Autosomal recessive organic acidemia caused by a defect in leucine catabolism.
Results from the deficiency of the enzyme Isovaleryl-CoA Dehydrogenase (IVD).
Caused by pathogenic variants in the IVD gene located on chromosome 15q15.1.
Estimated prevalence ranges from 1:62,500 to 1:250,000.
Pathophysiology
Failure to convert Isovaleryl-CoA to 3-Methylcrotonyl-CoA in the leucine degradation pathway.
Leads to the accumulation of isovaleric acid and toxic metabolites including Isovalerylcarnitine (C5), Isovalerylglycine, and 3-Hydroxyisovaleric acid.
Toxic metabolites induce severe encephalopathy and bone marrow suppression.
Causes secondary carnitine deficiency via urinary loss of isovalerylcarnitine, and secondary hyperammonemia due to urea cycle inhibition.
Clinical Features
The clinical presentation is highly variable and categorized into three main phenotypic forms.
Clinical Form
Onset
Characteristic Manifestations
Acute Neonatal
First few days of life
Sepsis-like presentation with poor feeding, vomiting, lethargy, and coma. Pathognomonic “Sweaty Feet” or “Rancid Cheese” odor. Severe hypotonia, seizures, and cerebral edema.
Chronic Intermittent
Infancy or childhood
Recurrent episodes of vomiting, lethargy, and ketoacidosis resembling diabetic ketoacidosis. Triggered by catabolic stress (infection, fasting) or high protein intake. Complications include acute pancreatitis, neutropenia, pancytopenia, and failure to thrive.
Asymptomatic
Detected via Newborn Screening (NBS)
Normal clinical phenotype, often associated with a common recurring missense mutation c.932C>T (p.A282V) resulting in partial IVD enzyme activity reduction.
Investigations
Investigation Type
Diagnostic Findings
Routine Screening Labs
High anion gap metabolic acidosis, severe ketosis, and moderate to severe hyperammonemia. Hematologic evaluation shows neutropenia, thrombocytopenia, or pancytopenia. Hypoglycemia and hypocalcemia may be present.
Newborn Screening (NBS)
Tandem Mass Spectrometry (TMS) detects elevated Isovalerylcarnitine (C5-carnitine).
Urine Organic Acids
Massive diagnostic elevation of Isovalerylglycine (hallmark) and 3-hydroxyisovaleric acid.
Confirmatory Tests
Molecular analysis of the IVD gene or specific IVD enzyme assay in cultured fibroblasts.
Management
Acute Decompensation
Dietary Arrest: Immediate cessation of exogenous protein intake for less than 24 hours.
Reversal Of Catabolism: Aggressive intravenous hydration with 10% Dextrose to halt endogenous protein breakdown.
Detoxification Therapy:
High-dose L-Carnitine (100 mg/kg/day) to conjugate toxic isovaleric acid into non-toxic, renally excreted isovalerylcarnitine.
Glycine supplementation (250 mg/kg/day) to enhance the formation and efficient urinary excretion of isovalerylglycine.
Ammonia scavengers (sodium benzoate or phenylacetate) or hemodialysis for severe hyperammonemia or refractory coma.
Chronic Maintenance
Dietary Modification: Leucine-restricted diet titrated to age-appropriate requirements, utilizing leucine-free medical foods.
Supplementation: Chronic L-Carnitine supplementation (50-100 mg/kg/day) to prevent secondary deficiency and optional adjunctive glycine therapy.
Monitoring: Regular assessment of growth and nutritional status to prevent malnutrition secondary to over-restriction.
Prognosis
Early diagnosis via NBS and strict therapeutic compliance yield good outcomes with normal neurocognitive development.
High mortality rate is associated with untreated severe neonatal coma presentations.
