Introduction and background - IVA

Disorders in the pathway of branched-chain amino acids: leucine, isoleucine and valine are referred to as the the organic acidemia’s. Isovaleric academia (IVA) is a rare inborn error of metabolism of branched-chain amino acids, caused by a deficiency in leucine degradation due to a deficiency of isovaleryl-CaA dehydrogenase. This can result in elevated, toxic concentrations of isovaleric acid and its derived metabolites in blood and urine of the patient, potentially causing an overwhelming illness. Isovaleric acid has the odor of ‘sweaty feet’, which can be prominent during catabolic episodes.

Clinical severity of IVA can vary between asymptomatic findings after a positive screen after New Born screening (NBS) up to acute overwhelming illness in the neonatal period if not detected in NBS that can become life-threatening^1,2. In IVA this translates in the need to rapidly reduce toxic metabolites by a restriction of dietary leucine, through restriction of natural protein and prevention of catabolism during intercurrent illness or fasting. Emergency management is a key part of dietary management, aiming for promotion of anabolism, including a high energy diet and transient lowering of natural protein intake and prevention of accumulation of toxic metabolites by enhancing alternative metabolic pathways, for which eg Carnitine is commonly used for this purpose in many of the organic acidemias.

Incidence of IVA ranges widely; from approximately 1:62.500 in Germany, as opposed to the US, with an incidence of 1:250.000 life births³.

Allthough IVA is known for more than 40 years, data on management are retrospective and scarce.

Since the neonatal onset of IVA will start in the first week of life, mortality and morbidity are dependent of the execution of the NBS. The outcome of IVA can vary between normal development and neurocognitive outcome up to severe mental retardation, which is less common.

References

E-IMD – isovaleric Aciduria: http://www.e-imd.org/en/healthcare-professionals/individual-conditions/organic-acidurias/iva/index.phtml
Dixon MD, MacDonald A, White F, Stafford J. Disorders of Amino Acid Metabolism, Organic Acidemias and Urea Cycle disorders. In: Clinical Paediatric Dietetics. 4^th ed: West Sussex: John Wiley & Sons Limited, 2014:381-525.
Ensenauer R, et al. Newborn screening for isovaleric acidemia using tandem mass spectrometry: data from 1.6 million newborns. Clin Chem. 2011;57(4):623–6.

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