Aspects of Newborn Screening in Isovaleric Acidemia

Abstract

Isovaleric acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). The inclusion of IVA in NBS programs in many countries has broadened knowledge of the variability of the condition, whereas prior to NBS, two distinct clinical phenotypes were known, an "acute neonatal" and a "chronic intermittent" form. An additional biochemically mild and potentially asymptomatic form of IVA and its association with a common missense mutation, c.932C>T (p.A282V), was discovered in subjects identified through NBS. Deficiency of short/branched chain specific acyl-CoA dehydrogenase (2-methylbutyryl-CoA dehydrogenase), a defect of isoleucine degradation whose clinical significance remains unclear, also results in elevated C5-carnitine, and may therefore be detected by NBS for IVA. Treatment strategies for the long-term management of symptomatic IVA comprise the prevention of catabolism, dietary restriction of natural protein or leucine intake, and supplementation with L-carnitine and/or L-glycine. Recommendations on how to counsel and manage individuals with the mild phenotype detected by NBS are required.

Effects of Three-Month Administration of High-Saturated Fat Diet and High-Polyunsaturated Fat Diets with Different Linoleic Acid (LA, C18:2n–6) to α-Linolenic Acid (ALA, C18:3n–3) Ratio on the Mouse Liver Proteome

“…A contrasting result was obtained by Guo et al who showed that mice fed a high fat died had elevated IVD levels in the liver compared to mice fed a normal diet, which was suggested as enhanced branched-chain amino acid (BCAA) degradation in liver mitochondria of mice fed the high-fat diet [ 44 ]. It should be emphasized, however, that IVD downregulation may lead to the accumulation of isovaleryl-CoA derivatives, including isovaleric acid (IVA), and reduced production of acetyl-CoA and acetoacetate [ 45 ]. The consequences of IVA accumulation may be the induction of oxidative stress and protein oxidative damage due to significantly elevated carbonyl formation [ 46 ].…”

Newborn screening and disease variants predict neurological outcome in isovaleric aciduria

“…None of the individuals with mild IVA (N = 67) experienced a metabolic decompensation during the study period, while 17 of 24 (71%) individuals of the classic IVA group had at least one metabolic decompensation, 13 of these (54%) already during the newborn period (EO group, Figure 1) and 11 (46%) before the NBS result was known. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] days; P = .0018; Table 2), with highest frequencies (mean [SD]) during the first year of life (classic 1.7 [1.6]; mild 0.5 [1.1]). The major cause of hospitalization in classic IVA was prevention of (impending) metabolic decompensation (83.5%).…”

Neurocognitive outcome in young child with Isovaleric Acidemia

“…3 Prenatal diagnosis may be accomplished by measuring IVG in amniotic fluid, by enzyme assay in cultured amniocytes, or by identification of the mutant gene. 4 Analysis of available evidence by Dionisi-Vici et al, showed a more than four times higher incidence of IVA in the screened population as compared to clinical diagnosis. 11 Our patient though presented with low GCS but improved with medical treatment.…”

“…3 With evolving technologies, Prenatal diagnosis is also possible for IVA. 4 The pathogenesis of the disease is still not fully understood. This condition is caused by the deficiency of the enzyme isovaleryl CoA dehydrogenase.…”