Methylmalonic acidemia

Clinical features

Methylmalonic acidemia (MMA) is an autosomal recessive disorder of amino acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA. The prevalence of methylmalonic acidemia is estimated between 1:50,000 and 1:100,000 ^{1, 2}. In Japan, the birth prevalence may be as high as 1:50,000 ³.

"Isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that results from a failure to convert methylmalonyl-CoA into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid ¹.

Isolated methylmalonic academia includes following phenotypes:

• Complete or partial deficiency of the enzyme methylmalonyl-CoA mutase
• Defect in transport or synthesis of the methylmalonyl-CoA mutase cofactor, adenosyl-cobalamin
• Deficiency of the enzyme methylmalonyl-CoA epimerase

All phenotypes are characterized by periods of intermittent metabolic decompensation associated with infection or stress, and periods of health.

The major clinical features of MMA in the neonatal period include lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia, resulting in death within the first four weeks of life.

Infantile onset MMA, non-responsive for B12, presents with developing lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age.

An intermediate B12-responsive MMA phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life. Affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake.

Atypical and benign adult onset MMA phenotypes are commonly associated with increased urinary excretion of methylmalonate.

Major secondary complications of methylmalonic acidemia include: intellectual impairment, tubulointerstitial nephritis with progressive renal failure, pancreatitis, growth failure, functional immune impairment, optic nerve atrophy and metabolic stroke, e.g. basal ganglia injury which results in choreoathetosis, dystonia, and para/quadriparesis.

Diagnosis of isolated MMA relies on analysis of organic acids in plasma and/or urine, cellular biochemical studies and molecular genetic testing. In a majority of MMA-affected cases the identification of biallelic pathogenic variants in one of the five genes (MUT, MMAA, MMAB, MCEE, and MMADHC) confirms the clinical diagnosis. Recent genetic research studies have indicated that defects in additional genes may also be associated with methylmalonic acidemia (table).

Therapy for MMA includes restoration of the volume status and acid-base balance and reduction or elimination of protein intake, and frequent monitoring of serum electrolytes and ammonia, venous or arterial blood gases, and urine output. Management includes a high-calorie diet low in propionic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; and antibiotics for treatment of infections. Other therapies include N-carbamylglutamate for the treatment of acute hyperammonemia episodes; liver, kidney, or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy.

CENTOGENE offers full gene sequencing and deletion/duplication analysis for the genes in the Methylmalonic acidemia panel (advanced) (ABCD4, ACSF3, CD320, LMBRD1, MCEE, MLYCD, MMAA, MMAB, MMACHC, MMADHC, MTR, MTRR, MUT, SUCLA2, SUCLG1).

The differential diagnosis of Methylmalonic acidemia-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

• Atypical methylmalonic acidemia
• "Benign" methylmalonic academia
• Combined malonic and methylmalonic aciduria (CMAMMA) caused by ACSF3 deficiency
• Methylmalonate semialdehyde dehydrogenase deficiency (MMSDH)
• Transcobalamin receptor defect (TCblR/CD320)
• Combined methylmalonic acidemia and hyperhomocysteinemia/homocystinuria
• Vitamin B12 deficiency
• Mitochondrial encephalomyopathy with elevated methylmalonic acid.

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for methylmalonic acidemia using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Methylmalonic acidemia panel (advanced). Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Methylmalonic acidemia panel (advanced), we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.

The following individuals are candidates for methylmalonic acidemia testing:

• Individuals with a family history of Methylmalonic acidemia and presentation of the most common symptoms
• Individuals without a positive family history of Methylmalonic acidemia, but with symptoms resembling the disease
• Individuals with a negative but suspected family history of Methylmalonic acidemia, in order to perform proper genetic counseling.

Sequencing, deletion/duplication of the Methylmalonic acidemia panel genes should be performed in all individuals suspected of having Methylmalonic acidemia-related disorders. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the Methylmalonic acidemia and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.

More information on Methylmalonic acidemia panel (advanced) can be found in our genetic test catalogue.