Branched Chain Amino Acid Metabolism and Maple Syrup Urine Disease
Metabolic Pathway of Branched Chain Amino Acids (Leucine, Isoleucine, and Valine)
Transamination of Branched Chain Amino Acid
- The first step in the catabolism of branched-chain amino acids including leucine, isoleucine, and valine
- Catalyzed by an enzyme branched-chain amino acid aminotransferase
- Conversion of branched-chain amino acids to respective branched-chain keto acids
- The amino group is transferred to alpha-ketoglutarate to form glutamate
Decarboxylation of Branched Chain Keto Acids
- Catalyzed by enzyme branch chain keto acid dehydrogenase complex (BCKDC)
- BCKDC consists of four different subunits E1-α, E1-β, E2 & E3
- E1- α2β2 tetramer is a thiamine pyrophosphate dependent decarboxylase encoded by BCKDHA & BCKDHB
- E2 is dihydrolipoamide branched-chain transacylase encoded by DBT
- E3 is a flavoprotein dihydrolipoamide dehydrogenase encoded by DLD
Multiple enzyme-catalyzed Steps to form Propionyl CoA, Acetyl CoA, and Acetoacetate
- Subsequent Degradative Pathway of valine results in the formation of propionyl CoA
- Subsequent Degradative Pathway of Isoleucine results in the formation of propionyl CoA and acetyl CoA
- Subsequent Degradative Pathway of leucine results in the formation of acetoacetate and acetyl CoA
Figure- Metabolic Pathway of Leucine, Isoleucine, and Valine
Maple Syrup Urine Disorder
Prevalence- MSUD is a rare Genetic Disorder of leucine, isoleucine, and valine catabolic pathway
- Incidence of 1 in 250,000 live births
- Incidence of 1 in 250,000 live births
- The disease is characterized by the presence of sweet-smelling urine with an order similar to that of maple syrup
Inheritance Pattern
Autosomal Recessive
Biochemical Basis
- Deficiency of enzyme branched-chain alpha-keto acid dehydrogenase (BCKDC) complex
- Several forms of the disease occur based on the gene affected and the severity of the mutation
- BCKDC consists of four subunits designated as E1-α, E1-β, E2 & E3
- Deficiency of enzyme branched-chain alpha-keto acid dehydrogenase (BCKDC) complex
- Several forms of the disease occur based on the gene affected and the severity of the mutation
- BCKDC consists of four subunits designated as E1-α, E1-β, E2 & E3
- Mutation of any of these subunits may result in defective catabolism of leucine, isoleucine, and valine
- Increased branched-chain amino acids in plasma, and keto-acids in blood, CSF & urine
Pathological Manifestation
- Infants with MSUD seem normal at birth but within a week, develop lethargy, vomiting, lack of appetite, and signed of failure of thrive
- Infants with MSUD seem normal at birth but within a week, develop lethargy, vomiting, lack of appetite, and signed of failure of thrive
- Neurological manifestation includes severe mental retardation, seizer, acidosis, and hypoglycemia.
- The intermediate form is also reported and has less severe symptoms.
Diagnosis
Screening test
Screening test
- Guthrie Test: B. substilis Inhibition test- use of bacteria to measure the presence of high leucine in a sample.
- 4-azaleucine is used as an inhibitor for bacterial synthesis of leucine,
- bacteria have restricted growth in absence of high leucine in the sample.
Confirmatory Diagnosis
Confirmatory Diagnosis
- Confirmed by Mutation analysis of the BCKDHA, BCKDHB & DBT gene using sequencing analysis
Other laboratory features
Other laboratory features
- Elevated plasma concentration of branched-chain amino acids and alloisoleucine
- Urinary branched-chain keto acids
Treatment
Diet
Diet
- Leucine restricted diet