial complex IV deficiency (summary by Echaniz-Laguna et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection
MedGen UID:
904009
Concept ID:
C4225260
Disease or Syndrome
Immunodeficiency-44 (IMD44) is an autosomal recessive primary immunodeficiency characterized by increased susceptibility to viral infections and adverse multisystemic reaction to vaccination in some patients. Affected individuals appear to have defects in mitochondrial fission and fusion (summary by Shahni et al., 2015).
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2
MedGen UID:
901897
Concept ID:
C4225312
Disease or Syndrome
Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-2 (PEOB2) is a mitochondrial disorder characterized by adult onset of progressive external ophthalmoplegia, exercise intolerance, muscle weakness, and signs and symptoms of spinocerebellar ataxia, such as impaired gait and dysarthria. Some patients may have respiratory insufficiency. Laboratory studies are consistent with a defect in mtDNA replication (summary by Reyes et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (258450).
Lissencephaly 7 with cerebellar hypoplasia
MedGen UID:
895680
Concept ID:
C4225359
Disease or Syndrome
Lissencephaly-7 with cerebellar hypoplasia (LIS7) is a severe neurodevelopmental disorder characterized by lack of psychomotor development, facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy (Magen et al., 2015). For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).
Lipoyl transferase 1 deficiency
MedGen UID:
904073
Concept ID:
C4225379
Disease or Syndrome
Lipoyl transferase 1 deficiency is a very rare inborn error of metabolism disorder, with a highly variable phenotype, typically characterized by neonatal to infancy-onset of seizures, psychomotor delay, and abnormal muscle tone that may include hypo- and/or hypertonia, resulting in generalized weakness, dystonic movements, and/or progressive respiratory distress, associated with severe lactic acidosis and elevated lactate, ketoglutarate and 2-oxoacids in urine. Additional manifestations may include dehydration, vomiting, signs of liver dysfunction, extrapyramidal signs, spastic tetraparesis, brisk deep tendon reflexes, speech impairment, swallowing difficulties, and pulmonary hypertension.
Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
MedGen UID:
902729
Concept ID:
C4225391
Disease or Syndrome
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) represents a clinical spectrum in which several phenotypes have been described: The most common phenotype presents in the neonatal period with severe encephalopathy and lactic acidosis and later manifests Leigh-like signs and symptoms. Those with presentation in the neonatal period typically have severe hypotonia, encephalopathy, or neonatal seizures within the first few days of life. Signs and symptoms typically progress quickly and the affected individual ultimately succumbs to central apnea or arrhythmia. A second group of affected individuals present in infancy with developmental regression resulting in severe developmental delay. A third group of affected individuals have normal development with isolated paroxysmal dystonia that may be exacerbated by illness or exertion. Across all three groups, T2 hyperintensity in the basal ganglia is very common, and may affect any part of the basal ganglia.
Optic atrophy 11
MedGen UID:
934595
Concept ID:
C4310628
Disease or Syndrome
Optic atrophy-11 (OPA11) is an autosomal recessive disorder characterized by delayed psychomotor development, intellectual disability, ataxia, optic atrophy, and leukoencephalopathy on brain imaging. Laboratory studies are consistent with mitochondrial dysfunction (summary by Hartmann et al., 2016). For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).
Epilepsy, early-onset, vitamin B6-dependent
MedGen UID:
934599
Concept ID:
C4310632
Disease or Syndrome
Early-onset vitamin B6-dependent epilepsy-1 (EPEO1) is an autosomal recessive neurologic disorder characterized by onset of seizures in the neonatal period or first months of life. The seizures show favorable response to treatment with activated vitamin B6 (pyridoxal 5-prime-phosphate; PLP) and/or pyridoxine. However, most patients show delayed psychomotor development (Darin et al., 2016). Genetic Heterogeneity of Early-Onset Epilepsy EPEO2 (618832) is caused by mutation in the SETD1A gene (611052) on chromosome 16p11. EPEO3 (620465) is caused by mutation in the ATP6V0C gene (108745) on chromosome 16p13. EPEO4 (266100) is caused by mutation in the ALDH7A1 gene (107323) on chromosome 5q23.
3-methylglutaconic aciduria type 8
MedGen UID:
934617
Concept ID:
C4310650
Disease or Syndrome
MGCA8 is an autosomal recessive metabolic disorder resulting in death in infancy. Features include hypotonia, abnormal movements, respiratory insufficiency with apneic episodes, and lack of developmental progress, often with seizures. Brain imaging is variable, but may show progressive cerebral atrophy. Laboratory studies show increased serum lactate and 3-methylglutaconic aciduria, suggesting a mitochondrial defect (summary by Mandel et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).
Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome
MedGen UID:
934628
Concept ID:
C4310661
Disease or Syndrome
Combined oxidative phosphorylation deficiency-31 is an autosomal recessive multisystem disorder characterized by left ventricular noncompaction (LVNC), global developmental delay, and severe hypotonia. More variable features include seizures, cataract, and abnormal movements. The disorder becomes apparent soon after birth or in early infancy, and patients may die in early childhood. Biochemical studies are consistent with a defect in mitochondrial function (summary by Eldomery et al., 2016). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1
MedGen UID:
934642
Concept ID:
C4310675
Disease or Syndrome
Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions (summary by Kremer et al., 2016). Genetic Heterogeneity of PEBEL See also PEBEL2 (618321), caused by mutation in the NAXD gene (615910) on chromosome 13q34.
Harel-Yoon syndrome
MedGen UID:
934644
Concept ID:
C4310677
Disease or Syndrome
Harel-Yoon syndrome is a syndromic neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, truncal hypotonia, spasticity, and peripheral neuropathy. Other more variable features such as optic atrophy may also occur. Laboratory studies in some patients show evidence of mitochondrial dysfunction (summary by Harel et al., 2016).
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4
MedGen UID:
934700
Concept ID:
C4310733
Disease or Syndrome
Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4) is characterized by adult onset of eye muscle weakness and proximal limb muscle weakness associated with deletions of mtDNA on skeletal muscle biopsy, which results from defective mtDNA replication in post-mitotic muscle tissue. Additional features are more variable (summary by Ronchi et al., 2012). For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (258450).
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3
MedGen UID:
934701
Concept ID:
C4310734
Disease or Syndrome
Any autosomal recessive progressive external ophthalmoplegia in which the cause of the disease is a mutation in the TK2 gene.
Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
MedGen UID:
934728
Concept ID:
C4310761
Disease or Syndrome
Hydrops, lactic acidosis, and sideroblastic anemia (HLASA) is an autosomal recessive multisystem disorder characterized by the onset of hydrops in utero. The severity of the hydrops and the disorder in general is highly variable. At birth, affected infants usually show poor growth, lactic acidosis, pulmonary hypertension with hypoxic respiratory insufficiency, and sideroblastic anemia. More variable features may include hepatosplenomegaly or cholestasis, hypoglycemia, pancreatic insufficiency, and micropenis or hypospadias. Death in infancy may occur. Those who survive tend to have resolution of lactic acidosis and anemia, but may show developmental delay and sensorineural deafness (summary by Riley et al., 2020).
Developmental and epileptic encephalopathy, 51
MedGen UID:
1372686
Concept ID:
C4479208
Disease or Syndrome
Developmental and epileptic encephalopathy-51 (DEE51) is an autosomal recessive severe neurodevelopmental disorder characterized by onset of intractable seizures and hypotonia in the first days or weeks of life. Affected individuals have severely delayed psychomotor development and may show abnormal movements. Brain imaging shows nonspecific abnormalities, such as cerebral atrophy, cerebellar atrophy, and delayed myelination. Laboratory studies showed increased lactate, suggesting mitochondrial dysfunction (summary by Ait-El-Mkadem et al., 2017). For a discussion of genetic heterogeneity of DEE, see 308350.
Developmental and epileptic encephalopathy, 53
MedGen UID:
1374886
Concept ID:
C4479313
Disease or Syndrome
Developmental and epileptic encephalopathy-53 (DEE53) is a severe autosomal recessive neurodegenerative disorder characterized by onset of intractable seizures in infancy. Affected individuals show hypotonia and very poor or absent global development, resulting in severe intellectual disability and spastic quadriplegia. Some patients may die in childhood (summary by Hardies et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Combined oxidative phosphorylation defect type 8
