Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 1293018007; ORPHA: 308425;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
2p13.3 | Methylmalonyl-CoA epimerase deficiency | 251120 | Autosomal recessive | 3 | MCEE | 608419 |
A number sign (#) is used with this entry because of evidence that methylmalonyl-CoA epimerase deficiency is caused by homozygous or compound heterozygous mutation in the MCEE gene (608419) on chromosome 2p13.
Methylmalonic aciduria III, previously thought to be distinct from the other forms and to be due to deficiency of methylmalonyl CoA racemase, is shown not to be distinct by complementation studies. Montgomery et al. (1983) concluded that deficiency of MM-CoA racemase need not result in symptomatic methylmalonic aciduria.
Bikker et al. (2006) presented a 16-year-old female patient with persisting moderate methylmalonic aciduria. She was born to consanguineous Caucasian parents originating from the northwest part of the Netherlands. At the age of 2 years, retarded motor development and signs of spasticity were seen. Selective screening for metabolic disease revealed moderate methylmalonic aciduria. Methylmalonic acid in cerebrospinal fluid was moderately increased. Treatment involved reduction of dietary protein, which resulted in significant lowering of urinary methylmalonic acid; however, no clinical effects were observed and the patient's motor function showed a gradual deterioration leading to dystonia. Analysis of pterins and aromatic neurotransmitter metabolites in cerebrospinal fluid at the age of 14 years suggested a defect in sepiapterin reductase (182125), which was subsequently confirmed (Abeling et al., 2006). Abeling et al. (2006) pointed out a rapid and favorable response on treatment with L-DOPA.
Dobson et al. (2006) reported a 12-year-old Caucasian female with methylmalonyl-CoA epimerase deficiency who had been assigned to the cblA complementation group (251100) on the basis of weak recovery of [(14)C]-propionate incorporation in complementation studies with members of the cblA group. She had failure to thrive and severe gastroesophageal reflux in infancy. At 13.5 months she presented with severe metabolic acidosis, dehydration, and tachypnea, requiring admission to intensive care following a 2-day history of intermittent vomiting and diarrhea. Urine organic acids indicated severe ketonuria and elevated methylmalonic and methylcitric acid, diagnostic of methylmalonic aciduria. Dobson et al. (2006) found that an older sister of the proband was also affected. Other than hydrocephalus diagnosed in the first year of life, she had been completely asymptomatic in terms of methylmalonic aciduria. She successfully self-regulated protein intake. Her growth and development were normal except for macrocephaly due to hydrocephalus.
Waters et al. (2016) reported a patient who presented with vomiting, dehydration, confusion, and hallucinations at 5 years of age. Laboratory testing showed severe metabolic acidosis, mild hyperammonemia, elevated creatine kinase, and ketosis. Urine and CSF organic acids showed elevated methylmalonate, methylcitrate, and 3-hydroxypropionate. After recovery from the acute episode, the patient was treated with carnitine and a low protein diet (which was eventually normalized), and she had no further metabolic decompensations. However, during a fever at 9 years of age, she had transient diplopia. Urine organic acid testing when she was well demonstrated elevated methylmalonate and milder elevations in methylcitrate and 3-hydroxypropionate compared to the acute state.
In a patient with methylmalonic aciduria and retarded development with spasticity, Bikker et al. (2006) found a homozygous mutation in the methylmalonyl-CoA epimerase gene (R47X; 608419.0001). A mutation in the gene encoding sepiapterin reductase (SPR) was also found (182125.0005); deficiency of SPR was shown to result in dystonia as a prominent symptom by Bonafe et al. (2001). The deficiency of methylmalonyl-CoA epimerase in the patient fully explained the in vitro biochemical findings that comprised a decreased propionate incorporation into macromolecules in cultured fibroblasts and a fully normal activity of methylmalonyl-CoA mutase in the same cells. As the patient of Bikker et al. (2006) did not seem to be more severely affected than the patient of Bonafe et al. (2001), Bikker et al. (2006) suggested that isolated methylmalonyl-CoA epimerase deficiency may not have a large clinical impact or could even be considered a nondisease.
Dobson et al. (2006) reported a patient with mild methylmalonic aciduria who was homozygous for the R47X mutation.
In a patient with methylmalonyl-CoA epimerase deficiency, Waters et al. (2016) identified compound heterozygous mutations in the MCEE gene: the R47X mutation and a novel intronic splice site mutation (c.379-644A-G; 608419.0002). The mother was heterozygous for the splice site mutation; the father was unavailable for study and was presumed to carry the R47X mutation. Studies in patient fibroblasts demonstrated reduced propionate incorporation, which was corrected with cellular complementation with fibroblasts from patients in the mut, cblA, and cblB complementation classes, but not with fibroblasts from a patient in the MCEE complementation class.
Kang et al. (1972) described a single infant with methylmalonic aciduria due to deficiency of methylmalonyl-CoA racemase. Bikker et al. (2006) stated that this was later shown to be a case of mutase deficiency (251000).
Abeling, N. G., Duran, M., Bakker, H. D., Stroomer, L., Thony, B., Blau, N., Booij, J., Poll-The, B. T. Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Molec. Genet. Metab. 89: 116-120, 2006. [PubMed: 16650784] [Full Text: https://doi.org/10.1016/j.ymgme.2006.03.010]
Bikker, H., Bakker, H. D., Abeling, N. G. G. M., Poll-The, B. T., Kleijer, W. J., Rosenblatt, D. S., Waterham, H. R., Wanders, R. J. A., Duran, M. A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria. Hum. Mutat. 27: 640-643, 2006. [PubMed: 16752391] [Full Text: https://doi.org/10.1002/humu.20373]
Bonafe, L., Thony, B., Penzien, J. M., Czarnecki, B., Blau, N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am. J. Hum. Genet. 69: 269-277, 2001. [PubMed: 11443547] [Full Text: https://doi.org/10.1086/321970]
Dobson, C. M., Gradinger, A., Longo, N., Wu, X., Leclerc, D., Lerner-Ellis, J., Lemieux, M., Belair, C., Watkins, D., Rosenblatt, D. S., Gravel, R. A. Homozygous nonsense mutations in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria. Molec. Genet. Metab. 88: 327-333, 2006. [PubMed: 16697227] [Full Text: https://doi.org/10.1016/j.ymgme.2006.03.009]
Kang, E. S., Snodgrass, P. J., Gerald, P. S. Methylmalonyl-CoA racemase defect: another cause of methylmalonic aciduria. (Abstract) Pediat. Res. 6: 393 only, 1972.
Montgomery, J. A., Mamer, O. A., Scriver, C. R. Metabolism of methylmalonic acid in rats: Is methylmalonyl-coenzyme A racemase deficiency symptomatic in man? J. Clin. Invest. 72: 1937-1947, 1983. [PubMed: 6643681] [Full Text: https://doi.org/10.1172/JCI111158]
Waters, P. J., Thuriot, F., Clarke, J. T., Gravel, S., Watkins, D., Rosenblatt, D. S., Levesque, S. Methylmalonyl-CoA epimerase deficiency: a new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene. Molec. Genet. Metab. Rep. 9: 19-24, 2016. [PubMed: 27699154] [Full Text: https://doi.org/10.1016/j.ymgmr.2016.09.001]