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1. Defects of Branched Chain Amino Acid Metabolism and Urea Cycle Disorders Consultant Level Presentation By Hemant Kumar

2. Introduction Amino acid metabolism is essential for energy production, nitrogen balance, and biosynthesis of biomolecules. Defects in these metabolic pathways lead to accumulation of toxic intermediates and metabolic disorders. Two key categories: • Disorders of branched-chain amino acid metabolism (e.g., Maple Syrup Urine Disease). • Disorders of urea cycle (e.g., Ornithine transcarbamylase deficiency).

3. Branched Chain Amino Acids (BCAAs) Include Leucine, Isoleucine, and Valine. Metabolized primarily in skeletal muscle. Key enzymes: Branched-chain aminotransferase and Branched-chain α-ketoacid dehydrogenase (BCKDH). Provide energy during stress and fasting.

4. Maple Syrup Urine Disease (MSUD) – Overview Autosomal recessive disorder due to deficiency of BCKDH complex. Leads to accumulation of branched-chain amino acids and their ketoacids. Characteristic maple syrup odor in urine. Incidence: ~1 in 185,000 live births globally.

5. MSUD – Pathophysiology Deficiency of BCKDH prevents oxidative decarboxylation of branched-chain α-ketoacids. Results in elevated levels of leucine, isoleucine, and valine. Neurotoxicity due to leucine accumulation. Metabolic acidosis and encephalopathy occur in severe cases.

6. MSUD – Clinical Features Poor feeding, vomiting, lethargy within first week of life. Maple syrup odor in urine and cerumen. Seizures, hypotonia, coma if untreated. Chronic cases may present with developmental delay.

7. MSUD – Diagnosis Plasma amino acid analysis: Elevated leucine, isoleucine, valine. Urine organic acid profile: Increased branched-chain ketoacids. Newborn screening: Tandem mass spectrometry. Genetic testing confirms BCKDHA, BCKDHB, or DBT gene mutations.

8. MSUD – Management Dietary restriction of branched-chain amino acids. Thiamine supplementation in responsive variants. Acute crisis: Dialysis, IV glucose, and insulin to suppress catabolism. Liver transplantation offers potential cure.

9. Urea Cycle – Overview Urea cycle detoxifies ammonia into urea in the liver. Key enzymes: CPS1, OTC, ASS1, ASL, and ARG1. Occurs in mitochondria and cytoplasm. Defects lead to hyperammonemia and neurotoxicity.

10. Urea Cycle Disorders – Classification Carbamoyl phosphate synthetase I deficiency (CPS1D). Ornithine transcarbamylase deficiency (OTCD). Argininosuccinate synthetase deficiency (Citrullinemia type I). Argininosuccinate lyase deficiency. Arginase deficiency.

11. Ornithine Transcarbamylase Deficiency (OTCD) Most common urea cycle disorder. X-linked recessive inheritance. Defect in conversion of carbamoyl phosphate + ornithine → citrulline. Leads to hyperammonemia and orotic aciduria.

12. OTC Deficiency – Clinical Features Vomiting, poor feeding, lethargy in neonates. Seizures, cerebral edema due to hyperammonemia. Females may have partial symptoms. Late-onset cases may present with behavioral changes or confusion.

13. OTC Deficiency – Diagnosis and Management Elevated plasma ammonia, low BUN, increased orotic acid in urine. Genetic testing confirms OTC gene mutation. Treatment: Protein restriction, sodium benzoate, phenylbutyrate to remove nitrogen. Arginine supplementation and liver transplantation in severe cases.

14. Flowchart – Amino Acid and Urea Cycle Defects Amino Acids → Transamination → Ketoacids → Energy or Urea Cycle. Defect in BCKDH → Accumulation of BCAAs → MSUD. Defect in Urea Cycle Enzymes → Hyperammonemia → Neurological Damage.

15. Summary and Key Differences MSUD – defect in BCAA degradation → maple syrup odor urine. Urea Cycle Disorders – defect in ammonia detoxification → hyperammonemia. Both lead to neurological dysfunction if untreated. Early diagnosis and dietary management are critical.