MedGen UID:
1377817
Concept ID:
C4518839
Disease or Syndrome
Combined oxidative phosphorylation deficiency-8 (COXPD8) is an autosomal recessive disorder caused by dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (summary by Gotz et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Multiple mitochondrial dysfunctions syndrome 5
MedGen UID:
1623132
Concept ID:
C4539919
Disease or Syndrome
ISCA1-related multiple mitochondrial dysfunctions syndrome (ISCA1-MMDS) is a severe neurodegenerative condition typically characterized by either no attainment of developmental milestones or very early loss of achieved milestones, seizures in early infancy, development of spasticity with exaggerated deep tendon reflexes, nystagmus, and risk for sensorineural hearing loss. Affected individuals may also demonstrate elevated blood lactate levels with an elevated lipid-lactate peak on brain MR spectroscopy. Further brain MRI findings may include extensive cerebral and cerebellar deep white matter hyperintensities, marked dilatation of the cerebral ventricles, and pachygyria. Prognosis is poor and most individuals succumb to an intercurrent illness in early childhood.
Combined oxidative phosphorylation deficiency 32
MedGen UID:
1617600
Concept ID:
C4540029
Disease or Syndrome
Combined oxidative phosphorylation deficiency-32 is an autosomal recessive neurodegenerative disorder characterized by onset of delayed psychomotor development and developmental regression in infancy. Affected individuals have multiple variable symptoms, including poor or absent speech, inability to walk, and abnormal movements. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem consistent with Leigh syndrome (256000). Patient cells showed decreased activities of mitochondrial respiratory chain complexes, I, III, and IV, as well as impaired mitochondrial translation (summary by Lake et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities
MedGen UID:
1624694
Concept ID:
C4540052
Disease or Syndrome
NELABA is a severe autosomal recessive metabolic disorder characterized by onset at birth of progressive encephalopathy associated with increased serum lactate. Affected individuals have little or no psychomotor development and show brain abnormalities, including cerebral atrophy, cysts, and white matter abnormalities. Some patients die in infancy (summary by Habarou et al., 2017).
3-methylglutaconic aciduria type 9
MedGen UID:
1622927
Concept ID:
C4540171
Disease or Syndrome
3-Methylglutaconic aciduria type IX (MGCA9) is an autosomal recessive disorder characterized by early-onset seizures, severely delayed psychomotor development and intellectual disability. Patients have hypotonia or spasticity, and laboratory investigations show increased serum lactate and 3-methylglutaconic aciduria, suggestive of a mitochondrial defect (summary by Shahrour et al., 2017). For a phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
MedGen UID:
1619876
Concept ID:
C4540192
Disease or Syndrome
NEMMLAS is an autosomal recessive multisystemic disorder characterized by delayed psychomotor development, intellectual disability, and abnormal motor function, including hypotonia, dystonia, ataxia, and spasticity. Patient tissues may show deficiencies in one or more of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes, but this is not a constant finding (summary by Wortmann et al., 2017).
Combined oxidative phosphorylation deficiency 33
MedGen UID:
1623699
Concept ID:
C4540209
Disease or Syndrome
COXPD33 is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. The phenotype is highly variable, ranging from death in infancy to adult-onset progressive external ophthalmoplegia (PEO) and myopathy. A common finding is cardiomyopathy and increased serum lactate (summary by Feichtinger et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Myopathy, lactic acidosis, and sideroblastic anemia 1
MedGen UID:
1634824
Concept ID:
C4551958
Disease or Syndrome
Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow (Bykhovskaya et al., 2004). Genetic Heterogeneity of Myopathy, Lactic Acidosis, and Sideroblastic Anemia MLASA2 (613561) is caused by mutation in the YARS2 gene (610957) on chromosome 12p11. MLASA3 (500011) is caused by heteroplasmic mutation in the mitochondrially-encoded MTATP6 gene (516060).
Combined oxidative phosphorylation deficiency 34
MedGen UID:
1631307
Concept ID:
C4693450
Disease or Syndrome
COXPD34 is an autosomal recessive disorder resulting from a defect in mitochondrial function. The phenotype is variable, but may include congenital sensorineural deafness, increased serum lactate, and hepatic and renal dysfunction. Neurologic function is relatively preserved (summary by Menezes et al., 2015). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Neurodegeneration with brain iron accumulation 8
MedGen UID:
1645224
Concept ID:
C4693587
Disease or Syndrome
Neurodegeneration with brain iron accumulation-8 (NBIA8) is characterized by iron accumulation in the basal ganglia and manifests as a progressive extrapyramidal syndrome with dystonia, rigidity, and choreoathetosis (Drecourt et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).
Combined oxidative phosphorylation deficiency 36
MedGen UID:
1644927
Concept ID:
C4693722
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome 6
MedGen UID:
1643082
Concept ID:
C4693741
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome-6 is an autosomal recessive severe neurodegenerative disorder with onset in early childhood. Affected individuals may have initial normal development, but show neurologic regression in the first year of life. They have hypotonia, inability to walk, poor speech, intellectual disability, and motor abnormalities, such as ataxia, dystonia, and spasticity. Some patients may die in childhood. Laboratory evidence indicates that the disorder results from mitochondrial dysfunction (summary by Vogtle et al., 2018). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).
Combined oxidative phosphorylation defect type 13
MedGen UID:
1631854
Concept ID:
C4706283
Disease or Syndrome
Combined oxidative phosphorylation deficiency-13 (COXPD13) is an autosomal recessive multisystem disorder resulting from mitochondrial dysfunction. Affected individuals develop severe neurologic impairment in the first months of life, including hypotonia, abnormal dystonic movements, hearing loss, poor feeding, global developmental delay, and abnormal eye movements. Brain imaging shows signal abnormalities in putamen, basal ganglia, caudate nuclei, or corpus callosum, as well as delayed myelination. Analysis of patient tissues shows multiple defects in enzymatic activities of the mitochondrial respiratory chain, although some tissues may show normal values since tissue expression of the mitochondrial defect and metabolic needs of specific tissues are variable (summary by Vedrenne et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation defect type 15
MedGen UID:
1646555
Concept ID:
C4706313
Disease or Syndrome
A rare mitochondrial disease due to a defect in mitochondrial protein synthesis with onset in infancy or early childhood of muscular hypotonia, gait ataxia, mild bilateral pyramidal tract signs, developmental delay (affecting mostly speech and coordination) and subsequent intellectual disability. Short stature, obesity, microcephaly, strabismus, nystagmus, reduced visual acuity, lactic acidosis, and a brain neuropathology consistent with Leigh syndrome are also reported. Caused by homozygous or compound heterozygous mutation in the MTFMT gene on chromosome 15q22.
Combined oxidative phosphorylation defect type 9
MedGen UID:
1634481
Concept ID:
C4706315
Disease or Syndrome
A rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by initially normal growth and development followed by the infantile-onset of failure to thrive, psychomotor delay, poor feeding, dyspnea, severe hypertrophic cardiomyopathy and hepatomegaly. Laboratory studies report increased plasma lactate and alanine, abnormal liver enzymes and decreased activity of mitochondrial respiratory chain complexes I, III, IV, and V. Caused by compound heterozygous mutation in the MRPL3 gene on chromosome 3q22.
Combined oxidative phosphorylation defect type 21
MedGen UID:
1638633
Concept ID:
C4706316
Disease or Syndrome
Combined oxidative phosphorylation deficiency-21 (COXPD21) is an autosomal recessive disorder characterized either by onset within the first months of life of severe hypotonia, failure to thrive, epilepsy and early death or by onset after 6 months of life with a milder course and longer survival (summary by Zheng et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome
MedGen UID:
1645614
Concept ID:
C4706421
Disease or Syndrome
Combined oxidative phosphorylation deficiency-12 (COXPD12) is an autosomal recessive mitochondrial neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability (summary by Steenweg et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Mitochondrial complex 1 deficiency, nuclear type 12
MedGen UID:
1648278
Concept ID:
C4746984
Disease or Syndrome
Cardiomyopathy, dilated, 2c
MedGen UID:
1648379
Concept ID:
C4748647
Disease or Syndrome
