Alternative titles; symbols
ORPHA: 28, 79310; DO: 0060742;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q31.21 | Methylmalonic aciduria, vitamin B12-responsive, cblA type | 251100 | Autosomal recessive | 3 | MMAA | 607481 |
A number sign (#) is used with this entry because methylmalonic aciduria of the cblA complementation type (MACA) is caused by homozygous or compound heterozygous mutation in the MMAA gene (607481) on chromosome 4q31. MMAA 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 cblA and cblB (251110), which is caused by mutation in the MMAB gene (607568) on 12q24. See also cblH (277410), which may be a subset of cblA. The 'mut' form of MMA (251000) is caused by mutation in the MUT gene on chromosome 6p. 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), cblF (277380), and cblJ (614857).
Rosenberg et al. (1968, 1968) described an 8-month-old boy with profound metabolic acidosis, developmental retardation, and an unusual biochemical triad: methylmalonic aciduria, long chain ketonuria, and intermittent hyperglycinemia. Valine, isoleucine, or high protein intake accentuated the biochemical abnormalities. The authors presented indirect evidence of deficient activity of methylmalonyl-CoA isomerase (mutase), but unlike other cases of methylmalonic aciduria, the patient responded to vitamin B12 administration. Rosenberg et al. (1969) suggested that the primary defect in B12-responsive methymalonic aciduria was impaired ability to synthesize the coenzyme AdoCbl.
Mahoney et al. (1975) identified 4 forms of methylmalonic aciduria as defined by ability to synthesize AdoCbl: patients with deficiency of the mutase apoenzyme retained the ability to synthesize both AdoCbl and MeCbl ('mut'); a second group had a deficiency in synthesis of both AdoCbl and MeCbl ('cblC'); a third had isolated AdoCbl deficiency which was corrected in a broken cell extract ('cblA'); and a fourth had isolated AdoCbl deficiency which persisted in a broken cell extract ('cblB'). Mahoney et al. (1975) concluded that the final 2-steps of AdoCbl synthesis, reduction of cob(II)alamin and subsequent adenosylation to form AdoCbl, occurred in the mitochondria, and postulated that a defect in entry to the mitochondrion may explain the cblA form that showed restitution of AdoCbl synthesis in broken cell extracts.
Gravel et al. (1975) confirmed the genetic heterogeneity of mut, cblA, cblB, and cblC. In vitro complementation studies measuring C14 incorporation into propionate showed that each of the mutants failed to incorporate C14 alone, whereas heterokaryons produced by fusing members of each of the 4 mutant classes with any other class produced results comparable to controls.
Matsui et al. (1983) collected detailed information on 45 patients with MMA: 15 with mut(0) type, 5 with mut(-), 14 with cblA, and 11 with cblB. The most common presenting symptoms at onset were lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and hypotonia. Other common features included hepatomegaly, developmental delay, and coma. Mut(0) patients presented earlier in infancy than the 3 other groups. All patients had methylmalonic acidemia and normal serum cobalamin, and most had metabolic acidosis, ketonuria, hyperammonemia, and hyperglycinemia. Approximately half of all the patients had pancytopenia. Most cblA and nearly half of cblB patients showed a decrease in urine and blood concentrations of methylmalonic acid in response to vitamin B12 supplementation, whereas none of the mut(0) or mut(-) responded. Most cblA, cblB, and mut(-) patients were still living at the time of the report; most mut(0) patients died during the first few months of life.
Dobson et al. (2002) confirmed the cblA phenotype by molecular analysis in 4 patients with MMA. Age at symptomatic onset was 2 days to 7 months. Clinical features included lethargy, vomiting, poor feeding, and cbl-responsive MMA. One patient had seizures and another had generalized fine tremors. After incubation with cobalamin, AdoCbl increased to 5 to 7.5% of total Cbl as compared to normal levels of about 10%. Methylmalonic mutase activity also increased, as evidenced by C14-propionate uptake.
Matmat et al. (2022) provided a systematic review of ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism from a literature review of 52 studies reporting 163 cbl and 24 mut patients. Ocular manifestations were identified in all cbl defects except for cblB and cblD-MMA; cblC was the most frequent disorder, affecting 137 patients (84%).
