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Ophthalmoplegia

MedGen UID:
45205
Concept ID:
C0029089
Sign or Symptom
Synonyms: Oculomotor Paralysis; Ophthalmoplegias; Paralysis, Oculomotor
SNOMED CT: Ophthalmoplegia (16110005)
 
HPO: HP:0000602
Monarch Initiative: MONDO:0003425

Definition

Paralysis of one or more extraocular muscles that are responsible for eye movements. [from HPO]

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).
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
MedGen UID:
56485
Concept ID:
C0162671
Disease or Syndrome
MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, normal early psychomotor development, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. During the stroke-like episodes neuroimaging shows increased T2-weighted signal areas that do not correspond to the classic vascular distribution (hence the term "stroke-like"). Lactic acidemia is very common and muscle biopsies typically show ragged red fibers.
Gordon syndrome
MedGen UID:
66314
Concept ID:
C0220666
Disease or Syndrome
DA3, or Gordon syndrome, is distinguished from other distal arthrogryposes by short stature and cleft palate (summary by Bamshad et al., 2009). There are 2 syndromes with features overlapping those of DA3 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 5 (DA5; 108145) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of ocular abnormalities and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition. For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Gaucher disease type II
MedGen UID:
78652
Concept ID:
C0268250
Disease or Syndrome
Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute. Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2. Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.
Wernicke-Korsakoff syndrome
MedGen UID:
83883
Concept ID:
C0349464
Mental or Behavioral Dysfunction
A psychotic syndrome caused by damage to the brain by lack of thiamine (vitamin B1). Signs and symptoms include anterograde and retrograde amnesia, confabulation, apathy, ataxia, and coma.
Myopathy, centronuclear, 2
MedGen UID:
98049
Concept ID:
C0410204
Disease or Syndrome
Any centronuclear myopathy in which the cause of the disease is a mutation in the BIN1 gene.
Congenital myopathy with fiber type disproportion
MedGen UID:
108177
Concept ID:
C0546264
Disease or Syndrome
Congenital fiber-type disproportion is a condition that primarily affects skeletal muscles, which are muscles used for movement. People with this condition typically experience muscle weakness (myopathy), particularly in the muscles of the shoulders, upper arms, hips, and thighs. Weakness can also affect the muscles of the face and muscles that control eye movement (ophthalmoplegia), sometimes causing droopy eyelids (ptosis). Individuals with congenital fiber-type disproportion generally have a long face, a high arch in the roof of the mouth (high-arched palate), and crowded teeth.\n\nIndividuals with congenital fiber-type disproportion may have joint deformities (contractures) and an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Approximately 30 percent of people with this disorder experience mild to severe breathing problems related to weakness of muscles needed for breathing. Some people who experience these breathing problems require use of a machine to help regulate their breathing at night (noninvasive mechanical ventilation), and occasionally during the day as well. About 30 percent of affected individuals have difficulty swallowing due to muscle weakness in the throat. Rarely, people with this condition have a weakened and enlarged heart muscle (dilated cardiomyopathy).\n\nThe severity of congenital fiber-type disproportion varies widely. It is estimated that up to 25 percent of affected individuals experience severe muscle weakness at birth and die in infancy or childhood. Others have only mild muscle weakness that becomes apparent in adulthood. Most often, the signs and symptoms of this condition appear by age 1. The first signs of this condition are usually decreased muscle tone (hypotonia) and muscle weakness. In most cases, muscle weakness does not worsen over time, and in some instances it may improve. Although motor skills such as standing and walking may be delayed, many affected children eventually learn to walk. These individuals often have less stamina than their peers, but they remain active. Rarely, people with this condition have a progressive decline in muscle strength over time. These individuals may lose the ability to walk and require wheelchair assistance.