CMD2C is characterized by dilated cardiomyopathy of variable severity, with age of onset ranging from 2 to 20 years. Affected individuals exhibit reduction in coenzyme A (CoA) levels. Some severely affected children die in the first few years of life (Iuso et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy (CMD), see 115200.
Mitochondrial complex 1 deficiency, nuclear type 2
MedGen UID:
1648466
Concept ID:
C4748737
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 4
MedGen UID:
1648324
Concept ID:
C4748753
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 5
MedGen UID:
1648292
Concept ID:
C4748754
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 6
MedGen UID:
1648496
Concept ID:
C4748759
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 8
MedGen UID:
1648411
Concept ID:
C4748766
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 11
MedGen UID:
1648356
Concept ID:
C4748769
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 14
MedGen UID:
1648440
Concept ID:
C4748777
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 15
MedGen UID:
1648320
Concept ID:
C4748778
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 17
MedGen UID:
1648418
Concept ID:
C4748786
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 23
MedGen UID:
1648408
Concept ID:
C4748799
Disease or Syndrome
Mitochondrial complex I deficiency nuclear type 23 (MC1DN23) is an autosomal recessive nuclear-encoded mitochondrial disease with clinical presentations ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI findings may include basal ganglia abnormalities or optic atrophy (summary by Magrinelli et al., 2022).
Mitochondrial complex 1 deficiency, nuclear type 24
MedGen UID:
1648364
Concept ID:
C4748803
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 26
MedGen UID:
1648283
Concept ID:
C4748809
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 28
MedGen UID:
1648493
Concept ID:
C4748827
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 29
MedGen UID:
1648451
Concept ID:
C4748830
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 32
MedGen UID:
1648336
Concept ID:
C4748839
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 33
MedGen UID:
1648420
Concept ID:
C4748840
Disease or Syndrome
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
MedGen UID:
1664257
Concept ID:
C4749921
Disease or Syndrome
Combined oxidative phosphorylation deficiency-10 (COXPD10) is an autosomal recessive disorder resulting in variable defects of mitochondrial oxidative respiration. Affected individuals present in infancy with hypertrophic cardiomyopathy and lactic acidosis. The severity is variable, but can be fatal in the most severe cases (summary by Ghezzi et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation defect type 14
MedGen UID:
1663069
Concept ID:
C4755312
Disease or Syndrome
The spectrum of FARS2 deficiency ranges from the infantile-onset phenotype, characterized by epileptic encephalopathy with lactic acidosis and poor prognosis (70% of affected individuals), to the later-onset phenotype, characterized by spastic paraplegia, less severe neurologic manifestations, and longer survival (30% of affected individuals). To date FARS2 deficiency has been reported in 37 individuals from 25 families. Infantile-onset phenotype. Seizures are difficult to control and may progress quickly at an early age to intractable seizures with frequent status epilepticus; some children have hypsarrhythmia on EEG. All have developmental delay; most are nonverbal and unable to walk. Feeding difficulties are common. More than half of affected children die in early childhood. Later-onset phenotype. All affected individuals have spastic paraplegia manifested by weakness, spasticity, and exaggerated reflexes of the lower extremities associated with walking difficulties; some have developmental delay/intellectual disability; some have brief seizures that resolve over time.
Combined oxidative phosphorylation defect type 11
MedGen UID:
1682397
Concept ID:
C5190991
Disease or Syndrome
Combined oxidative phosphorylation deficiency-21 (COXPD11) is a severe multisystemic autosomal recessive disorder characterized by neonatal hypotonia and lactic acidosis. Affected individuals may have respiratory insufficiency, foot deformities, or seizures, and all reported patients have died in infancy. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes (summary by Garcia-Diaz et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Paganini-Miozzo syndrome
MedGen UID:
1683361
Concept ID:
C5193010
Disease or Syndrome
Paganini-Miozzo syndrome (MRXSPM) is a neurodevelopmental disorder characterized by global developmental delay, impaired intellectual development, high myopia, and mild dysmorphic facial features (summary by Paganini et al., 2019)
NAD(P)HX dehydratase deficiency
MedGen UID:
1681210
Concept ID:
C5193026
Disease or Syndrome
Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, and sometimes seizures, resulting in death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions (summary by Van Bergen et al., 2019). For a discussion of genetic heterogeneity of PEBEL, see PEBEL1 (617186).
Combined oxidative phosphorylation deficiency 37
MedGen UID:
1675208
Concept ID:
C5193031
Disease or Syndrome
Combined oxidative phosphorylation deficiency-37 is an autosomal recessive multisystem disorder apparent at birth or in the first months of life. Affected individuals have hypotonia, failure to thrive, and neurodegeneration with loss of developmental milestones, as well as liver dysfunction. Some patients may have hypertrophic cardiomyopathy, loss of vision and hearing, and/or seizures. Mitochondrial respiratory dysfunction is apparent in liver and skeletal muscle tissue. Most patients die in childhood (summary by Zeharia et al., 2016). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation deficiency 38
MedGen UID:
1682102
Concept ID:
C5193064
Disease or Syndrome
Combined oxidative phosphorylation deficiency 39
MedGen UID:
1683958
Concept ID:
C5193075
Disease or Syndrome
Combined oxidative phosphorylation deficiency-39 (COXPD39) is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. Affected individuals show global developmental delay, sometimes with regression after normal early development, axial hypotonia with limb spasticity or abnormal involuntary movements, and impaired intellectual development with poor speech. More variable features may include hypotonia, seizures, and features of Leigh syndrome (256000) on brain imaging. There are variable deficiencies of the mitochondrial respiratory chain enzyme complexes in patient tissues (summary by Glasgow et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression
MedGen UID:
1681269
Concept ID:
C5193083
Disease or Syndrome
Recurrent metabolic crises with variable encephalomyopathic features and neurologic regression (MECREN) is an autosomal recessive metabolic disorder with a highly variable phenotype. Most affected individuals present in the first years of life with episodic lactic acidosis associated with illness or stress, resulting in transient or permanent neurologic dysfunction. Some patients may recover, whereas others show subsequent variable developmental regression of motor and cognitive skills. Other features may include dystonia, hypotonia with inability to sit or walk, seizures, and abnormal signals in the basal ganglia. There is significant phenotypic heterogeneity, even among patients with the same mutation (summary by Almannai et al., 2018).
Mitochondrial DNA depletion syndrome 16 (hepatic type)
MedGen UID:
1684495
Concept ID:
C5193142
Disease or Syndrome
Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy
MedGen UID:
1679560
Concept ID:
C5193223
Disease or Syndrome
Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is an autosomal recessive neuromuscular disorder characterized mainly by childhood onset of progressive muscle weakness and exercise intolerance. Patients have episodic exacerbation, which may be associated with increased serum creatine kinase or lactic acid. Additional more variable features may include optic atrophy, reversible leukoencephalopathy, and later onset of a sensorimotor polyneuropathy. The disorder results from impaired formation of Fe-S clusters, which are essential cofactors for proper mitochondrial function (summary by Gurgel-Giannetti et al., 2018)
Spastic tetraplegia and axial hypotonia, progressive
MedGen UID:
1684731
Concept ID:
C5231422
Disease or Syndrome
Progressive spastic tetraplegia and axial hypotonia (STAHP) is an autosomal recessive neurologic disorder characterized by onset of severe and progressive motor dysfunction in the first year of life. Affected individuals have severe axial hypotonia combined with spastic tetraplegia, hyperekplexia, hypertonia, and myokymia, reflecting upper motor neuron involvement. Cognitive development may be affected, but only 2 unrelated patients have been reported (Andersen et al., 2019; Park et al., 2019).
Developmental and epileptic encephalopathy, 82
MedGen UID:
1684694
Concept ID:
C5231473
Disease or Syndrome
