Abstract
Isovaleric acidemia (IVA) is an autosomal recessive leucine inborn error of metabolism caused by isovaleryl-CoA dehydrogenase deficiency. The disease has various courses, from severe ones manifesting in newborns to the intermittent form with first manifestation in children and adults. The aim of this study was to analyze clinical and neurological outcomes in Polish patients with IVA. Ten patients diagnosed and treated in The Children’s Memorial Health Institute were included in the study. The diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. A retrospective analysis of patients’ medical records included: demographics, symptoms at diagnosis, medical management, and biochemical and clinical outcomes following therapy. The median follow-up time (median; Q1–Q2) was 2.5 years (1.5–9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0–20) for symptomatic patients. Five patients were in a good clinical state, four children presented mild neurological symptoms, and one—severely delayed child. In the IVD gene, five known and two novel variants (p.466C>G, c.1132G>A) were identified. Molecular analysis was performed in seven patients leading to identification of biallelic pathogenic variants in the IVD gene in all of them. We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. Although early treatment did not prevent decompensations, they were milder in these patients.
Highlights
Isovaleric acidemia (IVA, OMIM: 243500) is an autosomal recessive leucine inborn error of metabolism caused by the deficiency of mitochondrial isovaleryl-CoA dehydrogenase (IVD; EC 1.2.99.10), encoded by the IVD gene
Two children were diagnosed by family screening (FS), and one child was identified through newborn screening (NBS)
Molecular analysis was performed in seven patients leading to detection of biallelic mutations in the IVD gene in all of them (Patients 1, 3, 4, 6, 7, 8, and 10)
Summary
Isovaleric acidemia (IVA, OMIM: 243500) is an autosomal recessive leucine inborn error of metabolism caused by the deficiency of mitochondrial isovaleryl-CoA dehydrogenase (IVD; EC 1.2.99.10), encoded by the IVD gene. It is one of the four “classical” organic acidemias: propionic (PA), methylmalonic (MMA), glutaric (GA), and IVA, with a prevalence 1–9/100,000 [1]. The IVD gene was mapped on chromosome 15q14-q15 [2]. It encodes a homonymous protein, IVD enzyme, which catalyses the third step in leucine catabolism. Isovaleric acid and IVG are potentially neurotoxic [3]
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