Methylmalonic Aciduria Due To Methylmalonyl-Coa Mutase Deficiency

A number sign (#) is used with this entry because methylmalonic aciduria (MMA) of the complementation group 'mut' is caused by mutation in the gene encoding methylmalonyl-CoA mutase (MUT; 609058).


Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Isolated methylmalonic aciduria is found in patients with mutations in the MUT gene causing partial, mut(-), or complete, mut(0), enzyme deficiency. This form is unresponsive to B12 therapy. Various forms of isolated methylmalonic aciduria also occur in a subset of patients with defects in the synthesis of the MUT coenzyme adenosylcobalamin (AdoCbl) and are classified according to complementation group: cblA (251100), caused by mutation in the MMAA gene (607481) on chromosome 4q31, and cblB (251110), caused by mutation in the MMAB gene (607568) on 12q24.

Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (277400), cblD (277410), and cblF (277380).

See the comprehensive review of Ledley (1990).

Clinical Features

The clinical spectrum of methylmalonic aciduria is wide, ranging from a benign condition (Ledley et al., 1984) to fatal neonatal disease (Matsui et al., 1983).

Oberholzer et al. (1967) reported an inborn error of metabolism characterized by methylmalonic aciduria associated with developmental retardation and chronic metabolic acidosis. Treatment with cobalamin was ineffective. Barness and Morrow (1968) noted that some cases of methylmalonic aciduria responded to vitamin B12. Of those not responsive to B12, only a subset had hyperglycinemia. Morrow et al. (1969) provided enzymatic proof of 2 forms of the disease with regard to response to cobalamin treatment: methylmalonyl-CoA mutase activity was essentially absent from the liver in a vitamin B12-unresponsive case, whereas residual enzyme activity increased to normal with added coenzyme in a vitamin B12-responsive case. The latter case was interpreted as having a defect in AdoCbl synthesis.

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.

Willard and Rosenberg (1977) found that the mutase enzyme in cells from some MMA patients showed decreased affinity for AdoCbl with abnormally high Km for the coenzyme. These cases were considered to represent a structurally abnormal enzyme and were characteristic of the mut(-) phenotype. By immunohistochemical analysis of the mutase enzyme, Kolhouse et al. (1981) found that cell lines from mut(-) patients had detectable crossreacting material (CRM) ranging from 20 to 100% of control, whereas cells from mut(0) patients had CRM ranging from no detectable protein to 40% of 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.

Shevell et al. (1993) compared the clinical features in 11 mut(0) patients with those in 9 mut(-) patients. All 11 mut(0) patients had an early neonatal presentation; 6 of these patients died in infancy and 3 of 5 survivors had a poor neurologic outcome as evidenced by severe developmental delay or spastic quadriparesis with dystonia. The 2 other survivors included a 27-month-old child with mild delay in verbal and fine motor skills and an adolescent with low normal intelligence. Of the 9 mut(-) patients, 7 became symptomatic in late infancy or childhood and 2 were found on screening. No episode of metabolic decompensation had occurred in 2 of the 9, yet both were neurologically compromised, one being severely retarded and autistic and the other mildly delayed. Four mut(-) patients had had episodic acidosis and were neurologically moderately affected, while 3 had had episodic acidosis but were neurologically intact. Although a broad correlation was found between mutase class and phenotype, survival with good outcome was possible among mut(0) patients and, conversely, significant morbidity occurred among mut(-) patients. Acidosis and metabolic imbalance were not necessary preconditions for significant morbidity. van den Bergh et al. (1992) reported sudden death in a child with MMA.

Giorgio et al. (1976) reported 2 French-Canadian brothers, aged 62 and 70 years, who had a benign form of MMA due to methylmalonyl-CoA mutase deficiency. Neither had anemia or hepatic dysfunction. Serum vitamin B12 was normal and the methylmalonic aciduria was unaffected by administration of vitamin B12 in large dosage. The brothers had presented with adult-onset diabetes mellitus. Ledley et al. (1984) reported a benign form of MMA due to deficiency of methylmalonyl-CoA mutase in 8 children identified through routine neonatal screening or screening of infants with affected sibs. Despite lack of dietary or vitamin therapy, the children had normal growth and development (age range, 18 months to 13 years) and performed as well as their unaffected sibs on psychometric tests. None responded to vitamin B12 treatment and there was no other evidence of a cofactor defect. In 2 sibs, complementation studies showed a defect in the mutase apoenzyme.

Renal insufficiency is frequently reported in mutase-deficient methylmalonic acidemia. Van Calcar et al. (1998) reported a patient with mut(-) MMA who developed chronic tubulointerstitial nephropathy during adolescence. After 24 years of age, she developed end-stage renal failure and underwent renal transplantation. Both plasma and urine methylmalonic acid levels decreased significantly with improved renal function following transplantation. Renal, metabolic, and clinical status remained improved at 3 years after the kidney transplant.

In a review of inherited metabolic disorders and stroke, Testai and Gorelick (2010) noted that patients with branched-chain organic aciduria, including isovaleric aciduria (243500), propionic aciduria (606054), and methylmalonic aciduria can rarely have strokes. Cerebellar hemorrhage has been described in all 3 disorders, and basal ganglia ischemic stroke has been described in propionic aciduria and methylmalonic aciduria. These events may occur in the absence of metabolic decompensation.

