Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q23.2 | Methylmalonic aciduria, cblD type | 620953 | Autosomal recessive | 3 | MMADHC | 611935 |
A number sign (#) is used with this entry because of evidence that isolated methylmalonic aciduria cblD type (MACD) is caused by homozygous or compound heterozygous mutation in the MMADHC gene (611935) on chromosome 2q23.
Biallelic mutation in the MMADHC gene can also cause homocystinuria-megaloblastic anemia cblD type (HMAD; 620952) and combined methylmalonic aciduria and homocystinuria cblD type (MAHCD; 277410), depending on the location of the mutation within the gene.
Isolated methylmalonic aciduria cblD type (MACD) is an autosomal recessive metabolic disorder of cobalamin (cbl; vitamin B12) metabolism. Affected individuals present in infancy with variable severe clinical features that may include respiratory distress syndrome, intracranial hemorrhage, seizures, and ketotic coma. Biochemical studies show isolated methylmalonic aciduria without homocystinuria. Treatment with B12 may result in improvement of the clinical and biochemical abnormalities, but patients usually have mild residual neurologic abnormalities, including learning disabilities and decreased IQ (Coelho et al., 2008).
Genetic Heterogeneity of Isolated Methylmalonic Aciduria
Isolated methylmalonic acidurias have historically been classified by complementation groups: MMA 'mut' (251000), caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (251100), caused by mutation in the MMAA gene (607481) on 4q31; and MMA cblB (251110), caused by mutation in the MMAB gene (607568) on 12q24. Another form of isolated MMA (613646) is caused by defect in the transcobalamin receptor (CD320; 606475).
Cooper et al. (1990) described a boy, born of unrelated Haitian parents, who presented at 11 months of age with severe ketotic coma, dehydration, hyperammonemia, leukopenia, and thrombocytopenia. Biochemical studies showed isolated methylmalonic aciduria with clinical and biochemical features similar to that of cblA (251100). Clinical details were limited. Fibroblasts from the patient complemented other cblA fibroblast lines as well as fibroblasts from all other classes of inborn errors resulting in methylmalonic aciduria, suggesting that this patient might represent a novel complementation class. By somatic cell complementation analysis of a fibroblast line from the patient studied by Cooper et al. (1990), Watkins et al. (2000) concluded that this variant cell line represented a new complementation group, which the authors designated 'cblH.' Coelho et al. (2008) subsequently showed that this 'cblH' complementation group belonged to the cblD complementation group.
Suormala et al. (2004) reported a patient (P3), born of unrelated Indian parents, with isolated methylmalonic aciduria and a biochemical phenotype consistent with cblD, which the authors termed 'cblD variant 2.' The patient was born prematurely at 32 weeks' gestation and had severe complications in the neonatal period, including respiratory distress requiring mechanical ventilation, intracranial hemorrhage, necrotizing enterocolitis, and seizures. Urinary methylmalonic acid and methylcitrate were elevated, whereas homocysteine was normal. B12 therapy was beneficial. At age 12 years, the patient had learning disabilities and attended a special school; IQ was 69. In vitro studies of patient cells showed decreased activity of methylmalonyl-CoA mutase and deficient AdoCbl synthesis. Enzyme activity responded to addition of AdoCbl. These cell lines complemented cblA, cblB, and cblC reference cells, but not cblD. The findings of Suormala et al. (2004) indicated that the cblD defect can cause combined or isolated deficiencies in both AdoCbl and MeCbl synthesis, indicating heterogeneity within the cblD class.
The transmission pattern of MACD in the families reported by Cooper et al. (1990) and Suormala et al. (2004) was consistent with autosomal recessive inheritance.
By complementation of cblD patient cells with somatic cell hybrids, Coelho et al. (2008) localized the defect to human chromosome 2. Fine mapping identified a 10.2-Mb regions on 2q22.1-2q23.3 between markers D2S150 and D2S2324.
In an Indian boy (P3 in Suormala et al., 2004) and an unrelated Haitian patient (Cooper et al., 1990) with MACD, Coelho et al. (2008) identified biallelic mutations in the MMADHC gene (611935.0004-611935.0006). The Indian boy was homozygous for a frameshift mutation predicted to result in premature termination at codon 20 (Cys19fsTer20) near the N terminus, thus lacking the mitochondrial leader sequence and resulting in MMA. The Haitian patient was compound heterozygous for a nonsense mutation (R54X) and an in-frame duplication (Leu103_Ser108). Parental DNA was not available for familial segregation studies for either patient. Coelho et al. (2008) speculated that reinitiation of translation could occur at a downstream initiation codon (Met62), producing a shorter semifunctional protein with normal methylcobalamin synthesis and absence of homocystinuria.
Stucki et al. (2012) studied the effect of various MMADHC constructs on protein function in cell lines. For example, mutant alleles associated with the cblD-homocystinuria (HC) phenotype were unable to rescue MeCbl synthesis, whereas mutant alleles associated with the cblD-methylmalonic aciduria (MMA) phenotype could restore MeCbl synthesis. In combined cblD-MMA/HC cells, improving mitochondrial targeting of MMADHC increased the formation of AdoCbl with a concomitant decrease in MeCbl formation. In cblD-MMA cells, this effect was dependent on the mutation and showed a negative correlation with endogenous MMADHC mRNA levels. The findings supported the hypothesis that the MMADHC protein contains various domains for targeting the protein towards the mitochondria, MeCbl synthesis, and AdoCbl synthesis. There is a delicate balance between cytosolic MeCbl and mitochondrial AdoCbl synthesis, suggesting that the cblD protein is a branch point in intracellular cobalamin trafficking. Detailed data analysis indicated that the sequence after met116 is sufficient for MeCbl synthesis, whereas the additional sequence between met62 and met116 is required for AdoCbl synthesis. The nature and location of mutations within the protein thus determines 1 of the 3 biochemical phenotypes, combined MMA/HC, isolated MMA, or isolated HC.
Coelho, D., Suormala, T., Stucki, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Newbold, R. F., Baumgartner, M. R., Fowler, B. Gene identification for the cblD defect of vitamin B12 metabolism. New Eng. J. Med. 358: 1454-1464, 2008. [PubMed: 18385497] [Full Text: https://doi.org/10.1056/NEJMoa072200]
Cooper, B. A., Rosenblatt, D. S., Watkins, D. Methylmalonic aciduria due to a new defect in adenosylcobalamin accumulation by cells. Am. J. Hemat. 34: 115-120, 1990. [PubMed: 2339678] [Full Text: https://doi.org/10.1002/ajh.2830340207]
Stucki, M., Coelho, D., Suormala, T., Burda, P., Fowler, B., Baumgartner, M. R. Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism. Hum. Molec. Genet. 21: 1410-1418, 2012. [PubMed: 22156578] [Full Text: https://doi.org/10.1093/hmg/ddr579]
Suormala, T., Baumgartner, M. R., Coelho, D., Zavadakova, P., Kozich, V., Koch, H. G., Berghauser, M., Wraith, J. E., Burlina, A., Sewell, A., Herwig, J., Fowler, B. The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J. Biol. Chem. 279: 42742-42749, 2004. [PubMed: 15292234] [Full Text: https://doi.org/10.1074/jbc.M407733200]
Watkins, D., Matiaszuk, N., Rosenblatt, D. S. Complementation studies in the cblA class of inborn error of cobalamin metabolism: evidence for interallelic complementation and for a new complementation class (cblH). J. Med. Genet. 37: 510-513, 2000. [PubMed: 10882753] [Full Text: https://doi.org/10.1136/jmg.37.7.510]