Alternative titles; symbols
ORPHA: 26, 28, 308380, 308442, 622, 79283; DO: 0050716;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q23.2 | Methylmalonic aciduria and homocystinuria, cblD type | 277410 | Autosomal recessive | 3 | MMADHC | 611935 |
A number sign (#) is used with this entry because of evidence that combined methylmalonic aciduria and homocystinuria type cblD (MAHCD) is caused by homozygous mutation in the MMADHC gene (611935) on chromosome 2q23.
Biallelic mutation in the MMADHC gene can also cause homocystinuria-megaloblastic anemia type cblD (HMAD; 620952) or methylmalonic aciduria type cblD (MACD; 620953), depending on the location of the mutation within the gene.
Methylmalonic aciduria (MMA) and homocystinuria type cblD (MAHCD) is an autosomal recessive disorder of cobalamin (cbl; vitamin B12) metabolism. Affected individuals typically present in infancy or early childhood with variable neurologic abnormalities, including developmental delay, encephalopathy, seizures, poor feeding, impaired intellectual development, and nystagmus. Onset of symptoms in the teenage years has also been reported. Most patients also have megaloblastic anemia. Laboratory studies show methylmalonic aciduria and homocystinuria (Coelho et al., 2008).
The metabolic defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570) (Coelho et al., 2008; review by Watkins and Rosenblatt, 2022).
Genetic Heterogeneity of Methylmalonic Aciduria and Homocystinuria
Different forms of combined methylmalonic aciduria and homocystinuria have been classified historically according to complementation groups of cells in vitro: cblC (MAHCC; 277400), cblD, cblF (MAHCF; 277380), cblJ (MAHCJ; 614857), and cblL (MAHCL; 620940).
Goodman et al. (1970) reported 2 brothers, from a consanguineous Spanish-American family, with combined homocystinuria and methylmalonic aciduria. The older boy presented at 14 years of age during an acute psychotic episode. Examination showed moderately impaired intellectual development (IQ of 50), a somewhat marfanoid appearance, and neurologic signs, including horizontal nystagmus increased by lateral gaze, hyperreflexia, and mildly impaired finger to nose movement. Laboratory studies showed methylmalonic aciduria and homocystinuria. After the acute psychotic episode, he remained in good health except for intellectual disability. His 2.5-year-old younger brother had normal physical and neurologic development. Laboratory studies at at 1 year showed methylmalonic aciduria, but no homocystinuria. However, repeat studies at age 2 showed homocystinuria. Plasma B12 was normal in both patients. Complementation studies on cell lines of these patients (Willard et al., 1978) indicated a fifth Cbl complementation group, designated CblD. Patient cells showed an abnormally low cobalamin content and deficient activity of both methylmalonyl-CoA mutase and N5-methyltetrahydrofolate-homocysteine S-methyltransferase, as well as decreased levels of their respective cofactors, adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). There was complementation with cblC, indicating that the 2 groups were genetically distinct. Fenton and Rosenberg (1978) suggested that the defect in cblD may involve cobalamin reductase (602568), which reduces the charge of the cobalt of cobalamin from +3 to +2.
Coelho et al. (2008) reported 2 additional unrelated patients with MAHCD. P6, a Scandinavian girl, presented at 3 months of age with developmental delay, seizures, and megaloblastic anemia. P7, a boy born of consanguineous Italian parents, presented at 22 days of age with poor feeding, encephalopathy, seizures, and increased red cell MCV.
The transmission pattern of MAHCD in the family reported by Goodman et al. (1970) 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 3 unrelated patients with MAHCD, Coelho et al. (2008) identified homozygous mutations in the MMADHC gene: P5 (previously reported by Goodman et al., 1970) was a Spanish-American boy with a homozygous nonsense mutation (R250X; 611935.0007); P6 was a Scandinavian girl with a homozygous frameshift (c.419dupA; 611935.0008); and P7 was an Italian boy with a homozygous splice site mutation resulting in the skipping of exon 7 and an in-frame deletion (611935.0009). All mutations occurred close to the C terminus. In vitro functional expression studies showed that wildtype MMADHC could rescue the biochemical abnormalities of cells carrying these mutations. Additional studies of patient cells were not performed, but all 3 mutations were predicted to result in a defective protein that lacks both functional domains or is subject to nonsense-mediated mRNA decay and a loss of function.
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 (HMAD) phenotype were unable to rescue MeCbl synthesis, whereas mutant alleles associated with the cblD-methylmalonic aciduria (MMAICD) phenotype could restore MeCbl synthesis. In combined cblD-MAHCD 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.
Carmel, R., Bedros, A. A., Mace, J. W., Goodman, S. I. Congenital methylmalonic aciduria-homocystinuria with megaloblastic anemia: observations on response to hydroxycobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test. Blood 55: 570-579, 1980. [PubMed: 7357085]
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]
Fenton, W. A., Rosenberg, L. E. Genetic and biochemical analysis of human cobalamin mutants in cell culture. Annu. Rev. Genet. 12: 223-248, 1978. [PubMed: 371525] [Full Text: https://doi.org/10.1146/annurev.ge.12.120178.001255]
Goodman, S. I., Moe, P. G., Hammond, K. B., Mudd, S. H., Uhlendorf, B. W. Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem. Med. 4: 500-515, 1970. [PubMed: 5524089] [Full Text: https://doi.org/10.1016/0006-2944(70)90080-3]
Mellman, I., Willard, H. F., Rosenberg, L. E. Cobalamin binding and cobalamin-dependent enzyme activity in normal and mutant human fibroblasts. J. Clin. Invest. 62: 952-960, 1978. [PubMed: 30783] [Full Text: https://doi.org/10.1172/JCI109224]
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]
Watkins, D., Rosenblatt, D. S. Inherited defects of cobalamin metabolism. Vitam. Horm. 119: 355-376, 2022. [PubMed: 35337626] [Full Text: https://doi.org/10.1016/bs.vh.2022.01.010]
Willard, H. F., Mellman, I. S., Rosenberg, L. E. Genetic complementation among inherited deficiencies of methylmalonyl-CoA mutase activity: evidence for a new class of human cobalamin mutant. Am. J. Hum. Genet. 30: 1-13, 1978. [PubMed: 23678]