Developmental and epileptic encephalopathy-82 (DEE82) is an autosomal recessive mitochondriopathy manifest as early-onset metabolic epileptic encephalopathy. Soon after birth, affected individuals exhibit hypotonia, feeding difficulties, and global developmental delay even before the onset of seizures in the first year of life. The severity is variable, but all patients have severely impaired intellectual development with absent speech and spastic tetraplegia. Other features include poor overall growth with microcephaly and recurrent infections. Brain imaging shows cerebral atrophy, thin corpus callosum, cerebellar hypoplasia, and white matter abnormalities. Laboratory studies show increased serum lactate and ammonia. Importantly, treatment with combined pyridoxine and serine can result in significant improvement in seizures as well as some mild developmental progress (summary by van Karnebeek et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal
MedGen UID:
1716458
Concept ID:
C5394137
Disease or Syndrome
Neonatal lethal pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome (PHRINL) is an autosomal recessive multisystem disorder with onset in utero and death in the neonatal period. Rare patients may survive a few months. Affected infants show respiratory insufficiency and almost no spontaneous movement at birth, usually requiring mechanical ventilation and admission to the neonatal intensive care unit. Additional features include corneal clouding, seizures, dysmorphic facies, contractures, and progressive pontocerebellar hypoplasia with simplified gyral pattern and white matter abnormalities. Some patients may have cardiac anomalies or cardiac hypertrophy. Laboratory studies show evidence consistent with mitochondrial defects and/or abnormal cholesterol or lipid metabolism. Depending on the type of mutation or deletion, some patients may have a less severe disorder (see GENOTYPE/PHENOTYPE CORRELATIONS) (summary by Desai et al., 2017).
Combined oxidative phosphorylation deficiency 43
MedGen UID:
1718250
Concept ID:
C5394284
Disease or Syndrome
Combined oxidative phosphorylation deficiency 44
MedGen UID:
1718899
Concept ID:
C5394293
Disease or Syndrome
Combined oxidative phosphorylation deficiency-44 (COXPD44) is an autosomal recessive mitochondrial disorder with multisystemic manifestations. Most affected individuals present in infancy or early childhood with global developmental delay, hypotonia, and abnormal movements. Most patients develop seizures, often associated with status epilepticus, and some patients may have optic atrophy. One patient with hypertrophic cardiomyopathy has been reported. Serum lactate may be increased, although that finding is inconsistent. Detailed biochemical analysis shows variable combined deficiencies of mitochondrial oxidative complexes that appear to be tissue-specific (summary by Wei et al., 2020). For discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
MedGen UID:
1748867
Concept ID:
C5399977
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 2 (MC4DN2) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms at birth or in the first weeks or months of life. Affected individuals have severe hypotonia, often associated with feeding difficulties and respiratory insufficiency necessitating tube feeding and mechanical ventilation. The vast majority of patients develop hypertrophic cardiomyopathy in the first days or weeks of life, which usually leads to death in infancy or early childhood. Patients also show neurologic abnormalities, including developmental delay, nystagmus, fasciculations, dystonia, EEG changes, and brain imaging abnormalities compatible with a diagnosis of Leigh syndrome (see 256000). There may also be evidence of systemic involvement with hepatomegaly and myopathy, although neurogenic muscle atrophy is more common and may resemble spinal muscular atrophy type I (SMA1; 253300). Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels in various tissues, including heart and skeletal muscle. Most patients die in infancy of cardiorespiratory failure (summary by Papadopoulou et al., 1999). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex IV deficiency, nuclear type 1
MedGen UID:
1750917
Concept ID:
C5435656
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 1 (MC4DN1) is an autosomal recessive metabolic disorder characterized by rapidly progressive neurodegeneration and encephalopathy with loss of motor and cognitive skills between about 5 and 18 months of age after normal early development. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, and poor eye contact. Other features may include oculomotor abnormalities, including slow saccades, strabismus, ophthalmoplegia, and nystagmus, as well as deafness, apneic episodes, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Some patients may also have abnormalities in the brainstem and cerebellum. Laboratory studies usually show increased serum and CSF lactate and decreased levels and activity of mitochondrial respiratory complex IV in patient tissues. There is phenotypic variability, but death in childhood, often due to central respiratory failure, is common (summary by Tiranti et al., 1998; Tiranti et al., 1999; Teraoka et al., 1999; Poyau et al., 2000) Genetic Heterogeneity of Mitochondrial Complex IV Deficiency Most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare (Shoubridge, 2001; Sacconi et al., 2003). Mitochondrial complex IV deficiency caused by mutation in nuclear-encoded genes, in addition to MC4DN1, include MC4DN2 (604377), caused by mutation in the SCO2 gene (604272); MC4DN3 (619046), caused by mutation in the COX10 gene (602125); MC4DN4 (619048), caused by mutation in the SCO1 gene (603664); MC4DN5 (220111), caused by mutation in the LRPPRC gene (607544); MC4DN6 (615119), caused by mutation in the COX15 gene (603646); MC4DN7 (619051), caused by mutation in the COX6B1 gene (124089); MC4DN8 (619052), caused by mutation in the TACO1 gene (612958); MC4DN9 (616500), caused by mutation in the COA5 gene (613920); MC4DN10 (619053), caused by mutation in the COX14 gene (614478); MC4DN11 (619054), caused by mutation in the COX20 gene (614698); MC4DN12 (619055), caused by mutation in the PET100 gene (614770); MC4DN13 (616501), caused by mutation in the COA6 gene (614772); MC4DN14 (619058), caused by mutation in the COA3 gene (614775); MC4DN15 (619059), caused by mutation in the COX8A gene (123870); MC4DN16 (619060), caused by mutation in the COX4I1 gene (123864); MC4DN17 (619061), caused by mutation in the APOPT1 gene (616003); MC4DN18 (619062), caused by mutation in the COX6A2 gene (602009); MC4DN19 (619063), caused by mutation in the PET117 gene (614771); MC4DN20 (619064), caused by mutation in the COX5A gene (603773); MC4DN21 (619065), caused by mutation in the COXFA4 gene (603883); MC4DN22 (619355), caused by mutation in the COX16 gene (618064); and MC4DN23 (620275), caused by mutation in the COX11 gene (603648). Mitochondrial complex IV deficiency has been associated with mutations in several mitochondrial genes, including MTCO1 (516030), MTCO2 (516040), MTCO3 (516050), MTTS1 (590080), MTTL1 (590050), and MTTN (590010).
Combined oxidative phosphorylation deficiency 45
MedGen UID:
1731010
Concept ID:
C5436461
Disease or Syndrome
Combined oxidative phosphorylation deficiency-45 (COXPD45) is an autosomal recessive multisystem disorder characterized by poor overall growth apparent from infancy, global developmental delay, seizures, and acute progressive neurologic deterioration with loss of skills. Other features may include dysmorphic facies and lesions on brain imaging. Laboratory studies show increased serum lactate and COXPD in patient tissues, consistent with a mitochondrial defect (summary by Serre et al., 2013). For discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation deficiency 47
MedGen UID:
1775535
Concept ID:
C5436476
Disease or Syndrome
Mitochondrial DNA depletion syndrome 19
MedGen UID:
1770258
Concept ID:
C5436514
Disease or Syndrome
Combined oxidative phosphorylation deficiency 48
MedGen UID:
1732052
Concept ID:
C5436602
Disease or Syndrome
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
MedGen UID:
1736667
Concept ID:
C5436628
Disease or Syndrome
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA) is an autosomal recessive disorder characterized by impaired psychomotor development apparent in infancy. Affected individuals show poor overall growth, progressive microcephaly, and axial hypotonia, with later onset of spasticity. The disorder is progressive. Some patients show normal early development, but later have regression of motor, cognitive, and language skills. More variable features include seizures, joint contractures, ocular disturbances, episodic respiratory failure, and nonspecific dysmorphic facial features. The intellectual impairment is variable, ranging from poor visual contact with inability to walk or speak to milder intellectual disability with the ability to say some words. Brain imaging shows variable white matter abnormalities, including thin corpus callosum and poor myelination (summary by Husain et al., 2020).
Mitochondrial complex 4 deficiency, nuclear type 3
MedGen UID:
1764816
Concept ID:
C5436682
