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Homocystinuria without methylmalonic aciduria
Homocystinuria without methylmalonic aciduria is an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, encephalopathy and, sometimes, developmental delay, and associated with homocystinuria and hyperhomocysteinemia. There are three types of homocystinuria without methylmalonic aciduria; cblE, cblG and cblD-variant 1 (cblDv1).
ORPHA:622Classification level: Disorder
Prevalence is unknown. To date, about 30 cases of cblE, about 38 cases of cblG, and 5 cases of cblDv1 have been reported.
Homocystinuria without methylmalonic aciduria manifests mainly in early childhood with failure to thrive, megaloblastic anemia, developmental delay, hypotonia, seizures and cerebral atrophy with white matter abnormalities. Some patients may have an acute expression in the first few months of life, with vomiting, poor feeding and lethargy. Patients develop homocystinuria, hyperhomocysteinemia and, sometimes, hypomethioninemia. A mild clinical phenotype and late-onset disease in the absence of neurological involvement have also been described for the cblE disorder. Presentation in adulthood with ataxia, dementia or psychosis has been observed in cblG.
These disorders are caused by a functional deficiency of the cytoplasmic enzyme methionine synthase (MS), which catalyzes remethylation of homocysteine to form methionine. cblG is caused by mutations of the MTR gene (1q43), which encodes MS, while cblE is caused by mutations of the MTRR gene (5p15.3-15.2), which encodes methionine synthase reductase, an accessory protein required to maintain MS-bound cobalamin in its active form. The cblDv1 disorder results in decreased provision of the cobalamin coenzyme required for MS activity.
Diagnosis is based on evidence of increased levels of homocystine in urine, and homocysteine or homocystine in plasma, and presence of megaloblastic anemia. Plasma methionine is frequently low. Genetic complementation analysis or identification of mutations in the MTR, MTRR or MMADHC genes can confirm the diagnosis.
Differential diagnosis includes multiple sclerosis, particularly for cblG. The forms of homocystinuria without methylmalonic aciduria can be distinguished on the basis of complementation analysis in cultured cells. In contrast to patients with classical homocystinuria due to cystathionine synthase deficiency, methionine is not elevated.
Prenatal diagnosis is possible by identification of elevated homocysteine in amniotic fluid or by biochemical studies of cultured amniocytes. Mutation analysis is possible when the disease causing mutations have been identified in the index case. Treatment of the mother of an affected fetus with cobalamin during pregnancy has been carried out, and appears to have been successful in preventing development of disease.
All three types of methylcobalamin deficiency are inherited in an autosomal recessive manner.
Management and treatment
Treatment is based on daily intramuscular injections of 1 mg hydroxycobalamin (OHCbl), tapering the frequency of injections over time to one dose, one to three times a week. A few patients with cblG have required additional treatment with folates and betaine.
With treatment, biochemical parameters rapidly normalize and clinical symptoms of hypotonia, lethargy and impaired responsiveness improve within 24-48 hours. Hematologic parameters also improve. The improvement in psychomotor status is slow and often incomplete.
- Summary information
- Polski (2012, PDF)