Methylmalonic Aciduria, Cblb Type

A number sign (#) is used with this entry because methylmalonic aciduria (MMA) of the cblB complementation type is caused by homozygous or compound heterozygous mutation in the MMAB gene (607568) on chromosome 12q24. MMAB encodes cob(I)alamin transferase, which is involved in the synthesis of adenosylcobalamin (AdoCbl), a coenzyme for methylmalonyl-CoA mutase (MUT; 609058).

Description

Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Different forms of isolated methylmalonic aciduria have been classified according to complementation groups of cells in vitro. Patients with defects in the synthesis of AdoCbl are usually responsive to vitamin B12 therapy and are classified as 'cbl' type: these include cblB and cblA (251100). The cblA type is caused by mutation in the MMAA gene (607481). The 'mut' type (251000) is caused by mutation in the MUT gene; in general, the mut form of MMA is unresponsive to vitamin B12 therapy.

Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (277400), cblD (277410), and cblF (277380).

Clinical Features

Fenton and Rosenberg (1981) reported deficiency of cob(I)alamin transferase in the cblB type of methylmalonic acidemia.

Dobson et al. (2002) reported the clinical features of 6 patients with the cblB type, confirmed by molecular analysis. Age at onset was in the first days of life with lethargy, vomiting, failure to thrive, respiratory distress, metabolic acidosis, methymalonic aciduria, neutropenia, thrombocytopenia, and moderate hyperammonemia. AdoCbl levels as a percentage of total Cbl ranged from 0.8 to 6.5%, although 1 patient had 13.1% (control value 15%). Propionate uptake, indicating MUT activity, was also decreased; however, addition of B12 to the medium did not significantly increase enzyme activity. The findings indicated that patients with cblB are less responsive to vitamin B12 therapy than those with cblA.

Jorge-Finnigan et al. (2010) reported 4 patients, including 2 sibs, with MMA type cblB. Two unrelated patients had onset as neonates with vastly different outcomes: 1 had severe encephalopathy at age 7 years, whereas the other was asymptomatic at age 12 years. Of the 2 sibs, 1 had late onset at age 4 years and died at age 4 years, whereas the younger sib was diagnosed at age 3 months and was asymptomatic at age 5 years. The patients who did well clinically were under protein restriction, had B12 supplementation, and were monitored and managed during metabolic crises.

Brasil et al. (2015) reported 2 asymptomatic sibs with MMA type cblB who were identified by newborn screening. By flow cytometry, Brasil et al. (2015) found increased levels of reactive oxygen species (ROS) in cells derived from the sibs, as well as in cells derived from the sibs reported by Jorge-Finnigan et al. (2010), with higher levels in the sib who died compared to the living sib. Patient fibroblasts also showed decreased oxygen consumption rate and mitochondrial abnormalities, including marked fission, reduced numbers of mitochondria, smaller mitochondria, lack of cristae, rarefaction of the matrix, and grain-like inclusions. The findings implicated mitochondrial dysfunction in the pathogenesis of this disorder.

Inheritance

The transmission pattern of MMA type cblB in the families reported by Brasil et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

Dobson et al. (2002) analyzed fibroblast cell lines from 6 cblB patients and identified 6 mutations in the MMAB gene (see, e.g., 607568.0001). One of the patients had been reported by Fenton and Rosenberg (1981).

In 4 patients, including 2 sibs, with MMA type cblB, Jorge-Finnigan et al. (2010) identified 5 different mutations in the MMAB gene (607568.0004-607568.0008). Two of the mutations were missense and demonstrated in vitro to have decreased stability and decreased enzymatic activity compared to wildtype; the 3 other mutations were demonstrated to cause splice site defects in patient cells.

In 2 sibs with MMA type cblB, Brasil et al. (2015) identified compound heterozygous mutations in the MMAB gene (607568.0009-607568.0010). The patient were asymptomatic and identified through newborn screening.