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 3 (MC4DN3) is an autosomal recessive multisystem metabolic disorder with a highly variable phenotype. Some patients present with encephalomyopathic features in early infancy, whereas others may present later in infancy or the first years of life after normal early development. Affected individuals show hypotonia, failure to thrive, and developmental delay or regression with poor eye contact and loss of motor skills with ataxia. Additional features observed in some patients include proximal renal tubulopathy, macrocytic anemia, sensorineural hearing loss, nystagmus, and hypertrophic cardiomyopathy, consistent with systemic involvement. Brain imaging in most patients shows lesions consistent with Leigh syndrome (see 256000). Laboratory studies show increased serum lactate and decreased levels and activity of mitochondrial respiratory complex IV. Most patients die in infancy (summary by Valnot et al., 2000 and Antonicka et al., 2003). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 4
MedGen UID:
1748100
Concept ID:
C5436683
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show hypotonia, failure to thrive, and neurologic distress. Additional features include hepatomegaly, hepatic steatosis, increased serum lactate, and metabolic acidosis. Some patients may develop hypertrophic cardiomyopathy. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. Death usually occurs in infancy (summary by Valnot et al., 2000 and Stiburek et al., 2009). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 7
MedGen UID:
1754683
Concept ID:
C5436685
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 7 (MC4DN7) is an autosomal recessive metabolic encephalomyopathic disorder with highly variable manifestations. Only a few patients have been reported. Some patients have normal early development then show rapid neurodegeneration with progressive muscle weakness, gait disturbances, and cognitive decline in mid to late childhood. Other features may include seizures and visual impairment. Brain imaging shows progressive leukodystrophy with cystic lesions. In contrast, at least 1 patient has been reported who presented in the neonatal period with metabolic acidosis, hydrocephalus, hypotonia, and cortical blindness. This patient developed hypertrophic cardiomyopathy resulting in early death. All patients had increased serum lactate and decreased levels and activity of mitochondrial respiratory complex IV (summary by Massa et al., 2008 and Abdulhag et al., 2015). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 10
MedGen UID:
1746545
Concept ID:
C5436692
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 10 (MC4DN10) is an autosomal recessive multisystem metabolic disorder characterized by the onset of severe symptoms soon after birth. Affected infants have respiratory and neurologic distress, metabolic lactic acidosis, and dysmorphic features, including microphthalmia. Death occurs in early infancy. Postmortem examination has demonstrated systemic involvement with hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal hyperplasia. There is also abnormal brain myelination and cavitating brain lesions. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (summary by Weraarpachai et al., 2012). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 11
MedGen UID:
1760275
Concept ID:
C5436694
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 11 (MC4DN11) is an autosomal recessive metabolic disorder characterized by a childhood-onset sensory neuronopathy and additional features which may include hypotonia, cerebellar ataxia, tremor, dystonia, choreoathetosis, and/or dysarthria. Patients may have variable motor delay, speech delay, or impaired intellectual development (summary by Doss et al., 2014; Otero et al., 2019; Xu et al., 2019; Dong et al., 2021). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 12
MedGen UID:
1745691
Concept ID:
C5436695
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 12 (MC4DN12) is an autosomal recessive metabolic disorder characterized by the onset of neurologic dysfunction in early infancy. Affected individuals demonstrate hypotonia with poor head control, profoundly delayed global development with inability to fix and follow, poor overall growth, abnormal spasms or myoclonus, and seizures. Most patients die in the first years of life; those that survive have spastic quadriplegia, feeding difficulties necessitating tube feeding, and profoundly impaired intellectual development with poor or absent communication. More variable features include cortical blindness, nystagmus, scoliosis, and hearing impairment. Brain imaging shows abnormalities consistent with Leigh syndrome (see 256000), as well as cystic cavitation. Laboratory studies show lactic acidosis, increased serum creatine kinase, and decreased levels and activity of mitochondrial respiratory complex IV (summary by Lim et al., 2014). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 15
MedGen UID:
1773430
Concept ID:
C5436712
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 15 (MC4DN15) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show global developmental delay, poor feeding, short stature with microcephaly, proximal muscle weakness, and distal spasticity. Other manifestations include scoliosis, primary pulmonary hypertension, childhood-onset refractory seizures, and inability to walk. Brain imaging shows features consistent with Leigh syndrome (see 256000) and enlarged ventricles. Laboratory studies show increased serum and CSF lactate, as well as decreased levels and activity of mitochondrial respiratory complex IV (summary by Hallmann et al., 2016). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 16
MedGen UID:
1762514
Concept ID:
C5436714
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 16 (MC4DN16) is an autosomal recessive metabolic disorder with highly variable manifestations. Common features include failure to thrive with poor overall growth, short stature, and microcephaly. Some patients additionally have neurologic involvement, including developmental regression with severe hypotonia, feeding difficulties, and seizures. Brain imaging in the more severely affected patients shows cerebral and cerebellar atrophy and abnormal lesions in the basal ganglia. In all cases, patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV (summary by Pillai et al., 2019). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 18
MedGen UID:
1752734
Concept ID:
C5436720
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 18 (MC4DN18) is an autosomal recessive metabolic disorder that primarily affects skeletal muscle tissue. Affected individuals present in infancy with hypotonia, limb muscle weakness, and high-arched palate. The severity of the disorder is variable: some patients may only have gait difficulties, whereas others may also have significant respiratory insufficiency and cardiomyopathy. Death in infancy has been reported. Patient skeletal muscle shows decreased levels and activity of mitochondrial respiratory complex IV (Inoue et al., 2019). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 19
MedGen UID:
1729504
Concept ID:
C5436723
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 19 (MC4DN19) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy or early childhood. Affected individuals show global developmental delay and developmental regression with a loss of acquired motor and language skills. Additional features include motor dysfunction, such as hypokinesia and pyramidal signs. More variable features may include recurrent infections with immunodeficiency and possibly protein-losing enteropathy. Serum lactate is increased; T2-weighted lesions in the medulla oblongata have also been reported. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (Renkema et al., 2017). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 20
MedGen UID:
1771040
Concept ID:
C5436726
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 20 (MC4DN20) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show hypotonia, failure to thrive, and global developmental delay. Additional features include elevated liver enzymes, increased serum lactate, metabolic acidosis, and pulmonary arterial hypertension (PAH), which may result in cardiorespiratory failure and early death. Patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV (Baertling et al., 2017). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 1 deficiency, nuclear type 36
MedGen UID:
1773965
Concept ID:
C5436935
Disease or Syndrome
Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Patient tissue showed isolated mitochondrial complex I deficiency. Death may occur in childhood (Alahmad et al., 2020). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
Leukoencephalopathy, progressive, infantile-onset, with or without deafness
MedGen UID:
1779519
Concept ID:
C5542996
Disease or Syndrome
Infantile-onset progressive leukoencephalopathy with or without deafness (LEPID) is an autosomal recessive complex neurodegenerative disorder with onset of symptoms in infancy or early childhood. Most patients present with sensorineural deafness or hypoacousia and global developmental delay. Affected individuals show episodic regression with progressive motor deterioration resulting in spastic tetraplegia and loss of ambulation, as well as impaired intellectual development with poor or absent speech. Additional more variable features may include poor overall growth with microcephaly, seizures, visual loss, microcytic anemia, and hepatic enlargement or abnormal liver enzymes. Brain imaging shows deep white matter abnormalities consistent with a progressive leukoencephalopathy. The brain and spinal cord are usually both involved; calcifications of these regions are often observed. Laboratory studies show increased serum lactate and deficiencies of mitochondrial respiratory chain complexes, consistent with global mitochondrial dysfunction. Early death often occurs (summary by Itoh et al., 2019).