Spinocerebellar ataxia type 2
MedGen UID:
155704
Concept ID:
C0752121
Disease or Syndrome
Spinocerebellar ataxia type 2 (SCA2) is characterized by progressive cerebellar ataxia, including nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis or parkinsonism. Pyramidal findings are present; deep tendon reflexes are brisk early on and absent later in the course. Age of onset is typically in the fourth decade with a ten- to 15-year disease duration.
Merosin deficient congenital muscular dystrophy
MedGen UID:
224728
Concept ID:
C1263858
Disease or Syndrome
Merosin-deficient congenital muscular dystrophy is an autosomal recessive form of muscular dystrophy characterized by muscle weakness apparent at birth or in the first 6 months of life. Patients show hypotonia, poor suck and cry, and delayed motor development; most never achieve independent ambulation. Most patients also have periventricular white matter abnormalities on brain imaging, but mental retardation and/or seizures occur only rarely (summary by Xiong et al., 2015).
Ophthalmoplegia, familial static
MedGen UID:
371666
Concept ID:
C1833839
Disease or Syndrome
Ophthalmoplegia, external, and myopia
MedGen UID:
326916
Concept ID:
C1839577
Disease or Syndrome
Oculogastrointestinal muscular dystrophy
MedGen UID:
336376
Concept ID:
C1848586
Disease or Syndrome
An extremely rare autosomal recessively inherited neuromuscular disease characterised by ocular manifestations such as ptosis and diplopia followed by chronic diarrhoea, malnutrition and intestinal pseudo-obstruction.
Infantile onset spinocerebellar ataxia
MedGen UID:
338613
Concept ID:
C1849096
Disease or Syndrome
Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. Ophthalmoplegia and sensorineural deafness develop by age seven years. By adolescence, affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness.
Ophthalmoplegic neuromuscular disorder with abnormal mitochondria
MedGen UID:
340508
Concept ID:
C1850302
Disease or Syndrome
Ophthalmoplegia totalis with ptosis and miosis
MedGen UID:
342471
Concept ID:
C1850314
Disease or Syndrome
Total ophthalmoplegia involves total paralysis of all extra- and intraocular muscles. If one or more of the external muscles, including the levator palpebrae, is not affected, the condition is known as incomplete or partial ophthalmoplegia. If only 1 nerve is affected, the palsy is named after that nerve (see, e.g., abducens palsy, 100200) (Waardenburg, 1963).
Myopathy, proximal, and ophthalmoplegia
MedGen UID:
381340
Concept ID:
C1854106
Disease or Syndrome
Congenital myopathy-6 with ophthalmoplegia (CMYP6) is a relatively mild muscle disorder characterized by childhood onset of symptoms. The disorder is either slowly progressive or nonprogressive, and affected individuals retain ambulation, although there is variable severity. CMYP6 can show both autosomal dominant and autosomal recessive inheritance; the phenotype is similar in both forms (summary by Lossos et al., 2005 and Tajsharghi et al., 2014). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
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).
Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
MedGen UID:
350678
Concept ID:
C1862472
Disease or Syndrome
Distal arthrogryposis type 5 is distinguished from other forms of DA by the presence of ocular abnormalities, typically ptosis, ophthalmoplegia, and/or strabismus, in addition to contractures of the skeletal muscles. Some cases have been reported to have pulmonary hypertension as a result of restrictive lung disease (summary by Bamshad et al., 2009). There are 2 syndromes with features overlapping those of DA5 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of cleft palate and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders might represent variable expressivity of the same condition. For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120). Genetic Heterogeneity of Distal Arthrogryposis 5 A subtype of DA5 due to mutation in the ECEL1 gene (605896) on chromosome 2q36 has been designated DA5D (615065). See NOMENCLATURE.
Christianson syndrome
MedGen UID:
394455
Concept ID:
C2678194
Disease or Syndrome
