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Methylmalonic acidemia with homocystinuria

Synonym(s) Combined defect in adenosylcobalamin and methylcobalamin synthesis
Methylmalonic aciduria with homocystinuria
Prevalence Unknown
Inheritance Autosomal recessive
or X-linked recessive
Age of onset All ages
  • E71.1
  • C1848561
  • C537359
MedDRA -


Disease definition

Methylmalonic acidemia with homocystinuria is an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures. There are four complementation classes of cobalamin defects (cblC, cblD, cblF and cb1J) that are responsible for methylmalonic acidemia - homocystinuria (methylmalonic acidemia - homocystinuria cblC, cblD cblF and cblJ; see these terms).


Annual incidence in the USA, based on the California newborn screening program, has been estimated at 1/67,000 (for the cblC form). cblC is the most frequent type (over 550 cases). To date, rare cases of cblD (6 cases), cblF (15 cases) and cblJ (3 cases) have been reported.

Clinical description

Onset of the disorder can be between early infancy to adulthood. Patients with methylmalonic acidemia with homocystinuria of all types can present with developmental delay, signs of megaloblastic anemia (pallor, fatigue, and anorexia), lethargy and seizures. In addition, patients with cblC present with acute neurological deterioration, retinal deterioration, microcephaly and severe brain abnormalities including hydrocephalus, white matter abnormalities and unusual basal ganglia lesions. Patients with cblD present with severe learning difficulties, behavioral problems and movement and gait abnormalities and patients with cblF and cblJ present with feeding difficulties, hypotonia, stomatitis, mild facial dysmorphism, cardiac malformations, and skin rashes. Patients who become symptomatic beyond infancy may present with ataxia, dementia or psychosis.


Methylmalonic acidemia - homocystinuria is caused by anomalies in the synthesis of both adenosylcobalamin (AdoCbl) and of methylcobalamin (MeCbl) resulting from genetic defects in the cbl complementation classes C, D, F and J. CblC is caused by mutations in the MMACHC gene (1p36.3), cblD by mutations in the MMADHC gene (2q23.2), cblF by mutations in the LMBRD1 gene (6q13) and cblJ by mutations in the ABCD4 gene.

Diagnostic methods

Measurement of organic acids and amino acids, in particular evidence of increased total plasma homocysteine (tHcy), is suggestive of the disease. Diagnosis is confirmed by complementation analysis of cultured patient fibroblasts or by identification of mutations in the MMACHC, MMADHC, LMBRD1 or ABCD4 genes.

Differential diagnosis

Differential diagnoses include acquired vitamin B12 deficiency, vitamin B12-responsive methylmalonic aciduria, and homocystinuria without methylmalonic aciduria (see these terms). The combination of methylmalonic aciduria, homocystinuria and normal serum cobalamin concentrations is required to distinguish patients.

Antenatal diagnosis

Antenatal diagnosis is possible by measurement of methylmalonate and homocysteine in amniotic fluid and maternal urine at mid-trimester and by studies of cobalamin metabolism in cultured amniotic fluid cells. Molecular diagnosis is possible when the affected gene and the mutation(s) segregating in the family are known. Prenatal therapy (treating the mother with hydroxycobalamin during pregnancy) has been reported in two cases with apparent success.

Genetic counseling

All four forms of the disorder are transmitted in an autosomal recessive manner. Genetic counseling should be provided to affected families.

Management and treatment

Patients are treated with intramuscular injections of hydroxycobalamin, oral betaine, and folic acid. Good metabolic control and correction of hematologic problems can sometimes be achieved with this treatment but most patients continue to have signs of motor and language delay, intellectual deficit and abnormal ophthalmologic findings. Early diagnosis and treatment are important.


Prognosis is better in patients with later-onset disease.

Expert reviewer(s)

  • Dr David WATKINS

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