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.

Combined malonic and methylmalonic aciduria (CMAMMA) is a rare recessive inborn error of metabolism characterized by elevations of urine malonic acid (MA) and methylmalonic acid (MMA). MMA excretion is higher than MA in CMAMMA patients, unlike patients with malonyl-CoA decarboxylase deficiency (248360) in whom the biochemical abnormalities include elevated MA alone or combined elevations of MA and MMA with MA mainly being higher than MMA. The clinical significance of CMAMMA is controversial. Initially, CMAMMA patients were ascertained during investigation of children with symptoms suggestive of a metabolic disorder or adults with neurologic manifestations (Sloan et al., 2011). Levtova et al. (2019) described CMAMMA patients identified by neonatal screening who had a favorable clinical course.

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.

Alfares et al. (2011) described 2 probands with CMAMMA identified through the Quebec, Canada, newborn urine screening program. Patient 1 was a 14-year-old boy born to Ashkenazi Jewish parents, and patient 2 was a 4-year-old girl born to first-cousin French Canadian parents. Both patients were born at term, were clinically asymptomatic, had normal cardiac examinations, and had age-appropriate development. Patient 2 had a similarly affected 2-year-old brother. Both probands demonstrated elevated urine methylmalonic acid and urine malonic acid. Plasma methylmalonic acid was elevated as well. No other organic acid abnormalities were detected. Carnitine levels, acylcarnitine profiles, plasma amino acids, blood gas values, folate, and vitamin B12 were all within reference ranges. MMA levels were not responsive to protein restriction or vitamin B12 supplementation, and those treatments were not instituted.

Levtova et al. (2019) questioned the clinical significance of CMAMMA due to ACSF3 deficiency. They identified 25 CMAMMA patients, aged 6 months to 30 years, with a favorable outcome regardless of treatment. All but 1 patient came to clinical attention through the Quebec Provincial Neonatal Urine Screening Program, which uses urine-soaked filter paper collected at 3 weeks of age. Median urine methylmalonic acid levels ranged from 107 to 857 mmol/mol creatinine (normal less than 10) and median urine malonic acid ranged from 9 to 280 mmol/mol creatinine (normal less than 5) with MMA consistently higher than MA. Patient 20 was the only patient with a history of severe metabolic acidosis following an episode of bloody diarrhea causing dehydration at 4 weeks of age. Her subsequent clinical course was benign. Given the absence of any consistent pattern of overt clinical symptoms despite follow-up for a total of 297.5 patient years, Levtova et al. (2019) concluded that the favorable clinical course of their patients suggested that CMAMMA is likely a benign condition. The authors allowed that they could not completely exclude the possibility of CMAMMA being associated with manifestations later in life as their oldest patient was 30 years of age and 4 of 9 patients reported by Sloan et al. (2011) were older.

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.

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.

Many of the 25 patients with CMAMMA reported by Levtova et al. (2019) were followed by metabolic teams. Eleven patients (44%) were initially treated with mild protein restriction; for most, the restriction was lifted, relaxed, or discontinued by the patients themselves. Four patients received L-carnitine supplementation, including patient 20 (the only patient to have an episode of metabolic acidosis at age 4 years) who had received L-carnitine continuously. Ten of 25 patients (40%) received cobalamin at some point. Seven were treated with intramuscular hydroxycobalamin; in all cases, the treatment had no clinical or biochemical effect and was discontinued.

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.

In 2 probands with CMAMMA detected through the Quebec, Canada, newborn urine screening program, Alfares et al. (2011) identified homozygous mutations in the ACSF3 gene. Patient 2 and her affected younger brother were found to have an E359K mutation (614245.0003) by exome sequencing. The parents were heterozygous for the mutation. Sequencing of the ACSF3 gene in patient 1 revealed an R471W mutation (614245.0004).

Levtova et al. (2019) performed ACFS3 sequencing in 19 of 25 patients with CMAMMA. The most common mutations were E359K (614245.0003) and R558W (614245.0001), representing 38.2% and 20.6% of alleles in genotyped families. All mutations were missense except for a splice site mutation (c.1239+2T-G; 614245.0010) in 2 patients, representing 2/50 alleles, and 3 frameshift mutations. All genotyped patients carried at least 1 missense mutation.

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.