MedGen

Fumarate hydratase (FH) deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are nonverbal and nonambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported. [from GeneReviews]

Combined D-2- and L-2-hydroxyglutaric aciduria (D2L2AD) is an autosomal recessive neurometabolic disorder characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death. Brain imaging shows abnormalities including enlarged ventricles, delayed myelination, and germinal layer cysts (Muntau et al., 2000). See also isolated L-2-hydroxyglutaric aciduria (236792) and isolated D-2-hydroxyglutaric aciduria (see 600721). [from OMIM]

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. [from OMIM]

Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is an autosomal recessive disorder characterized by acute reversible neurologic deterioration in the context of a febrile illness. The disorder is associated with transient leukoencephalopathy on brain imaging concurrent with the acute episode, as well as persistently increased excretion of dicarboxylic acids, particularly alpha-ketoglutarate (summary by Dewulf et al., 2019). [from OMIM]