Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia

Isovaleric acidemia (iva) is a rare disorder of leucine metabolism. we carried out a multicenter study of iva patients diagnosed by newborn screening (nbs) or symptoms clinics over a period of 28 years in spain. evaluated at diagnosis, data included age, detection method, levels of c5 and ivg, enzymatic studies, clinical presentation parameters and genotype in 16 patients. follow-up data included c5 levels, intellectual quotient and correlation genotype–phenotype. iva was detected by nbs in 8 patients (prevalence of 1/326 629). except 1, all the 8 patients identified by nbs were asymptomatic at diagnosis and had isovalerylcarnitine (c5) levels of 1.6–6.4 μm and isovalerylglycine (ivg) levels <1100 mmol per mol creatinine; they remained asymptomatic with a natural protein intake ⩾1.5 g kg−1 per day. symptomatic patients with chronic intermittent or acute neonatal iva had c5 levels of 3.9–16.3 μm and ivg levels >3400 mmol per mol creatinine. the percentage of isovalerate incorporation in fibroblasts was 64–80% in patients detected by nbs and 4.9–13% in symptomatic patients. cognitive function was within normal ranges in all patients but was negatively correlated with ivg at detection (−0.592; p<0.05). the genetic analysis revealed nine novel mutations. the clinical/biochemical phenotype correlated fairly well with the phenotype predicted by the mutations found. in conclusion, although blood c5 levels have traditionally been considered the prognostic marker of choice, urine ivg levels would appear to be a better predictor, as they correlated well with severity of mutations and were associated with a lower incorporation rate of iva in fibroblasts and a less favorable clinical course.