Prenatal Diagnosis
By culture of amniotic cells, Ampola et al. (1975) performed prenatal diagnosis of MMA due to deficient synthesis of AdoCbl. Methylmalonic acid was elevated in the amniotic fluid and maternal urine. Treatment with vitamin B12 lowered the levels in blood and urine of the mother and newborn child. The infant was developing normally on a restricted diet.
In cell lines from 5 patients with MMA cblA, Dobson et al. (2002) identified 4 mutations in the MMAA gene (607481.0001-607481.0004).
Ampola, M. G., Mahoney, M. J., Nakamura, E., Tanaka, K. Prenatal therapy of a patient with vitamin-B12 responsive methylmalonic acidemia. New Eng. J. Med. 293: 313-317, 1975. [PubMed: 239344] [Full Text: https://doi.org/10.1056/NEJM197508142930701]
Dobson, C. M., Wai, T., Leclerc, D., Wilson, A., Wu, X., Dore, C., Hudson, T., Rosenblatt, D. S., Gravel, R. A. Identification of the gene responsible for the cblA complementation group of vitamin B(12)-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements. Proc. Nat. Acad. Sci. 99: 15554-15559, 2002. [PubMed: 12438653] [Full Text: https://doi.org/10.1073/pnas.242614799]
Gravel, R. A., Mahoney, M. J., Ruddle, F. H., Rosenberg, L. E. Genetic complementation in heterokaryons of human fibroblasts defective in cobalamin metabolism. Proc. Nat. Acad. Sci. 72: 3181-3185, 1975. [PubMed: 1059104] [Full Text: https://doi.org/10.1073/pnas.72.8.3181]
Mahoney, M. J., Hart, A. C., Steen, V. D., Rosenberg, L. E. Methylmalonicacidemia: biochemical heterogeneity in defects of 5-prime-deoxyadenosylcobalamin synthesis. Proc. Nat. Acad. Sci. 72: 2799-2803, 1975. [PubMed: 1058495] [Full Text: https://doi.org/10.1073/pnas.72.7.2799]
Matmat, K., Gueant-Rodriguez, R. M., Oussalah, A., Wiedemann-Fode, A., Dionisi-Vici, C., Coelho, D., Gueant, J. L., Conart, J. B. Ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism: a systematic review. Hum. Genet. 141: 1239-1251, 2022. [PubMed: 34652574] [Full Text: https://doi.org/10.1007/s00439-021-02350-8]
Matsui, S. M., Mahoney, M. J., Rosenberg, L. E. The natural history of the inherited methylmalonic acidemias. New Eng. J. Med. 308: 857-861, 1983. [PubMed: 6132336] [Full Text: https://doi.org/10.1056/NEJM198304143081501]
Rosenberg, L. E., Lilljeqvist, A. C., Hsia, Y. E., Rosenbloom, F. M. Vitamin B12 dependent methylmalonic-aciduria: defective B12 metabolism in cultured fibroblasts. Biochem. Biophys. Res. Commun. 37: 607-614, 1969. [PubMed: 5353892] [Full Text: https://doi.org/10.1016/0006-291x(69)90853-5]
Rosenberg, L. E., Lilljeqvist, A. C., Hsia, Y. E. Methylmalonic aciduria: an inborn error leading to metabolic acidosis, long-chain ketonuria and hyperglycinemia. New Eng. J. Med. 278: 1319-1322, 1968. [PubMed: 5648598] [Full Text: https://doi.org/10.1056/NEJM196806132782404]
Rosenberg, L. E., Lilljeqvist, A. C., Hsia, Y. E. Methylmalonic aciduria: metabolic block localization and vitamin B12 dependency. Science 162: 805-807, 1968. [PubMed: 5686220] [Full Text: https://doi.org/10.1126/science.162.3855.805]
Wilcken, B., Kilham, H. A., Faull, K. Methylmalonic aciduria--a variant form of methylmalonyl coenzyme A apomutase deficiency. J. Pediat. 91: 428-430, 1977. [PubMed: 19569] [Full Text: https://doi.org/10.1016/s0022-3476(77)81313-9]