Megaloblastic anemia, folate-responsive

An autosomal recessive metabolic disorder characterized by megaloblastic anemia resulting from decreased folate transport into erythrocytes. Disease manifestations include hemolytic anemia, hyperhomocysteinemia, and low vitamin B12. Serum folate levels are normal, but erythrocyte folate levels are decreased. Treatment with oral folate corrects the anemia and normalizes homocysteine.

Basal ganglia disease, biotin-thiamine responsive

An autosomal recessive metabolic disorder characterized by episodic encephalopathy, often triggered by febrile illness, presenting as confusion, seizures, external ophthalmoplegia, dysphagia, and sometimes coma and death. If untreated, encephalopathies can result in permanent dystonia. Brain imaging may show characteristic bilateral lesions of the basal ganglia.

Microcephaly, Amish type

A disorder characterized by severe congenital microcephaly and severe 2-ketoglutaric aciduria leading to death within the first year.

Megaloblastic anemia due to dihydrofolate reductase deficiency

An inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.

Methylmalonic aciduria and homocystinuria type cblL

An autosomal recessive disorder of cobalamin metabolism clinically characterized by early-onset seizures, and profound global developmental delay with severe intellectual disability. Metabolic features are mild methylmalonic aciduria, low-normal plasma methionine, and high-normal plasma homocysteine.

Hereditary folate malabsorption

Rare autosomal recessive disorder characterized by impaired intestinal folate absorption with folate deficiency resulting in anemia, hypoimmunoglobulinemia with recurrent infections, and recurrent or chronic diarrhea. In many patients, neurological abnormalities such as seizures or intellectual disability become apparent during early childhood, attributed to impaired transport of folates into the central nervous system. When diagnosed early, the disorder can be treated by administration of folate. If untreated, it can be fatal and, if treatment is delayed, the neurological defects can become permanent.

Methylmalonic aciduria and homocystinuria, cblD type

An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinical features include developmental delay, hyotonia, intellectual disability, seizures, and megaloblastic anemia. Laboratory studies show methylmalonic aciduria and homocystinuria.

Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activity

An autosomal recessive inborn error of folate metabolism. Clinical severity is variable, ranging from severe neurologic features to absence of symptoms. Clinical features include homocysteinuria, homocysteinemia, developmental delay, severe intellectual disability, perinatal death, psychiatric disturbances, and later-onset neurodegenerative disorders.

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination

An autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy, and characterized by microcephaly, short stature, severe global developmental delay, progressive spasticity, and epilepsy. Brain imaging shows delayed myelination, hypomyelination, enlarged ventricles, and cerebellar atrophy.

Methylmalonic aciduria and homocystinuria, cblC type

An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood.

Transcobalamin II deficiency

An autosomal recessive disorder manifesting in early infancy and characterized by failure to thrive, megaloblastic anemia, pancytopenia, and agammaglobulinemia. Additional features include methylmalonic aciduria, recurrent infections, vomiting and diarrhea. TCN2D may be accompanied by neurological complications, including psychomotor and mental developmental delay, if untreated.

Methylmalonic aciduria, transient, due to transcobalamin receptor defect

An autosomal recessive metabolic condition characterized by moderate methymalonicaciduria, and normal plasma vitamin B12 levels. Serum homocysteine may be increased in some affected individuals. Most cases are clinically asymptomatic.

Methylmalonic aciduria and homocystinuria type cblJ

A disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinical features include feeding difficulties, poor growth, hypotonia, lethargy, anemia, and developmental delay.

Thiamine-responsive megaloblastic anemia syndrome

An autosomal recessive disease characterized by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Onset is typically between infancy and adolescence, but all of the cardinal findings are often not present initially. The anemia, and sometimes the diabetes, improves with high doses of thiamine. Other more variable features include optic atrophy, congenital heart defects, short stature, and stroke.

Homocystinuria-megaloblastic anemia, cblG type

An autosomal recessive inborn error of metabolism resulting from defects in the cobalamin-dependent pathway that converts homocysteine to methionine. It causes delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia.

Methylmalonic aciduria, cblB type

An autosomal recessive disorder of methylmalonate and cobalamin metabolism due to defective synthesis of adenosylcobalamin.

Hypercarotenemia and vitamin A deficiency, autosomal dominant

A disorder characterized by increased serum beta-carotene, decreased conversion of beta-carotene to vitamin A and decreased serum vitamin A.

Neurodegeneration due to cerebral folate transport deficiency

An autosomal recessive neurodegenerative disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy and leukodystrophy.

Homocystinuria-megaloblastic anemia, cblE type

An autosomal recessive inborn error of metabolism resulting from defects in the cobalamin-dependent pathway that converts homocysteine to methionine. It causes delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia. Cells from patients with HMAE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent.

Methylmalonic aciduria and homocystinuria, cblX type

An X-linked recessive metabolic disorder characterized by severely delayed psychomotor development apparent in infancy, failure to thrive, impaired intellectual development, and intractable epilepsy. Additional features may include microcephaly and choreoathetosis.

Thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type

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.

Imerslund-Grasbeck syndrome 1

A form of Imerslund-Grasbeck syndrome, a rare autosomal recessive disorder characterized by vitamin B12 deficiency commonly resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in infancy or early childhood. Clinical manifestations include failure to thrive, infections and neurological damage. Mild proteinuria, with no signs of kidney disease, is present in about half of the patients.

Hereditary intrinsic factor deficiency

Autosomal recessive disorder characterized by megaloblastic anemia.

Glutamate formiminotransferase deficiency

Autosomal recessive disorder. Features of a severe phenotype, include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and intellectual disability. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematological abnormalities.

Methylmalonic aciduria and homocystinuria, cblF type

An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). It is due to accumulation of free cobalamin in lysosomes, thus hindering its conversion to cofactors. Clinical features include developmental delay, stomatitis, glossitis, seizures and methylmalonic aciduria responsive to vitamin B12.

Imerslund-Grasbeck syndrome 2

A form of Imerslund-Grasbeck syndrome, a rare autosomal recessive disorder characterized by vitamin B12 deficiency commonly resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in infancy or early childhood. Clinical manifestations include failure to thrive, infections and neurological damage. Mild proteinuria, with no signs of kidney disease, is present in about half of the patients.