Deafness, congenital, and adult-onset progressive leukoencephalopathy
MedGen UID:
1784506
Concept ID:
C5543087
Disease or Syndrome
Congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE) is an autosomal recessive complex neurodegenerative disorder characterized by congenital neurosensory deafness followed by onset of neurodegenerative symptoms, including pyramidal signs and cognitive decline, in young adulthood. Some patients may have mild developmental delay or learning difficulties in childhood, but most can function independently. The onset of motor and cognitive decline in adulthood can be rapid and may result in early death. Brain imaging shows diffuse white matter abnormalities affecting various brain regions, consistent with a progressive leukoencephalopathy. More variable additional features may include visual impairment and axonal peripheral neuropathy (summary by Scheidecker et al., 2019).
Mitochondrial complex 2 deficiency, nuclear type 4
MedGen UID:
1782861
Concept ID:
C5543176
Disease or Syndrome
Mitochondrial complex II deficiency nuclear type 4 (MC2DN4) is a severe autosomal recessive disorder characterized by early-onset progressive neurodegeneration with leukoencephalopathy. Acute episodes of neurodegeneration are often triggered by catabolic stress such as infection or fasting.
Mitochondrial complex 1 deficiency, nuclear type 37
MedGen UID:
1783339
Concept ID:
C5543281
Disease or Syndrome
Combined oxidative phosphorylation deficiency 52
MedGen UID:
1780479
Concept ID:
C5543592
Disease or Syndrome
Combined oxidative phosphorylation deficiency-52 (COXPD52) is an autosomal recessive infantile mitochondrial complex II/III deficiency characterized by lactic acidemia, multiorgan system failure, and abnormal mitochondria. Intrafamilial variability has been reported (Farhan et al., 2014; Hershkovitz et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Spinocerebellar ataxia, autosomal recessive 30
MedGen UID:
1778853
Concept ID:
C5543620
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-30 (SCAR30) is a progressive neurologic disorder characterized by childhood-onset global developmental delay with variably impaired intellectual development, motor dysfunction, and cerebellar ataxia. Affected individuals may also have psychiatric abnormalities, such as obsessive behavior, psychotic episodes, or hallucinations. Brain imaging usually shows cerebellar atrophy, although this may be an age-dependent feature (summary by Langer et al., 2018).
Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2
MedGen UID:
1778117
Concept ID:
C5543623
Disease or Syndrome
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2) is an autosomal recessive multisystemic disorder characterized by cholestatic hepatitis, poor feeding associated with poor overall growth, and hypoglycemia apparent from infancy. Most, but not all, patients have variable global developmental delay. Additional common features include sensorineural deafness, retinal abnormalities with visual defects, and hypotonia. Some patients have endocrine abnormalities, including hyperinsulinemic hypoglycemia, pancreatic dysfunction, hypothyroidism, and primary amenorrhea. Additional features may include hypertriglyceridemia, anemia, proteinuria, increased lactate, and recurrent infections. Brain imaging often shows dysmyelination, thin corpus callosum, cerebral atrophy, and white matter abnormalities. Although the clinical manifestations and severity of the disorder are highly variable, death in early childhood may occur (summary by Williams et al., 2019 and Zeiad et al., 2021). For a discussion of genetic heterogeneity of IMNEPD, see IMNEPD1 (616263).
Biliary, renal, neurologic, and skeletal syndrome
MedGen UID:
1794200
Concept ID:
C5561990
Disease or Syndrome
Biliary, renal, neurologic, and skeletal syndrome (BRENS) is an autosomal recessive complex ciliopathy with multisystemic manifestations. The most common presentation is severe neonatal cholestasis that progresses to liver fibrosis and cirrhosis. Most patients have additional clinical features suggestive of a ciliopathy, including postaxial polydactyly, hydrocephalus, retinal abnormalities, and situs inversus. Additional features of the syndrome may include congenital cardiac defects, echogenic kidneys with renal failure, ocular abnormalities, joint hyperextensibility, and dysmorphic facial features. Some patients have global developmental delay. Brain imaging typically shows dilated ventricles, hypomyelination, and white matter abnormalities, although some patients have been described with abnormal pituitary development (summary by Shaheen et al., 2020 and David et al., 2020).
Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
MedGen UID:
1798947
Concept ID:
C5567524
Disease or Syndrome
Individuals with TANGO2-related metabolic encephalopathy and arrhythmias can present in acute metabolic crisis (hypoglycemia, elevated lactate, mild hyperammonemia) or with developmental delay, regression, and/or seizures. The acute presentation varies from profound muscle weakness, ataxia, and/or disorientation to a comatose state. Individuals can present with intermittent acute episodes of rhabdomyolysis. The first episode of myoglobinuria has been known to occur as early as age five months. Acute renal tubular damage due to myoglobinuria can result in acute kidney injury and renal failure. During acute illness, transient electrocardiogram changes can be seen; the most common is QT prolongation. Life-threatening recurrent ventricular tachycardia or torsade de pointes occurs primarily during times of acute illness. Individuals who do not present in metabolic crises may present with gait incoordination, progressively unsteady gait, difficulty with speech, or clumsiness. Intellectual disability of variable severity is observed in almost all individuals. Seizures are observed outside the periods of crises in more than 75% of individuals. Hypothyroidism has been reported in more than one third of individuals.
Combined oxidative phosphorylation defect type 30
MedGen UID:
1799028
Concept ID:
C5567605
Disease or Syndrome
A rare mitochondrial oxidative phosphorylation disorder with characteristics of neonatal onset of hypotonia, feeding difficulties, deafness, and early fatal respiratory failure. Cardiac and liver involvement has been reported. Serum lactate is increased and metabolic studies show decreased activity of mitochondrial respiratory complexes I and IV in skeletal muscle.
Combined oxidative phosphorylation deficiency 29
MedGen UID:
1799030
Concept ID:
C5567607
Disease or Syndrome
A rare mitochondrial oxidative phosphorylation disorder with characteristics of microcephaly, global developmental delay, spastic-dystonic movement disorder, intractable seizures, optic atrophy, autonomic dysfunction and peripheral neuropathy. Serum lactate is increased, and muscle biopsy shows decreased activity of mitochondrial respiratory complexes I and III. Brain imaging reveals progressive cerebellar atrophy and delayed myelination.
Combined oxidative phosphorylation defect type 27
MedGen UID:
1799031
Concept ID:
C5567608
Disease or Syndrome
Combined oxidative phosphorylation deficiency-27 (COXPD27) is an autosomal recessive multisystem disorder characterized mainly by neurologic features, including delayed development, seizures, abnormal movements, and neurologic regression. Age at onset, ranging from infancy to late childhood, and severity are variable. Other features include hypotonia, myoclonus, brain imaging abnormalities, and evidence of mitochondrial dysfunction in skeletal muscle. Liver dysfunction has also been reported (summary by Samanta et al., 2018). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation defect type 26
MedGen UID:
1799164
Concept ID:
C5567741
Disease or Syndrome
Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED) is an autosomal recessive multisystemic disorder with highly variable manifestations, even within the same family. Some patients present in infancy with hypotonia and global developmental delay with poor or absent motor skill acquisition and poor growth, whereas others present as young adults with exercise intolerance and muscle weakness. All patients have signs of a peripheral neuropathy, usually demyelinating, with distal muscle weakness and atrophy and distal sensory impairment; many become wheelchair-bound. Additional features include spasticity, extensor plantar responses, contractures, cerebellar signs, seizures, short stature, and rare involvement of other organ systems, including the heart, pancreas, and kidney. Biochemical analysis may show deficiencies in mitochondrial respiratory complex enzyme activities in patient tissue, although this is not always apparent. Lactate is frequently increased, suggesting mitochondrial dysfunction (Powell et al., 2015; Argente-Escrig et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation defect type 23