Christianson syndrome (referred to as CS in this GeneReview), an X-linked disorder, is characterized in males by cognitive dysfunction, behavioral disorder, and neurologic findings (e.g., seizures, ataxia, postnatal microcephaly, and eye movement abnormalities). Males with CS typically present with developmental delay, later meeting criteria for severe intellectual disability (ID). Behaviorally, autism spectrum disorder and hyperactivity are common, and may resemble the behaviors observed in Angelman syndrome. Hypotonia and oropharyngeal dysphagia in infancy may result in failure to thrive. Seizures, typically beginning before age three years, can include infantile spasms and tonic, tonic-clonic, myoclonic, and atonic seizures. Subsequently, regression (e.g., loss of ambulation and ability to feed independently) may occur. Manifestations in heterozygous females range from asymptomatic to mild ID and/or behavioral issues.
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.
Congenital myasthenic syndrome 1A
MedGen UID:
419336
Concept ID:
C2931107
Disease or Syndrome
Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic, as well as by pathologic mechanism and electrophysiologic studies (i.e., acetylcholine receptor (AChR) deficiency, slow-channel or fast-channel kinetic defects at the AChR) (summary by Engel et al., 2003; Engel et al., 2015). Approximately 10% of CMS cases are presynaptic, 15% are synaptic, and 75% are postsynaptic, the majority of which are caused by AChR deficiency (Engel et al., 2003). Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic NMJ characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically prolonged opening and activity of the channel, which causes prolonged synaptic currents resulting in a depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. Treatment with quinine, quinidine, or fluoxetine may be helpful; acetylcholinesterase inhibitors and amifampridine should be avoided (summary by Engel et al., 2015). Genetic Heterogeneity of Congenital Myasthenic Syndromes Recessive mutations in subunits of the acetylcholine receptor are the most common cause of CMS (Harper, 2004). CMS1A and CMS1B (608930) are caused by mutation in the CHRNA1 gene (100690); CMS2A (616313) and CMS2C (616314) are caused by mutation in the CHRNB1 gene (100710) on 17p12; CMS3A (616321), CMS3B (616322), and CMS3C (616323) are caused by mutation in the CHRND gene (100720) on 2q33; and CMS4A (605809), CMS4B (616324), and CMS4C (608931) are caused by mutation in the CHRNE gene (100725) on 17p13. CMS5 (603034) is caused by mutation in the COLQ gene (603033) on 3p25; CMS6 (254210) is caused by mutation in the CHAT gene (118490) on 10q; CMS7 (616040) is caused by mutation in the SYT2 gene (600104) on 1q32; CMS8 (615120) is caused by mutation in the AGRN gene (103320) on 1p; CMS9 (616325) is caused by mutation in the MUSK gene (601296) on 9q31; CMS10 (254300) is caused by mutation in the DOK7 gene (610285) on 4p; CMS11 (616326) is caused by mutation in the RAPSN gene (601592) on 11p11; CMS12 (610542) is caused by mutation in the GFPT1 gene (138292) on 2p14; CMS13 (614750) is caused by mutation in the DPAGT1 gene (191350) on 11q23; CMS14 (616228) is caused by mutation in the ALG2 gene (607905) on 9q22; CMS15 (616227) is caused by mutation in the ALG14 gene (612866) on 1p21; CMS16 (614198) is caused by mutation in the SCN4A gene (603967) on 17q; CMS17 (616304) is caused by mutation in the LRP4 gene (604270) on 11p12; CMS18 (616330) is caused by mutation in the SNAP25 gene (600322) on 20p11; CMS19 (616720) is caused by mutation in the COL13A1 gene (120350) on 10q22; CMS20 (617143) is caused by mutation in the SLC5A7 gene (608761) on 2q12; CMS21 (617239) is caused by mutation in the SLC18A3 gene (600336) on 10q11; CMS22 (616224) is caused by mutation in the PREPL gene (609557) on 2p21; CMS23 (618197) is caused by mutation in the SLC25A1 gene (190315) on 22q11; CMS24 (618198) is caused by mutation in the MYO9A gene (604875) on 15q22; and CMS25 (618323) is caused by mutation in the VAMP1 gene (185880) on 12p13.
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.
Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy
MedGen UID:
478179
Concept ID:
C3276549
Disease or Syndrome
Syndromic optic atrophy, also known as DOA+ syndrome, is a neurologic disorder characterized most commonly by an insidious onset of visual loss and sensorineural hearing loss in childhood with variable presentation of other clinical manifestations including progressive external ophthalmoplegia (PEO), muscle cramps, hyperreflexia, and ataxia. There appears to be a wide range of intermediate phenotypes (Yu-Wai-Man et al., 2010).
