MedGen

If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress. [from GeneReviews]

The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy. Isolated cardiomyopathy can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits. Manifestations of neonatal and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure. [from GeneReviews]

Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms. [from GeneReviews]

Holocarboxylase synthetase deficiency, a biotin-responsive multiple carboxylase deficiency (MCD), is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period (summary by Suzuki et al., 2005). Also see biotinidase deficiency (253260), another form of MCD with a later onset. Care must be taken to differentiate the inherited multiple carboxylase deficiencies from acquired biotin deficiencies, such as those that develop after excessive dietary intake of avidin, an egg-white glycoprotein that binds specifically and essentially irreversibly to biotin (Sweetman et al., 1981) or prolonged parenteral alimentation without supplemental biotin (Mock et al., 1981). [from OMIM]

Inborn errors of pulmonary surfactant metabolism are genetically heterogeneous disorders resulting in severe respiratory insufficiency or failure in full-term neonates or infants. These disorders are associated with various pathologic entities, including pulmonary alveolar proteinosis (PAP), desquamative interstitial pneumonitis (DIP), or cellular nonspecific interstitial pneumonitis (NSIP) (Clark and Clark, 2005). A clinically similar disorder characterized by respiratory distress (267450) can affect preterm infants, who show developmental deficiency of surfactant. Acquired PAP (610910) is an autoimmune disorder characterized by the presence of autoantibodies to CSF2 (138960). Genetic Heterogeneity of Pulmonary Surfactant Metabolism Dysfunction See also SMDP2 (610913), caused by mutation in the SPTPC gene (178620) on 8p21; SMDP3 (610921), caused by mutation in the ABCA3 gene (601615) on 16p13; SMDP4 (300770), caused by mutation in the CSF2RA gene (306250) on Xp22; and SMDP5 (614370), caused by mutation in the CSF2RB gene (138981) on 22q12. [from OMIM]

Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen. [from GeneReviews]

NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark of NKX2-1-related disorders, may or may not be associated with respiratory distress syndrome or congenital hypothyroidism. Chorea generally begins in early infancy or about age one year (most commonly) or in late childhood or adolescence, and progresses into the second decade after which it remains static or (rarely) remits. Pulmonary disease, the second most common manifestation, can include respiratory distress syndrome in neonates, interstitial lung disease in young children, and pulmonary fibrosis in older persons. The risk for pulmonary carcinoma is increased in young adults with an NKX2-1-related disorder. Thyroid dysfunction, the result of dysembryogenesis, can present as congenital hypothyroidism or compensated hypothyroidism. The risk for thyroid cancer is unknown and may not be increased. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had involvement of brain and thyroid only, and 13% had isolated chorea only. [from GeneReviews]

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an inherited condition that causes muscle weakness and respiratory failure typically beginning in infancy. Early features of this condition are difficult and noisy breathing, especially when inhaling; a weak cry; problems feeding; and recurrent episodes of pneumonia. Typically between the ages of 6 weeks and 6 months, infants with this condition will experience a sudden inability to breathe due to paralysis of the muscle that separates the abdomen from the chest cavity (the diaphragm). Normally, the diaphragm contracts and moves downward during inhalation to allow the lungs to expand. With diaphragm paralysis, affected individuals require life-long support with a machine to help them breathe (mechanical ventilation). Rarely, children with SMARD1 develop signs or symptoms of the disorder later in childhood.

Soon after respiratory failure occurs, individuals with SMARD1 develop muscle weakness in their distal muscles. These are the muscles farther from the center of the body, such as muscles in the hands and feet. The weakness soon spreads to all muscles; however, within 2 years, the muscle weakness typically stops getting worse. Some individuals may retain a low level of muscle function, while others lose all ability to move their muscles. Muscle weakness severely impairs motor development, such as sitting, standing, and walking. Some affected children develop an abnormal side-to-side and back-to-front curvature of the spine (scoliosis and kyphosis, often called kyphoscoliosis when they occur together). After approximately the first year of life, individuals with SMARD1 may lose their deep tendon reflexes, such as the reflex being tested when a doctor taps the knee with a hammer.

Other features of SMARD1 can include reduced pain sensitivity, excessive sweating (hyperhidrosis), loss of bladder and bowel control, and an irregular heartbeat (arrhythmia). [from MedlinePlus Genetics]

Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous metabolic disorder of cobalamin (cbl; vitamin B12) metabolism, which is essential for hematologic and neurologic function. Biochemically, the defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). The cblJ type is phenotypically and biochemically similar to the cblF type (MAHCF; 277380) (summary by Coelho et al., 2012). [from OMIM]

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. [from OMIM]

Pulmonary surfactant metabolism dysfunction-2 (SMDP2) is a rare autosomal dominant disease associated with progressive respiratory insufficiency and lung disease with a variable clinical course. The pathophysiology of the disorder is postulated to involve intracellular accumulation of a structurally defective SPC protein (Thomas et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of pulmonary surfactant metabolism dysfunction, see SMDP1 (265120). [from OMIM]

Neonatal severe hyperparathyroidism usually manifests in the first 6 months of life with severe hypercalcemia, bone demineralization, and failure to thrive. Early diagnosis is critical because untreated NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. Some infants have milder hyperparathyroidism and a substantially milder clinical presentation and natural history (summary by Egbuna and Brown, 2008). [from OMIM]

For a general phenotypic description and a discussion of genetic heterogeneity of pulmonary surfactant metabolism dysfunction, see SMDP1 (265120). [from OMIM]

Ketone bodies are major vectors of energy transfer from the liver to extrahepatic tissues and are the main source of lipid-derived energy for the brain. Mitchell et al. (1995) reviewed medical aspects of ketone body metabolism, including the differential diagnosis of abnormalities. As the first step of ketone body utilization, succinyl-CoA:3-oxoacid CoA transferase (SCOT, or OXCT1; EC 2.8.3.5) catalyzes the reversible transfer of CoA from succinyl-CoA to acetoacetate. [from OMIM]

Multisystemic smooth muscle dysfunction syndrome (MSMDS) presents with a recognizable pattern of complications, including congenital mydriasis, patent ductus arteriosus (PDA), pulmonary artery hypertension, aortic and other arterial aneurysms, moyamoya-like cerebrovascular disease, intestinal hypoperistalsis and malrotation, and hypotonic bladder. It is caused by heterozygous mutations of the ACTA2 gene altering the arginine-179 codon (summary by Regalado et al., 2018). [from OMIM]

Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die 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 MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711). [from OMIM]

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. Three forms of PAP have been described: hereditary (usually congenital), secondary, and acquired. Hereditary PAP is associated with mutations in the CSF2RA gene or in genes encoding surfactant proteins. Secondary PAP develops in conditions in which there are reduced numbers or functional impairment of alveolar macrophages and is associated with inhalation of inorganic dust (silica) or toxic fumes, hematologic malignancies, pharmacologic immunosuppression, infections, and impaired CSF2RB (138960) expression. Acquired PAP (610910), the most common form, usually occurs in adults and is caused by neutralizing autoantibodies to CSF2 (138960) (Martinez-Moczygemba et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of congenital pulmonary surfactant metabolism dysfunction, see SMDP1 (265120). [from OMIM]

Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen. [from GeneReviews]

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. [from GeneReviews]

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). [from OMIM]