Clinical characteristics: Individuals with clinical manifestations of isovaleric acidemia (IVA) have either classic IVA identified on newborn screening or classic IVA with a later diagnosis due to a missed diagnosis or later onset of clinical manifestations. Classic IVA is characterized by acute metabolic decompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet). Acute metabolic decompensations are typically triggered by fasting, (febrile) illness (especially gastroenteritis), or increased protein intake. Clinical deterioration often occurs within hours to days after birth. Additional manifestations of classic IVA include developmental delay, intellectual disability and/or impaired cognition, epilepsy, and movement disorder (tremor, dysmetria, extrapyramidal movements). Early treatment in those identified by newborn screening can significantly reduce morbidity and mortality in individuals with classic IVA.

Diagnosis/testing: The diagnosis of classic IVA is established in a proband by identification of C5-carnitine metabolites by tandem mass spectrometry and isovalerylglycine (IVG) and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry, or identification of biallelic pathogenic variants in IVD by molecular genetic testing.

Management: Targeted therapy: Low-leucine/protein-reduced diet and the supplementation of a leucine-free formula in infants or leucine-free amino acid mixture in older children; carnitine and/or glycine supplementation.

Supportive care: Routine daily treatment includes education of affected individuals and caregivers about the natural history, maintenance and emergency treatment, prognosis, and risks of acute encephalopathic crises; emergency treatment letter and MedicAlert^®; management of movement disorder per neurologist; physical therapy and aggressive rehabilitation therapy for gross motor delay; notify metabolic center prior to planned surgeries; consult metabolic disease specialist with any emergency surgery/procedure.

Emergency outpatient treatment includes carbohydrate supplementation orally or via tube feeding, transient reduction of natural protein intake, elevation of carnitine supplementation, and glycine; antipyretics for fever; antiemetics for vomiting.

Acute inpatient treatment includes stopping protein intake, intravenous glucose, and hydration with normal saline; adjusting treatments for new or evolving neurologic manifestations; consider buffers as needed for life-threatening metabolic acidosis; nitrogen scavengers for hyperammonemia.

Surveillance: Quantitative analysis of plasma amino acids at least every three months until age one year, every six months from age one to six years, and annually in those age six years and older; blood gases, albumin, calcium, phosphate, parathyroid hormone, complete blood count, and vitamin B₁₂ at least annually in those on a protein-restricted diet; measurement of growth and head circumference at each visit throughout childhood; monitor weight throughout adulthood; monitor developmental milestones at each visit; neuropsychological testing and standardized quality-of-life assessments as needed; assessment of movement disorder at each visit.

Agents/circumstances to avoid: Excess of dietary protein or protein malnutrition inducing catabolic state; prolonged fasting; catabolism during illness.

Evaluation of relatives at risk: Biochemical or molecular genetic testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of classic IVA.

Genetic counseling: Classic IVA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an IVD pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the IVD pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.