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).
Charcot-Marie-Tooth disease type 4B3
MedGen UID:
811329
Concept ID:
C3695063
Disease or Syndrome
A subtype of Charcot-Marie-Tooth type 4 with characteristics of childhood onset of slowly progressing, demyelinating sensorimotor neuropathy, focally folded myelin sheaths in nerve biopsy, reduced nerve conduction velocities and the typical Charcot-Marie-Tooth phenotype (i.e. distal muscle weakness and atrophy, and sensory loss). There is evidence this disease is caused by homozygous or compound heterozygous mutation in the SBF1 gene on chromosome 22q.
Vasculitis due to ADA2 deficiency
MedGen UID:
854497
Concept ID:
C3887654
Disease or Syndrome
Adenosine deaminase 2 deficiency (DADA2) is a complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, and/or hematologic abnormalities may predominate. Inflammatory features include intermittent fevers, rash (often livedo racemosa/reticularis), and musculoskeletal involvement (myalgia/arthralgia, arthritis, myositis). Vasculitis, which usually begins before age ten years, may manifest as early-onset ischemic (lacunar) and/or hemorrhagic strokes, or as cutaneous or systemic polyarteritis nodosa. Hypertension and hepatosplenomegaly are often found. More severe involvement may lead to progressive central neurologic deficits (dysarthria, ataxia, cranial nerve palsies, cognitive impairment) or to ischemic injury to the kidney, intestine, and/or digits. Dysregulation of immune function can lead to immunodeficiency or autoimmunity of varying severity; lymphadenopathy may be present and some affected individuals have had lymphoproliferative disease. Hematologic disorders may begin early in life or in late adulthood, and can include lymphopenia, neutropenia, pure red cell aplasia, thrombocytopenia, or pancytopenia. Of note, both interfamilial and intrafamilial phenotypic variability (e.g., in age of onset, frequency and severity of manifestations) can be observed; also, individuals with biallelic ADA2 pathogenic variants may remain asymptomatic until adulthood or may never develop clinical manifestations of DADA2.
Myopathy, centronuclear, 5
MedGen UID:
863251
Concept ID:
C4014814
Disease or Syndrome
Centronuclear myopathy-5 (CNM5) is an autosomal recessive congenital myopathy characterized by severe neonatal hypotonia with respiratory insufficiency and difficulty feeding. Some patients die in infancy, and some develop dilated cardiomyopathy. Children show severely delayed motor development (summary by Agrawal et al., 2014). For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150).
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.
Nemaline myopathy 10
MedGen UID:
863797
Concept ID:
C4015360
Disease or Syndrome
Nemaline myopathy-10 (NEM10) is an autosomal recessive severe congenital myopathy characterized by early-onset generalized muscle weakness and hypotonia with respiratory insufficiency and feeding difficulties. Many patients present antenatally with decreased fetal movements, and most die of respiratory failure in early infancy (summary by Yuen et al., 2014). Patients with a stable and much milder disease course have been described (Schatz et al., 2018). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM3 (161800).
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).
Congenital myasthenic syndrome 9
MedGen UID:
895641
Concept ID:
C4225368
Disease or Syndrome
Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Patients may show a favorable response to amifampridine (summary by Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Congenital myasthenic syndrome 4B
MedGen UID:
904424
Concept ID:
C4225369
Disease or Syndrome
Fast-channel congenital myasthenic syndrome (FCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (summary by Sine et al., 2003 and Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Congenital myasthenic syndrome 3B
MedGen UID:
909404
Concept ID:
C4225371
Disease or Syndrome
Fast-channel congenital myasthenic syndrome (FCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (summary by Sine et al., 2003 and Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Congenital myasthenic syndrome 2A
MedGen UID:
908185
Concept ID:
C4225374
Disease or Syndrome
Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor channel, specifically from prolonged opening and activity of the channel, which causes prolonged synaptic currents resulting in a depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. Treatment with quinine, quinidine, or fluoxetine may be helpful; cholinesterase inhibitors and amifampridine should be avoided (summary by Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Congenital myasthenic syndrome 21
MedGen UID:
934621
Concept ID:
C4310654
Disease or Syndrome
Any congenital myasthenic syndrome in which the cause of the disease is a mutation in the SLC18A3 gene.
Linear nevus sebaceous syndrome
MedGen UID:
1646345
Concept ID:
C4552097
Disease or Syndrome
Schimmelpenning-Feuerstein-Mims syndrome, also known as linear sebaceous nevus syndrome, is characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects (summary by Happle, 1991 and Ernst et al., 2007). The linear sebaceous nevi follow the lines of Blaschko (Hornstein and Knickenberg, 1974; Bouwes Bavinck and van de Kamp, 1985). All cases are sporadic. The syndrome is believed to be caused by an autosomal dominant lethal mutation that survives by somatic mosaicism (Gorlin et al., 2001).
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).
Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development
MedGen UID:
1648480
Concept ID:
C4748283
Disease or Syndrome
Autosomal recessive peripheral neuropathy with or without impaired intellectual development is an early childhood-onset neurologic disorder characterized by slowly progressive distal motor impairment resulting in gait difficulties, often with loss of ambulation, and difficulties using the hands in most patients. Most affected individuals also have impaired intellectual development, although some have normal cognition. Electrophysiologic testing and sural nerve biopsy are most compatible with an axonal motor neuropathy; some patients may show signs of demyelination. Additional features may include eye movement abnormalities, claw hands, foot deformities, and scoliosis (summary by Ylikallio et al., 2017).
Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
MedGen UID:
1648391
Concept ID:
C4748527
Disease or Syndrome
Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive neurodegenerative disorder with onset in the first years of life following normal early development. Patient have cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some patients develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy (summary by Ghosh et al., 2018).
Myasthenic syndrome, congenital, 24, presynaptic
MedGen UID:
1648337
Concept ID:
C4748684
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
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).
Mitochondrial complex 5 (ATP synthase) deficiency, nuclear type 6
MedGen UID:
1684729
Concept ID:
C5231461
Disease or Syndrome
Mitochondrial complex V (ATP synthase) deficiency nuclear type 6 (MC5DN6) is an autosomal recessive progressive and degenerative disorder characterized by episodic regression of gross motor skills beginning in early childhood. The episodes are associated with metabolic stress, including fever, illness, and general anesthesia. Patients develop gait difficulties or loss of ambulation, as well as other variable abnormalities, including abnormal movements, hemiplegia, and persistent lethargy. Brain imaging shows degenerative features in the basal ganglia and brainstem consistent with a diagnosis of Leigh syndrome (see 256000) (summary by Barca et al., 2018). For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see MC5DN1 (604273).
Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies
MedGen UID:
1684772
Concept ID:
C5231481
Disease or Syndrome
Oculopharyngodistal myopathy 3
MedGen UID:
1794166
Concept ID:
C5561956
Disease or Syndrome
