Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by the body's inability to process certain amino acids, leading to a buildup of these amino acids and their toxic byproducts. There are different types of MSUD, and type 1B refers specifically to a form of the condition caused by a deficiency of the enzyme dihydrolipoyl dehydrogenase (DLD). This disease affects the metabolism of the amino acids leucine, isoleucine, and valine. It is estimated to affect 1 in 185.000 children worldwide. However, it has a higher incidence in specific populations.
Maple syrup urine disease type 1B 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 Maple Syrup Urine Disease Type 1B include:
- Deficiency of Dihydrolipoyl Dehydrogenase: MSUD type 1B is caused by mutations in the DLD gene, leading to a deficiency of the enzyme dihydrolipoyl dehydrogenase. This enzyme is part of the branched-chain alpha-keto acid dehydrogenase complex, which breaks the branched-chain amino acids (leucine, isoleucine, and valine).
- Accumulation of Amino Acids: Due to enzyme deficiency, branched-chain amino acids accumulate in the blood and tissues, leading to toxicity. These amino acids and their keto acids can harm the nervous system.
- Neurological Symptoms: Elevated levels of branched-chain amino acids can affect the central nervous system, leading to neurological symptoms. These may include intellectual disability, developmental delays, seizures, and other neurological abnormalities.
- Maple Syrup Odor: The characteristic maple syrup odor is often noted in the urine, earwax, and sweat of affected individuals, giving the disorder its name.
- Feeding Difficulties: Infants with MSUD type 1B may experience feeding difficulties and fail to thrive.
- Medical Emergencies: Without proper management, individuals with MSUD type 1B are at risk of metabolic decompensation, which can result in acute episodes of severe neurological impairment, coma, and even death.
Management of Maple Syrup Urine Disease Type 1B involves dietary restrictions to limit the intake of branched-chain amino acids. This typically includes a specialized formula with reduced leucine, isoleucine, and valine levels. Monitoring and adjusting the dietary protein intake is essential to prevent metabolic decompensation.
Additionally, individuals with MSUD type 1B may require close medical supervision, regular blood testing, and ongoing monitoring of growth and development. The goal of treatment is to maintain appropriate levels of branched-chain amino acids in the blood to prevent neurological complications.
Genetic counseling is essential for affected individuals and their families to understand the inheritance pattern and the risk of having affected children.
More Information
MSUD is an autosomal recessive disease caused by mutations in the genes that produce the subunits of the branched-chain keto acid dehydrogenase complex or BCKDC. The complex has four subunits: E1a, E1b, E2 and E3, which are encoded by the BCKDHA, BCKDHB, DBT and DLD genes, respectively. Most cases are due to pathogenic variants in the BCKDHA (45%), BCKDHB (35%) and DBT (20%) genes.
BCKAC gene variations cause the accumulation of branched-chain amino acids, especially leucine, and their alpha-ketoacids.
The c.1312T>A variant in the E1a subunit prevents its correct assembly, leading to degradation and loss of BCKDC activity. The c.1312T>A mutation can also be found in some patients in compound heterozygosis and is typical of Swiss Mennonites.
The most frequent pathogenic variant in the Ashkenazi Jewish population is c.548G>C (BCKDHB gene), with a prevalence of 1 in 113 persons.
Maple syrup urine disease type 1B genetic testing analyzes the 12 most frequent pathogenic mutations of the BCKDHA gene, the 12 most frequent pathogenic mutations of the BCKDHB gene, and the 6 most frequent pathogenic mutations of the DBT 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).
