Isovaleric acidaemia

The clinical spectrum of classic isovaleric acidaemia is broad and ranges from severe neonatal-onset disease to attenuated, largely asymptomatic phenotypes. Affected individuals not identified through newborn screening typically present within the first two weeks of life, after a short symptom-free interval, with feeding refusal, recurrent vomiting, progressive weight loss, generalised hypotonia, abnormal posturing and movements, and a distinctive odour of sweaty feet.

Acute metabolic decompensations are life-threatening episodes triggered by fasting, febrile illness (especially gastroenteritis), or increased protein intake and may also manifest later in life.

Additional features include epilepsy, developmental delay, intellectual disability or impaired cognition, and movement disorders. Untreated individuals can progress to cerebral oedema, intracranial haemorrhage, coma, and death; neonatal mortality during initial decompensation is approximately 30%.

Inter-individual variability of presentation is wide, and outcomes depend strongly on timely diagnosis through newborn screening and prompt initiation of treatment.

The estimated prevalence is 1/100,000.

Isovaleric acidaemia is caused by biallelic germline pathogenic variants in IVD (15q15.1), which encodes the mitochondrial enzyme isovaleryl-CoA dehydrogenase. Reduced enzyme activity leads to accumulation of isovaleryl-CoA and its downstream metabolites in affected tissues. The underlying molecular mechanism is loss of function.

Isovaleric acidaemia is inherited in an autosomal recessive manner. The recurrence risk for siblings of an affected individual is 25%. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis is established biochemically through analysis of the acylcarnitine profile and urinary organic acids. Elevated C5-carnitine on tandem mass spectrometry, together with isovalerylglycine and 3-hydroxyisovaleric acid on urinary organic-acid analysis by gas chromatography-mass spectrometry, supports the diagnosis. Confirmation is provided by identification of biallelic pathogenic variants in IVD on molecular genetic testing.

Main differential diagnoses include:

• Isolated methylmalonic acidaemia: metabolic acidosis with hyperammonaemia, methylmalonic acid in urine, propionylcarnitine on acylcarnitine analysis, cardiomyopathy, kidney failure and pancreatitis; MCEE, MMAA, MMAB, MMADHC, MMUT
• : metabolic acidosis with hyperammonaemia, 3-hydroxy-propionic acid and 2-methylcitrate in urine, propionylcarnitine on acylcarnitine analysis, cardiomyopathy and kidney failure; PCCA, PCCB
• Multiple acyl-CoA dehydrogenase deficiency (MADD; glutaric aciduria II): elevated C5-carnitine on newborn screening with metabolic acidosis and hypoglycaemia, muscular hypotonia and weakness, liver dysfunction, cardiomyopathy; ETFA, ETFB, ETFDH

• Establishing the molecular genetic diagnosis enables aetiological clarification and ends the diagnostic odyssey for affected individuals and their families.
• The molecular diagnosis is a prerequisite for specific and individualised surveillance and clinical management; the concrete measures are determined by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variants are identified, targeted testing of at-risk family members allows clarification of their genetic status and informs reproductive decision-making.

Mütze U, Reischl-Hajiabadi A, Kölker S. Classic isovaleric acidemia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024 [updated 2024 Mar 14]. Available from: . PMID: .