MedGen UID:
1799166
Concept ID:
C5567743
Disease or Syndrome
Combined oxidative phosphorylation deficiency-23 (COXPD23) is an autosomal recessive disorder characterized by early childhood onset of hypertrophic cardiomyopathy and/or neurologic symptoms, including hypotonia and delayed psychomotor development. Laboratory investigations are consistent with a defect in mitochondrial function resulting in lactic acidosis, impaired activities of respiratory complexes I and IV, and defective translation of mitochondrial proteins. Brain imaging shows abnormal lesions in the basal ganglia, thalamus, and brainstem. The severity of the disorder is variable, ranging from death in early infancy to survival into the second decade (summary by Kopajtich et al., 2014). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
MedGen UID:
1799985
Concept ID:
C5568562
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Combined oxidative phosphorylation deficiency 28
MedGen UID:
1800504
Concept ID:
C5569081
Disease or Syndrome
Combined oxidative phosphorylation deficiency-28 (COXPD28) is a complex autosomal recessive multisystem disorder associated with mitochondrial dysfunction. The phenotype is variable, but includes episodic metabolic decompensation beginning in infancy that can result in mild muscle weakness, cardiorespiratory insufficiency, developmental delay, or even death. Biochemical studies of patient tissues show variable mitochondrial defects, including decreased activities of respiratory chain enzymes (summary by Kishita et al., 2015). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
3-methylglutaconic aciduria, type VIIB
MedGen UID:
1810214
Concept ID:
C5676893
Disease or Syndrome
CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which can range from severe to mild. In severe CLPB deficiency, death usually occurs at a few months of age due to significant neonatal neurologic involvement (hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy) and severe neutropenia associated with life-threatening infections. Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability. Neutropenia is variable, but not life threatening. In those with mild CLPB deficiency there is no neurologic involvement, intellect is normal, neutropenia is mild and intermittent, and life expectancy is normal.
Combined oxidative phosphorylation deficiency 54
MedGen UID:
1812715
Concept ID:
C5676912
Disease or Syndrome
Combined oxidative phosphorylation deficiency-54 (COXPD54) is an autosomal recessive disorder with pleiotropic multisystem presentations resulting from a disruption in mitochondrial transcription and translation. The phenotype is highly variable. Many patients have early-onset sensorineural hearing loss, sometimes in isolation, and sometimes associated with global developmental delay or primary ovarian failure. Other features may include peripheral hypertonia, seizures, muscle weakness, behavioral abnormalities, and leukoencephalopathy on brain imaging. Serum lactate may or may not be elevated (summary by Hochberg et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation deficiency 55
MedGen UID:
1806598
Concept ID:
C5676915
Disease or Syndrome
Combined oxidative phosphorylation deficiency-55 (COXPD55) is characterized by global developmental delay, hypotonia, short stature, and impaired intellectual development with speech disabilities in childhood. Indolent progressive external ophthalmoplegia phenotype has been described in 1 patient (summary by Olahova et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Neurodegeneration, childhood-onset, with progressive microcephaly
MedGen UID:
1801540
Concept ID:
C5676972
Disease or Syndrome
Childhood-onset neurodegeneration with progressive microcephaly (CONPM) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from infancy. The phenotype is highly variable: the most severely affected individuals have severe and progressive microcephaly, early-onset seizures, lack of visual tracking, and almost no developmental milestones, resulting in early death. Less severely affected individuals have a small head circumference and severely impaired intellectual development with poor speech and motor delay. Additional features may include poor overall growth, axial hypotonia, limb hypertonia with spasticity, undescended testes, and cerebral atrophy with neuronal loss (Lam et al., 2019 and Vanoevelen et al., 2022).
Mitochondrial complex II deficiency, nuclear type 1
MedGen UID:
1814582
Concept ID:
C5700310
Disease or Syndrome
Mitochondrial complex II deficiency is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, and muscle with onset in infancy, whereas others have only isolated cardiac or muscle involvement. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013). Complex II, also known as succinate dehydrogenase, is part of the mitochondrial respiratory chain. Genetic Heterogeneity of Mitochondrial Complex II Deficiency See MC2DN2 (619166), caused by mutation in the SDHAF1 gene (612848) on chromosome 19q13; MC2DN3 (619167), caused by mutation in the SDHD gene (602690) on chromosome 11q23; and MC2DN4 (619224), caused by mutation in the SDHB gene (185470) on chromosome 1p36. Fullerton et al. (2020) reviewed the genetic basis of isolated mitochondrial complex II deficiency.
Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction
MedGen UID:
1824013
Concept ID:
C5774240
Disease or Syndrome
Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM) is an autosomal recessive syndromic disorder characterized primarily by neurologic deficits. Patients show global developmental delay and variably impaired intellectual development with speech delay apparent from infancy. Affected individuals have hypotonia, poor feeding, poor overall growth, and respiratory distress early in life. Other features include visual impairment due to optic atrophy, sensorineural hearing loss, and neuromuscular abnormalities. The severity is highly variable. The disorder is progressive; about half of patients show developmental regression with loss of previous skills. Features suggestive of a mitochondrial disorder include cataracts, cardiomyopathy, diabetes mellitus, combined oxidative phosphorylation deficiency, and increased lactate. Some patients develop seizures, some have dysmorphic facial features, and some have nonspecific abnormalities on brain imaging. Death in childhood may occur (Kaiyrzhanov et al., 2022).
Mitochondrial complex 3 deficiency, nuclear type 11
MedGen UID:
1824032
Concept ID:
C5774259
Disease or Syndrome
Mitochondrial complex III deficiency nuclear type 11 (MC3DN11) is an autosomal recessive disorder characterized by recurrent episodes of severe lactic acidosis, hyperammonemia, hypoglycemia, and encephalopathy (Vidali et al., 2021) For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Mitochondrial complex IV deficiency, nuclear type 23
MedGen UID:
1840958
Concept ID:
C5830322
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 23 (MC4DN23) is an autosomal recessive disorder characterized by infantile-onset encephalopathy (Rius et al., 2022). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial trifunctional protein deficiency 2
MedGen UID:
1841010
Concept ID:
C5830374
Disease or Syndrome
The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, classic trifunctional protein deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death (SIDS; 272120), infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy (summary by Spiekerkoetter et al., 2003). Some patients with MTP deficiency show a protracted progressive course associated with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy. These patients tend to survive into adolescence and adulthood (den Boer et al., 2003). See mitochondrial trifunctional protein deficiency-1 (609015), caused by mutation in the HADHA gene (600890), the alpha subunit of mitochondrial trifunctional protein.
Neurodegeneration and seizures due to copper transport defect
MedGen UID:
1841021
Concept ID:
C5830385
Disease or Syndrome
Neurodegeneration and seizures due to copper transport defect (NSCT) is an autosomal recessive disorder of copper transport characterized by hypotonia, global developmental delay, seizures, and rapid brain atrophy (summary by Dame et al., 2023).
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A
MedGen UID:
1841116
Concept ID:
C5830480
Disease or Syndrome
Mitochondrial complex V deficiency nuclear type 4A (MC5DN4A) is an autosomal dominant metabolic disorder characterized by poor feeding and failure to thrive in early infancy. Laboratory studies show increased serum lactate, alanine, and ammonia, suggesting mitochondrial dysfunction. Some affected individuals show spontaneous resolution of these symptoms in early childhood and have subsequent normal growth and development, whereas others show developmental delay with impaired intellectual development and movement abnormalities, including dystonia, ataxia, or spasticity; these neurologic deficits are persistent (Lines et al., 2021, Zech et al., 2022). For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, nuclear types, see MC5DN1 (604273).
Congenital disorder of deglycosylation 1
MedGen UID:
989503
Concept ID:
CN306977
Disease or Syndrome
Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.

