Combined Malonic And Methylmalonic Aciduria

A number sign (#) is used with this entry because combined malonic and methylmalonic aciduria (CMAMMA) is caused by homozygous or compound heterozygous mutation in the ACSF3 gene (614245) on chromosome 16q24.

Clinical Features

Ozand et al. (1994) reported 2 sibs with CMAMMA but normal malonyl-CoA decarboxylase activity (see 248360).

Gregg et al. (1998) reported a patient with combined malonic and methylmalonic aciduria who excreted much larger amounts of methylmalonic acid (MMA) than malonic acid (MA). He had normal malonyl-CoA decarboxylase activity. The patient, 6 years old at the time of the report, was born at 34 weeks' gestation to nonconsanguineous parents. At 2 months he was hospitalized for diarrhea, vomiting, and dehydration and had recurrent similar episodes throughout the first year, necessitating placement of a gastric tube for failure to thrive. He had apnea and pneumonia at 2 months of age; he had episodes of tachypnea at 2 years. He was hospitalized for clonic seizures at age 2, at which time a routine urine organic acid analysis revealed CMAMMA.

Sloan et al. (2011) studied 9 patients with CMAMMA, 6 of whom were evaluated at the United States National Institutes of Health (NIH). Age at evaluation ranged from 16 months to 66 years. Four patients had adult onset with neurologic manifestations, including seizures, memory problems, psychiatric disease, and/or cognitive decline, without vitamin B12 deficiency. Five subjects presented during childhood with symptoms suggestive of an intermediary metabolic disorder (coma, ketoacidosis, hypoglycemia, failure to thrive, elevated transaminases, microcephaly, dystonia, axial hypotonia, and/or developmental delay). Methylmalonic and malonic aciduria with urinary MMA/MA ratio greater than 5 was present in 7 of the 9 subjects. The characteristic pattern of biochemical and genetic testing results in these subjects showed elevated serum MMA but normal serum B12, acylcarnitines, total homocysteine, malonyl-CoA decarboxylase activity, 1-C14-propionate incorporation, malonyl-CoA decarboxylase genetic testing, and sequencing of known methylmalonic acidemia genes. Plasma malonic acid levels were markedly elevated in 6 subjects in whom it was measured, ranging from 2- to greater than 10-fold increases.

Population Genetics

Based on the frequency of mutations in ACSF3 in the ClinSeq cohort followed at NIH and the 1000 Genomes Project, Sloan et al. (2011) estimated a disease incidence of about 1 in 30,000 with 95% confidence intervals of 1 in 9,000 to 1 in 92,000, and predicted that ACSF3 deficiency is one of the most common forms of methylmalonic acidemia.

Clinical Management

Gregg et al. (1998) compared the effect on MA and MMA excretion of 4 different isocaloric diets (high carbohydrate, fat, protein, or medium-chain triglyceride) provided serially each for 3 days. Their data demonstrated that patients with CMAMMA and normal enzyme activity may best be treated with a diet high in carbohydrates and that these patients should avoid diets with a high protein content.

Molecular Genetics

In 8 of 9 patients with CMAMMA, Sloan et al. (2011) identified mutations in the ACSF3 gene in homozygosity or compound heterozygosity, including 9 missense mutations, 1 in-frame deletion, and 1 nonsense mutation (see, e.g., 614245.0001-614245.0009). Four subjects were homozygous for their variants. Most of the variants resided in the C-terminal portion of ACSF3. Fibroblasts from subjects 1 through 4 produced 2.4- to 6-fold more MMA than control cells after chemical stimulation. Viral expression of ACSF3 but not GFP restored metabolism and provided validation of ACSF3 function in a cell culture biochemical assay.

Animal Model

Podell et al. (1996) identified a 12-week-old female Labrador retriever dog with signs of progressive diffuse degeneration of the brain and spinal cord who was found to have methylmalonic and malonic aciduria. Over a 5-month period the dog developed neurologic signs compatible with disease of the central nervous system with predominant diffuse cerebral and right lateralizing brainstem deficits. Gross pathologic examination of the brain showed that the lateral, third, and fourth ventricles of the brain were markedly enlarged and associated with white and gray matter atrophy. Syringomyelia and hydromyelia of the central canal into the dorsal funiculus of the spinal cord beginning at the level of the cervical intumescence and extending to the lumbar intumescence was also present. The dog had significant biochemical abnormalities including methylmalonic and malonic aciduria and mild lactic and pyruvic aciduria. There was also accumulation of citric acid cycle intermediates including succinic, aconitic, and fumaric acids. There was increased excretion of adipic, ethylmalonic, suberic, and sebacic acids. Ketoacidosis and hyperammonemia were not present, and serum cobalamin levels were normal.

Sloan et al. (2011) found a homozygous gly430-to-ser mutation in the Labrador retriever reported by Podell et al. (1996). Canine gly430 is orthologous to human gly480.