Isovaleric Acidemia

1. DEFINITION AND ETIOLOGY

Definition: An autosomal recessive organic acidemia caused by a defect in the catabolism of Leucine.
Enzyme Defect: Deficiency of Isovaleryl-CoA Dehydrogenase.
Gene: IVD gene.
Epidemiology: Prevalence ranges from 1:62,500 to 1:250,000.

Metabolic Block: Inability to convert Isovaleryl-CoA to 3-Methylcrotonyl-CoA in the leucine degradation pathway.
Accumulation: Accumulation of isovaleric acid and its toxic metabolites:
- Isovalerylcarnitine (Diagnostic marker in blood).
- Isovalerylglycine (Non-toxic conjugate excreted in urine).
- 3-Hydroxyisovaleric acid.
Consequences:
- Toxic metabolites cause encephalopathy and bone marrow suppression.
- Secondary carnitine deficiency due to urinary loss of isovalerylcarnitine.
- Secondary hyperammonemia (inhibition of urea cycle).

The clinical presentation is highly variable, ranging from severe neonatal illness to asymptomatic adults.

Onset: First few days of life.
Symptoms: Poor feeding, vomiting, lethargy progressing to coma.
Odor: Characteristic "Sweaty Feet" or "Rancid Cheese" odor (due to isovaleric acid).
Neurologic: Hypotonia, seizures, cerebral edema.
Systemic: Dehydration, sepsis-like picture (often misdiagnosed as sepsis).

Onset: Infancy or childhood (months to years).
Triggers: Catabolic stress (URTI, infection), high-protein intake, fasting.
Episodes: Recurrent episodes of vomiting, lethargy, acidosis, and coma (often mistaken for DKA).
Complications:
- Acute Pancreatitis: Recurrent episodes are a known complication.
- Hematologic: Neutropenia, thrombocytopenia, or pancytopenia (bone marrow suppression).
- Failure to thrive and developmental delay (if recurrent decompensations occur).

General Labs:
- Metabolic Acidosis: High anion gap (ketosis present).
- Hyperammonemia: Moderate to severe.
- Hematology: Neutropenia, thrombocytopenia, pancytopenia.
- Metabolites: Hypoglycemia, hypocalcemia.
Specific Diagnostic Tests:
- Urine Organic Acids: Massive elevation of Isovalerylglycine (hallmark) and 3-hydroxyisovaleric acid.
- Plasma Acylcarnitine Profile: Elevated C5-carnitine (Isovalerylcarnitine). Used in Newborn Screening (NBS).
- Confirmation: Molecular analysis of IVD gene or enzyme assay in fibroblasts.

Goal: Stop catabolism and remove toxic metabolites.
General: Stop protein intake (for <24 hours), aggressive IV hydration with 10% Dextrose (to reverse catabolism).
Detoxification:
- L-Carnitine: High dose (100 mg/kg/day). Conjugates isovaleric acid to isovalerylcarnitine (non-toxic, renally excreted).
- Glycine: Supplementation (250 mg/kg/day) to enhance formation of isovalerylglycine (efficient urinary excretion).
- Ammonia Scavengers: Sodium benzoate/phenylacetate if severe hyperammonemia is present.
- Hemodialysis: If conservative measures fail or in severe coma/hyperammonemia.

Diet:
- Protein restriction (titrated to age-appropriate requirements) to limit leucine load.
- High-calorie diet to prevent catabolism.
- Medical foods free of leucine.
Medication:
- L-Carnitine: Chronic supplementation (50-100 mg/kg/day).
- Glycine: Optional adjunctive therapy.
Monitoring: Growth, development, and nutritional status (avoid malnutrition from over-restriction).

Good Outcome: With early diagnosis (Newborn Screening) and strict compliance, normal neurocognitive development is achievable.
Mortality: High in untreated severe neonatal coma.
Asymptomatic Cases: Some individuals (and siblings of patients) with the biochemical defect remain asymptomatic throughout life ("mild" mutation status).