Professional guidelines

PubMed

Olofsson P
Am J Obstet Gynecol 2023 May;228(5S):S1222-S1240. Epub 2023 Mar 19 doi: 10.1016/j.ajog.2022.07.001. PMID: 37164495
Chen H, Zhou J, Zhao X, Liu Q, Shao L, Zhu Y, Ou Q
BMC Infect Dis 2022 Jun 14;22(1):543. doi: 10.1186/s12879-022-07506-z. PMID: 35701741Free PMC Article
Deshpande S, Tytarenko RG, Wang Y, Boyle EM, Ashby C, Schinke CD, Thanendrarajan S, Zangari M, Zhan F, Davies FE, Morgan GJ, van Rhee F, Walker BA
Eur J Haematol 2021 Feb;106(2):230-240. Epub 2020 Nov 10 doi: 10.1111/ejh.13541. PMID: 33107092

Recent clinical studies

Etiology

Olofsson P
Am J Obstet Gynecol 2023 May;228(5S):S1222-S1240. Epub 2023 Mar 19 doi: 10.1016/j.ajog.2022.07.001. PMID: 37164495
Guasch-Ferré M, Santos JL, Martínez-González MA, Clish CB, Razquin C, Wang D, Liang L, Li J, Dennis C, Corella D, Muñoz-Bravo C, Romaguera D, Estruch R, Santos-Lozano JM, Castañer O, Alonso-Gómez A, Serra-Majem L, Ros E, Canudas S, Asensio EM, Fitó M, Pierce K, Martínez JA, Salas-Salvadó J, Toledo E, Hu FB, Ruiz-Canela M
Am J Clin Nutr 2020 Apr 1;111(4):835-844. doi: 10.1093/ajcn/nqaa016. PMID: 32060497Free PMC Article
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Diagnosis

Emhoff CW, Messonnier LA
Nutrients 2023 Jul 20;15(14) doi: 10.3390/nu15143213. PMID: 37513631Free PMC Article
Olofsson P
Am J Obstet Gynecol 2023 May;228(5S):S1222-S1240. Epub 2023 Mar 19 doi: 10.1016/j.ajog.2022.07.001. PMID: 37164495
He L
Trends Pharmacol Sci 2020 Nov;41(11):868-881. Epub 2020 Sep 28 doi: 10.1016/j.tips.2020.09.001. PMID: 32994049Free PMC Article
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Therapy

He L
Trends Pharmacol Sci 2020 Nov;41(11):868-881. Epub 2020 Sep 28 doi: 10.1016/j.tips.2020.09.001. PMID: 32994049Free PMC Article
Guasch-Ferré M, Santos JL, Martínez-González MA, Clish CB, Razquin C, Wang D, Liang L, Li J, Dennis C, Corella D, Muñoz-Bravo C, Romaguera D, Estruch R, Santos-Lozano JM, Castañer O, Alonso-Gómez A, Serra-Majem L, Ros E, Canudas S, Asensio EM, Fitó M, Pierce K, Martínez JA, Salas-Salvadó J, Toledo E, Hu FB, Ruiz-Canela M
Am J Clin Nutr 2020 Apr 1;111(4):835-844. doi: 10.1093/ajcn/nqaa016. PMID: 32060497Free PMC Article
Stacpoole PW, Greene YJ
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Gronert GA
Anesthesiology 1980 Nov;53(5):395-423. doi: 10.1097/00000542-198011000-00007. PMID: 6999950

Prognosis

Langeland H, Bergum D, Løberg M, Bjørnstad K, Skaug TR, Nordseth T, Klepstad P, Skjærvold NK
Open Heart 2022 Jan;9(1) doi: 10.1136/openhrt-2021-001890. PMID: 35046124Free PMC Article
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Gronert GA
Anesthesiology 1980 Nov;53(5):395-423. doi: 10.1097/00000542-198011000-00007. PMID: 6999950

Clinical prediction guides

Olofsson P
Am J Obstet Gynecol 2023 May;228(5S):S1222-S1240. Epub 2023 Mar 19 doi: 10.1016/j.ajog.2022.07.001. PMID: 37164495
Walden TP, Fairchild T, Girard O, Peiffer JJ, Jonson AM, Dempsey AR
Eur J Sport Sci 2023 Aug;23(8):1528-1537. Epub 2023 Apr 4 doi: 10.1080/17461391.2023.2194274. PMID: 36946174
Barbato A, Giallongo C, Giallongo S, Romano A, Scandura G, Concetta S, Zuppelli T, Lolicato M, Lazzarino G, Parrinello N, Del Fabro V, Fontana P, Aguennoz M, Li Volti G, Palumbo GA, Di Raimondo F, Tibullo D
Cell Prolif 2023 Apr;56(4):e13388. Epub 2023 Feb 15 doi: 10.1111/cpr.13388. PMID: 36794373Free PMC Article
Guasch-Ferré M, Santos JL, Martínez-González MA, Clish CB, Razquin C, Wang D, Liang L, Li J, Dennis C, Corella D, Muñoz-Bravo C, Romaguera D, Estruch R, Santos-Lozano JM, Castañer O, Alonso-Gómez A, Serra-Majem L, Ros E, Canudas S, Asensio EM, Fitó M, Pierce K, Martínez JA, Salas-Salvadó J, Toledo E, Hu FB, Ruiz-Canela M
Am J Clin Nutr 2020 Apr 1;111(4):835-844. doi: 10.1093/ajcn/nqaa016. PMID: 32060497Free PMC Article
Gronert GA
Anesthesiology 1980 Nov;53(5):395-423. doi: 10.1097/00000542-198011000-00007. PMID: 6999950

Recent systematic reviews

Linden-Torres E, Zambrano-Galván G, Sahebkar A, Ríos-Mier M, Simental-Mendía LE
Nutr Res 2022 Oct;106:24-34. Epub 2022 Aug 5 doi: 10.1016/j.nutres.2022.07.010. PMID: 36126527

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