Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (MMA-MUT deficiency) is a rare inherited metabolic disorder that falls under the broader category of organic acidemias. It is characterized by the body's inability to properly break down specific proteins and fats, leading to the accumulation of methylmalonic acid in the blood and tissues.
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of MMA-MUT deficiency include:
- Enzyme Deficiency: MMA-MUT deficiency is caused by mutations in the MMUT gene, leading to a deficiency of the enzyme methylmalonyl-CoA mutase. This enzyme is essential for breaking certain amino acids and fatty acids.
- Accumulation of Methylmalonic Acid: Due to enzyme deficiency, methylmalonic acid, a toxic substance that can affect various organs and systems in the body, accumulates.
- Neurological Symptoms: MMA-MUT deficiency often presents with neurological symptoms, including developmental delays, intellectual disability, seizures, and muscle weakness.
- Metabolic Decompensation: Individuals with MMA-MUT deficiency are at risk of metabolic decompensation, particularly during illness, fasting, or stress. This can lead to episodes of severe metabolic imbalance.
- Failure to Thrive: Infants with MMA-MUT deficiency may experience failure to thrive, feeding difficulties, and poor weight gain.
- Vomiting and Dehydration: Episodes of vomiting, dehydration, and metabolic acidosis may occur during metabolic crises.
- Enlarged Liver: Hepatomegaly (enlarged liver) may be present due to the accumulation of substances that the body cannot process.
- Maple Syrup Odor: Some individuals with MMA-MUT deficiency may have a distinctive maple syrup odor in their sweat and urine, similar to other organic acidemias.
Management of MMA-MUT deficiency involves dietary restrictions and supplementation to address the metabolic imbalance. Treatment may include:
- Low-Protein Diet: Individuals with MMA-MUT deficiency are often placed on a low-protein diet to limit the intake of amino acids that cannot be properly metabolized.
- Cobalamin (Vitamin B12) Supplementation: Some individuals with MMA-MUT deficiency may benefit from vitamin B12 supplementation.
- Emergency Measures: During episodes of metabolic decompensation, emergency measures may be needed to correct acidosis and prevent organ damage.
MMA-MUT deficiency is a lifelong condition, and management requires close monitoring by healthcare professionals. Genetic counseling is crucial for affected individuals and their families to understand the inheritance pattern and assess the risk of having affected children. Early diagnosis and intervention are essential for optimizing outcomes and preventing metabolic crises.
More Information
Methylmalonic acidemia (MMA) is a genetically heterogeneous group of disorders caused by alterations in different genes that metabolize specific amino acids, lipids, and cholesterol. These disorders are classified into two types: isolated MMA and combined MMA.
Isolated MMA is caused by deficiencies in the enzyme methylmalonyl-CoA mutase (mut), in the transport or synthesis of its cofactors (cblA, cblB, cblD-MMA, cblH), or by a deficiency of the enzyme methylmalonyl-CoA epimerase.
Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency is the most common cause of isolated MMA. The mut enzyme, produced by the MMUT gene, is located in the mitochondria, which is involved in the catabolic pathway of the Krebs cycle. Depending on the mutation, there may be a complete (mut0 subtype) or partial (mut- subtype) deficiency of the enzyme activity.
Two pathogenic variants have been described in MMUT, which are frequent in the Japanese and African-American populations (c.349G>T and c.2150G>T, respectively).
More than 100 mutations have been reported in the MMUT gene with autosomal recessive inheritance.
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency genetic testing analyzes the 25 most frequent pathogenic mutations of the MMUT gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