Oculopharyngodistal myopathy-3 (OPDM3) is a neuromyodegenerative disease characterized by progressive muscle weakness with ocular, facial, pharyngeal, and distal limb involvement, resulting in dysarthria and gait difficulties. The onset of the disorder is usually in adulthood, although childhood onset has rarely been reported. Additional features include hyporeflexia, proximal muscle weakness, neck muscle weakness, dysarthria, dysphagia, and ptosis. Some patients may develop pigmentary retinopathy, peripheral neuropathy, or hearing loss. Cognition is usually not affected, but there may be deficits or psychiatric manifestations. Brain imaging tends to show a leukoencephalopathy, often with a characteristic linear signal along the corticomedullary junction on brain imaging. Skin and muscle biopsy show intranuclear inclusions and rimmed vacuoles. Many of the clinical features are reminiscent of NIID, suggesting that these disorders likely fall within a broad phenotypic spectrum of diseases with neuromyodegenerative features associated with abnormal repeat expansions in this gene (summary by Ogasawara et al., 2020 and Yu et al., 2021). For a discussion of genetic heterogeneity of OPDM, see OPDM1 (164310).
Carey-Fineman-Ziter syndrome 1
MedGen UID:
1804638
Concept ID:
C5676876
Disease or Syndrome
Carey-Fineman-Ziter syndrome-1 (CFZS1) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. More variable features include dysmorphic facial features, brain abnormalities, and intellectual disability. It has been postulated that many clinical features in CFZS1 may be secondary effects of muscle weakness during development or brainstem anomalies (summary by Pasetti et al., 2016). Di Gioia et al. (2017) determined that CFZS1 represents a slowly progressive congenital myopathy resulting from a defect in myoblast fusion. Genetic Heterogeneity of Carey-Fineman-Ziter Syndrome Carey-Fineman-Ziter syndrome-2 (CFZS2) is caused by mutation in the MYMX gene (619912) on chromosome 6p21.
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.
Congenital myopathy 18
MedGen UID:
1840919
Concept ID:
C5830283
Disease or Syndrome
Congenital myopathy-18 (CMYP18) is a disorder of the skeletal muscle characterized by the onset of symptoms of muscle weakness in early childhood, including in utero and infancy. There is clinical heterogeneity in the manifestations and severity, ranging from fetal akinesia sequence causing early death to onset of symptoms in adulthood. Most affected individuals show delayed motor development with generalized hypotonia and progressive axial and limb muscle weakness beginning soon after birth or in infancy. Additional features may include swallowing difficulties, external ophthalmoplegia, ptosis, high-arched palate, and respiratory insufficiency, which can lead to death in severe cases. Muscle biopsy shows variable morphologic abnormalities, including alveolar changes in the intermyofibrillar network, fiber size variability, focal disorganization, internal nuclei, and dilated sarcoplasmic reticulum and T-tubules. The disorder results from a defect in excitation-contraction coupling in skeletal muscle (Schartner et al., 2017; Ravenscroft et al., 2021; Mauri et al., 2021; Yis et al., 2019). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
Congenital myopathy 22A, classic
MedGen UID:
1841089
Concept ID:
C5830453
Disease or Syndrome
Classic congenital myopathy-22A (CMYP22A) is an autosomal recessive muscle disorder characterized by onset of muscle weakness in utero or soon after birth. Early features may include fetal hypokinesia, breech presentation, and polyhydramnios. Affected individuals are born with severe hypotonia and require respiratory and feeding assistance. Those who survive the neonatal period show a 'classic' phenotype of congenital myopathy with delayed motor development, difficulty walking, proximal muscle weakness of the upper and lower limbs, facial and neck muscle weakness, easy fatigability, and mild limb contractures or foot deformities. Some have persistent respiratory insufficiency; dysmorphic facial features may be present (Zaharieva et al., 2016). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
Congenital myopathy 22B, severe fetal
MedGen UID:
1841137
Concept ID:
C5830501
Disease or Syndrome
Severe fetal congenital myopathy-22B (CMYP22B) is an autosomal recessive muscle disorder characterized by in utero onset of severe muscle weakness manifest as fetal akinesia. The pregnancies are often complicated by polyhydramnios, and affected individuals develop fetal hydrops with pulmonary hypoplasia, severe joint contractures, and generalized muscle hypoplasia. Those who are born have respiratory failure resulting in death. Dysmorphic facial features may be present. The features in these patients overlap with fetal akinesia deformation sequence (FADS; see 208150) and lethal congenital contractures syndrome (LCCS; see 253310) (Zaharieva et al., 2016). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Professional guidelines

