CblA type methylmalonic aciduria is a form of methylmalonic acidemia, a rare genetic disorder characterized by the inability to break down specific proteins and fats. This condition is part of a group of disorders known as inborn errors of metabolism. Methylmalonic aciduria is often caused by defects in the enzymes or cofactors involved in the metabolism of vitamin B12 (cobalamin).
CblA type methylmalonic aciduria 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).
The key features and aspects of cblA type methylmalonic aciduria include:
- Genetic Basis: CblA type methylmalonic aciduria is one of the subtypes of methylmalonic acidemia. It is caused by mutations in the MMAA gene, which provides instructions for producing a protein involved in processing vitamin B12.
- Vitamin B12 Metabolism: Vitamin B12 is essential for breaking specific amino and fatty acids in the body. In cblA type methylmalonic aciduria, the mutation in the MMAA gene leads to a deficiency in the conversion of methylmalonyl-CoA to succinyl-CoA, accumulating methylmalonic acid in the body.
- Clinical Presentation: Individuals with cblA type methylmalonic aciduria may present with symptoms such as feeding difficulties, failure to thrive, developmental delays, intellectual disability, and neurological symptoms. The severity of symptoms can vary among affected individuals.
- Metabolic Crisis: Methylmalonic acidemia, including cblA type, is associated with the risk of metabolic crises. These crises may be triggered by infections, stress, or periods of fasting and can lead to life-threatening complications.
- Diagnostic Testing: Diagnosis is typically confirmed through biochemical testing, which reveals elevated levels of methylmalonic acid in blood and urine. Genetic testing can identify mutations in the MMAA gene, confirming the specific subtype.
- Treatment: Management of cblA type methylmalonic aciduria involves a combination of dietary measures and medical interventions. Vitamin B12 supplementation may bypass the metabolic block and improve the conversion of methylmalonyl-CoA to succinyl-CoA. Additionally, dietary restrictions may be implemented to limit the intake of specific amino acids.
- Lifelong Management: Individuals with cblA type methylmalonic aciduria require lifelong management to prevent metabolic crises and minimize the impact of the disorder on their health. Regular medical monitoring and follow-up with metabolic specialists are essential components of care.
More Information
CblA type methylmalonic aciduria is a type of methylmalonic acidemia (MMA) responsible for approximately 20% of isolated MMA cases.
The protein encoded by the MMAA gene is involved in the translocation of cobalamin to the mitochondria, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the enzyme methylmalonyl-CoA mutase (mut) activity.
One of the most frequent pathogenic variants in patients with methylmalonic aciduria type cblA is c.433C>T, also called R145X, which consists of the substitution of an arginine amino acid (R) for a termination codon (X), making the protein shorter.
Although the disease follows an autosomal recessive mode of inheritance, cases have been described of patients who were carriers of MMAA variants in compound heterozygosis, i.e. the patient has one copy of a pathogenic variant and another copy of a different pathogenic variant in the same gene.
CblA type methylmalonic aciduria genetic testing analyzes the 8 most frequent pathogenic mutations of the MMAA 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).