Kruszka et al. (2013) studied renal growth in isolated MMA. Fifty patients with MMA (35 mut subtype, 9 cblA subtype, and 6 cblB subtype), followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple regression analyses. Comparisons with age-matched controls showed that renal length in subjects with MMA was significantly decreased (p less than 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C (604312), and serum methylmalonic acid concentrations best predicted kidney size. Kruszka et al. (2013) concluded that renal length, reflective of kidney growth, significantly decreased in patients with MMA over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population.

Clinical Management

Kaplan et al. (2006) reported the long-term (9 years) outcome for the first patient with severe methylmalonic acidopathy transplanted in the United States and provided new biochemical data that indicated why transplanted patients remain susceptible to 'metabolic strokes.' In their 10-year-old male patient, there was clear evidence that the de novo synthesis of propionyl-CoA within the central nervous system led to brain methylmalonate accumulation that was largely unaffected by transplantation. Kaplan et al. (2006) concluded that liver transplantation is not a cure for methylmalonic acidopathy.


Using 3D organotypic brain cell cultures derived from embryos of a brain-specific Mut -/- mouse, Remacle et al. (2018) investigated mechanisms leading to brain damage in methylmalonic aciduria. The in vitro model was challenged with the catabolic stress of temperature shift. Remacle et al. (2018) found typical metabolites for methylmalonic aciduria as well as a massive ammonia increase in the media of mutant mouse brain cultures. Investigation of pathways involved in intracerebral ammonia production revealed increased expression of glutaminase-2 (GLS2; 606365) and diminished expression of glutamate dehydrogenase-1 (GLUD1; 138130) in Mut -/- aggregates. Astrocytes showed swollen fibers and cell bodies, and oligodendrocytes showed inhibited axonal elongation and delayed myelination. Most effects were even more pronounced after 48 hours at 39 degrees C. Microglia activation and an increased apoptosis rate suggested degeneration of Mut -/- brain cells.

Other Features

Because of improvements in therapy, many patients with MMA reach childbearing age. Wasserstein et al. (1999) reported a successful pregnancy and delivery of a healthy baby to a 20-year-old woman with vitamin B12-unresponsive methylmalonic acidemia complicated by moderate renal insufficiency, chronic pancreatitis, anemia, and optic atrophy. Strict metabolic control was maintained throughout her pregnancy. The patient remained clinically asymptomatic during and after delivery, and her metabolic condition remained stable after discharge except for a slight decline in her renal function.


Wilkemeyer et al. (1991) showed that the mut and cbl forms of MMA can be differentiated not only by somatic cell complementation but also by DNA-mediated gene transfer of a methylmalonyl CoA mutase cDNA clone. Transfer of the MUT clone into mut fibroblasts reconstituted holoenzyme activity, whereas the same process had no effect on cbl fibroblasts.


Abramowicz et al. (1994) studied a newborn female with a mut(0) form of MMA and complete absence of insulin-producing beta cells in otherwise normal-appearing pancreatic islets, causing insulin-dependent diabetes mellitus (IDDM; 222100). The patient died 2 weeks after birth. Serotyping of the HLA antigens, DNA typing of HLA-B and HLA class II loci, study of polymorphic DNA markers of chromosome 6, and cytogenetic analysis demonstrated paternal uniparental isodisomy, involving at least a 25-cM portion of chromosome 6 that encompasses the major histocompatibility complex. Duplication of the mutated allele on chromosome 6 inherited from the father was thought to be responsible for methylmalonic acidemia. It was also considered likely that isodisomy was etiologically related to the agenesis of beta cells, and the authors postulated the existence of a gene on chromosome 6 involved in beta-cell differentiation.

Molecular Genetics

In a patient with MMA mut(0), defined as having no residual enzyme activity, Jansen and Ledley (1990) identified compound heterozygosity for 2 mutations in the MUT gene (609058.0001 and 609058.0002).

In a patient with MMA mut(-), defined as having some residual enzyme activity, who had been reported by Ledley et al. (1990), Crane et al. (1992) identified a homozygous mutation in the MUT gene (609058.0005).

Acquaviva et al. (2001) reported a novel MUT missense mutation (609058.0010) in 5 unrelated families of French and Turkish descent from a population of 19 patients with MCM apoenzyme deficiency. All the patients exhibited a severe mut(0) methylmalonic acidemia phenotype, and 3 of them were homozygous for the mutation. The findings represented the first frequent MUT mutation reported in the Caucasian population.

Champattanachai et al. (2003) reported 2 novel mutations in a Thai patient with mut(0) methylmalonic acidemia.


Hoffman (1991) recounted the story of Patricia Stallings who was sentenced to life in prison for the presumed murder of her infant son with ethylene glycol, an ingredient of antifreeze. While in prison, the woman gave birth to a second son, who was found to have methylmalonic acidemia. William Sly and James Shoemaker at St. Louis University performed analyses of the first son's blood and did not detect ethylene glycol; Piero Rinaldo at Yale University demonstrated the biochemical features of methylmalonic acidemia and found no evidence of ethylene glycol in the body fluids. All charges against Patricia Stallings were dropped. Shoemaker et al. (1992) determined that the gas chromatographic peak that had been identified as ethylene glycol by a clinical laboratory was actually due to propionic acid. Woolf et al. (1992) noted that the opposite situation could occur: intentional infantile ethylene glycol poisoning being misinterpreted as an inborn error of metabolism leading to recurrent infantile metabolic acidosis.