PubMed

McGinley MP, Goldschmidt CH, Rae-Grant AD
JAMA 2021 Feb 23;325(8):765-779. doi: 10.1001/jama.2020.26858. PMID: 33620411
Carlisle RT, Digiovanni J
Am Fam Physician 2015 Jul 15;92(2):106-12. PMID: 26176369
Freda PU, Beckers AM, Katznelson L, Molitch ME, Montori VM, Post KD, Vance ML; Endocrine Society
J Clin Endocrinol Metab 2011 Apr;96(4):894-904. doi: 10.1210/jc.2010-1048. PMID: 21474686Free PMC Article

Recent clinical studies

Etiology

Topaloglu H
Acta Myol 2020 Dec;39(4):266-273. Epub 2020 Dec 1 doi: 10.36185/2532-1900-029. PMID: 33458581Free PMC Article
Chan TM, Prospero Ponce CM, Allen RC, Bell D, Lee AG
Orbit 2020 Feb;39(1):68-70. Epub 2019 Apr 25 doi: 10.1080/01676830.2019.1594980. PMID: 31020884
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Spector RH
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Diagnosis

Ranjan R, Singh D, Mahesh KV, Takkar AK, Ray S, Lal V
J Neurol Sci 2021 Aug 15;427:117504. Epub 2021 May 21 doi: 10.1016/j.jns.2021.117504. PMID: 34082150
Weidauer S, Hofmann C, Wagner M, Hattingen E
Neuroradiology 2019 Apr;61(4):365-387. Epub 2019 Feb 12 doi: 10.1007/s00234-019-02183-3. PMID: 30747268
Dietz E
J Binocul Vis Ocul Motil 2018 Jan-Mar;68(1):4-6. Epub 2018 Jan 19 doi: 10.1080/2576117X.2017.1416239. PMID: 30196777
Oystreck DT
J Binocul Vis Ocul Motil 2018 Jan-Mar;68(1):31-33. Epub 2018 Jan 31 doi: 10.1080/2576117X.2017.1416242. PMID: 30196776
McClelland C, Manousakis G, Lee MS
Curr Neurol Neurosci Rep 2016 Jun;16(6):53. doi: 10.1007/s11910-016-0652-7. PMID: 27072953

Therapy

Zhou L, Wei X
Front Immunol 2021;12:701951. Epub 2021 Aug 24 doi: 10.3389/fimmu.2021.701951. PMID: 34504488Free PMC Article
Al Othman B, Raabe J, Kini A, Lee AG
Curr Opin Ophthalmol 2019 Nov;30(6):462-466. doi: 10.1097/ICU.0000000000000611. PMID: 31567467
Arnoldi K
J Binocul Vis Ocul Motil 2018 Jan-Mar;68(1):24-27. Epub 2018 Jan 17 doi: 10.1080/2576117X.2017.1418459. PMID: 30196779
Freund PR, Chen SH
CMAJ 2018 May 28;190(21):E656. doi: 10.1503/cmaj.180063. PMID: 29807938Free PMC Article
Pellegrini F, Prosdocimo G, Barton JJ
Surv Ophthalmol 2016 Mar-Apr;61(2):248-54. Epub 2015 Aug 20 doi: 10.1016/j.survophthal.2015.08.004. PMID: 26297877

