Alternative titles; symbols
ORPHA: 28, 79311; DO: 0060743;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Methylmalonic aciduria, vitamin B12-responsive, cblB type | 251110 | Autosomal recessive | 3 | MMAB | 607568 |
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).
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).
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, methylmalonic 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: one 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.
Agnarsdottir et al. (2022) reported an Icelandic infant who died before 6 months of age with MMA type cblB. The patient presented with metabolic decompensation 4 hours after birth and showed B12 responsiveness; she was treated with cyanocobalamin throughout life. She experienced 2 additional episodes of metabolic decompensation: at age 3 months, associated with rhinovirus infection, and at age 5 months, associated with norovirus/enterovirus coinfection. Examination at age 3 months showed intermittent tachypnea, hypotonic core muscles with neck lag, and delay in gross motor skills. At age 4 months, feeding became increasingly difficult and her weight fell from the 70th to the 33rd centile over 6 weeks. Although echocardiography in the first week of life had shown a structurally normal heart with good biventricular contractility, echocardiography at 5 months revealed dilated cardiomyopathy (CMD) with severe heart failure. Despite maximum supportive measures, including intubation and continuous renal replacement therapy, cardiac function only marginally improved, and the patient died several days after support was withdrawn. Given the severity of CMD at the time of diagnosis, the authors considered it likely that the onset of cardiomyopathy occurred at an early age in the setting of metabolic stability, suggesting that cardiomyopathy in MMA may be independent of metabolic control.
The transmission pattern of MMA type cblB in the families reported by Brasil et al. (2015) was consistent with autosomal recessive inheritance.
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.
In an Icelandic infant who died with severe heart failure due to CMD and MMA type cblB, Agnarsdottir et al. (2022) performed Sanger sequencing of the MMAB gene and identified homozygosity for the Icelandic founder mutation R191W (607568.0006). Her unaffected parents were heterozygous for the variant, which the authors stated has a frequency of 1 in 270 Icelanders. Analysis of a comprehensive panel of 54 genes associated with organic acidemia/aciduria and cobalamin deficiency was negative, as was whole-genome screening for pathogenic variants in known cardiomyopathy-associated genes.
Forny et al. (2022) identified 33 individual mutations in the MMAB gene in 97 patients with MMA type cblB, including 16 novel mutations. Missense mutations were the most common mutation type, and the most frequent missense mutations were R186W (607568.0001), identified in 57 alleles, and R191W (607568.0006), identified in 19 alleles. Q234X was the most common truncating mutation, identified in 14 alleles. Most of the mutations affected the C-terminal half of the protein, with a hotspot in exon 7. This hotspot, corresponding to residues 173-195, contributes to the binding sites of cobalamin and ATP.
Forny et al. (2022) performed functional studies in fibroblasts from 76 patients with MMA type cblB and found that responsiveness to cobalamin, as measured by a propionate incorporation assay, correlated with clinical response to cobalamin and time of disease onset. The Q234X mutation in the MMAB gene was associated with in vitro cobalamin response and later disease onset, and the R286W (607568.0001) and R191W (607568.0006) mutations demonstrated no cobalamin response and were associated with early disease onset.
Agnarsdottir, D., Sigurjonsdottir, V. K., Emilsdottir, A. R., Petersen, E., Sigfusson, G., Rognvaldsson, I., Franzson, L., Vernon, H., Bjornsson, H. T. Early cardiomyopathy without severe metabolic dysregulation in a patient with cblB-type methylmalonic acidemia. Molec. Genet. Genomic Med. 10: e1971, 2022. [PubMed: 35712814] [Full Text: https://doi.org/10.1002/mgg3.1971]
Brasil, S., Richard, E., Jorge-Finnigan, A., Leal, F., Merinero, B., Banerjee, R., Desviat, L. R., Ugarte, M., Perez, B. Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies. Clin. Genet. 87: 576-581, 2015. [PubMed: 24813872] [Full Text: https://doi.org/10.1111/cge.12426]
Dobson, C. M., Wai, T., Leclerc, D., Kadir, H., Narang, M., Lerner-Ellis, J. P., Hudson, T. J., Rosenblatt, D. S., Gravel, R. A. Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Hum. Molec. Genet. 11: 3361-3369, 2002. [PubMed: 12471062] [Full Text: https://doi.org/10.1093/hmg/11.26.3361]
Fenton, W. A., Rosenberg, L. E. The defect in the cbl B class of human methylmalonic acidemia: deficiency of cob(I)alamin adenosyltransferase activity in extracts of cultured fibroblasts. Biochem. Biophys. Res. Commun. 98: 283-289, 1981. [PubMed: 7213387] [Full Text: https://doi.org/10.1016/0006-291x(81)91900-8]
Forny, P., Plessl, T., Frei, C., Burer, C., Froese, D. S., Baumgartner, M. R. Spectrum and characterization of bi-allelic variants in MMAB causing cblB-type methylmalonic aciduria. Hum. Genet. 141: 1253-1267, 2022. [PubMed: 34796408] [Full Text: https://doi.org/10.1007/s00439-021-02398-6]
Jorge-Finnigan, A., Aguado, C., Sanchez-Alcudia, R., Abia, D., Richard, E., Merinero, B., Gamez, A., Banerjee, R., Desviat, L. R., Ugarte, M., Perez, B. Functional and structural analysis of five mutations identified in methylmalonic aciduria cblB type. Hum. Mutat. 31: 1033-1042, 2010. [PubMed: 20556797] [Full Text: https://doi.org/10.1002/humu.21307]