Prognosis

Chan TM, Prospero Ponce CM, Allen RC, Bell D, Lee AG
Orbit 2020 Feb;39(1):68-70. Epub 2019 Apr 25 doi: 10.1080/01676830.2019.1594980. PMID: 31020884
Weidauer S, Hofmann C, Wagner M, Hattingen E
Neuroradiology 2019 Apr;61(4):365-387. Epub 2019 Feb 12 doi: 10.1007/s00234-019-02183-3. PMID: 30747268
Freda PU, Beckers AM, Katznelson L, Molitch ME, Montori VM, Post KD, Vance ML; Endocrine Society
J Clin Endocrinol Metab 2011 Apr;96(4):894-904. doi: 10.1210/jc.2010-1048. PMID: 21474686Free PMC Article
Levin M, Ward TN
Curr Pain Headache Rep 2004 Aug;8(4):306-9. doi: 10.1007/s11916-004-0013-0. PMID: 15228891
Hynd GW, Pirozzolo FJ, Maletta GJ
Int J Neurosci 1982 Mar;16(2):87-98. doi: 10.3109/00207458209147609. PMID: 6762362

Clinical prediction guides

Lin Y, Wang J, Ren H, Ma X, Wang W, Zhao Y, Xu Z, Liu S, Wang W, Xu X, Wang B, Zhao D, Wang D, Li W, Liu F, Zhao Y, Lu J, Yan C, Ji K
J Neurol 2024 Feb;271(2):864-876. Epub 2023 Oct 17 doi: 10.1007/s00415-023-12005-5. PMID: 37847292
Keene KR, Kan HE, van der Meeren S, Verbist BM, Tannemaat MR, Beenakker JM, Verschuuren JJGM
J Cachexia Sarcopenia Muscle 2022 Dec;13(6):2820-2834. Epub 2022 Sep 29 doi: 10.1002/jcsm.13089. PMID: 36172973Free PMC Article
Qian S, Kumar P, Testai FD
Curr Neurol Neurosci Rep 2022 Jul;22(7):343-353. Epub 2022 May 19 doi: 10.1007/s11910-022-01204-8. PMID: 35588044
Levin M, Ward TN
Curr Pain Headache Rep 2004 Aug;8(4):306-9. doi: 10.1007/s11916-004-0013-0. PMID: 15228891
Spector RH
Surv Ophthalmol 1993 Jul-Aug;38(1):31-62. doi: 10.1016/0039-6257(93)90054-b. PMID: 8235994

Recent systematic reviews

Ghiam BK, Liu BJ, Echegaray JJ, Prendes MA
Ophthalmic Plast Reconstr Surg 2023 Nov-Dec 01;39(6):548-557. Epub 2023 Jul 21 doi: 10.1097/IOP.0000000000002430. PMID: 37486344
Neophytou P, Artemiadis A, Hadjigeorgiou GM, Zis P
Acta Neurol Belg 2023 Oct;123(5):1693-1701. Epub 2023 Jul 19 doi: 10.1007/s13760-023-02336-5. PMID: 37468803Free PMC Article
Van Swol JM, Myers WK, Nguyen SA, Wilson ME
J Binocul Vis Ocul Motil 2023 Apr-Jun;73(2):43-52. Epub 2023 Feb 13 PMID: 36780505
Watanabe A, So M, Mitaka H, Ishisaka Y, Takagi H, Inokuchi R, Iwagami M, Kuno T
Mycopathologia 2022 Jun;187(2-3):271-289. Epub 2022 Mar 21 doi: 10.1007/s11046-022-00627-8. PMID: 35312945Free PMC Article
Mortada H, Seraj H, Barasain O, Bamakhrama B, Alhindi NI, Arab K
Aesthetic Plast Surg 2022 Apr;46(2):760-773. Epub 2022 Jan 29 doi: 10.1007/s00266-021-02730-5. PMID: 35091771

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