Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia

Abstract

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 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.

Aspects of Newborn Screening in Isovaleric Acidemia

“…It may be assumed that individuals with the mild phenotype identified by NBS may remain asymptomatic throughout their lives [30]. This hypothesis is supported by family studies identifying asymptomatic individuals with biochemical evidence of IVA and genotypes identical to their younger siblings identified by NBS [30] and by the reported increase in the prevalence of organic acidurias in screened cohorts as compared to clinical ascertainment [32,37,48,66,67].…”

“…This trend disappeared after the omission of patients with the "mild" phenotype from the analysis [38]. Cognitive function in a series of 16 Spanish patients was shown to be within the normal range in both patients diagnosed clinically and patients detected by NBS [32]. Overall, neurological sequelae and organ manifestations in IVA have been shown to be less common as compared with other classic organic acidurias [39,71,89].…”

“…The first life-threatening catabolic episode in patients with the acute form usually occurs by the end of the first week of life ("acute neonatal form") [38,39,66]. Depending on the time of NBS sampling and turnaround time, patients with this form may even present clinically before the NBS result is reported [32]. Early symptoms are nonspecific.…”

“…They may become symptomatic within the first days or weeks of life, presenting with poor feeding or vomiting and severe metabolic acidosis accompanied by neurological signs including lethargy, potentially progressing to coma or death [39]. Alternatively, patients may present later in childhood with acute acidotic episodes often triggered by catabolic stress such as intercurrent illness [32,40]. In 1966, IVA was first reported by Tanaka and coworkers [41], who described two siblings of preschool age with recurrent episodes of vomiting and lethargy and an unusual odor of "sweaty feet", in whom a massive urinary excretion of isovalerylglycine and other metabolites of isovaleryl-CoA were detected using gas chromatography (GC) and mass spectrometry (MS) [42].…”

“…More than 60 disease-causing mutations in the IVD gene have been described. The majority are point mutations, but splice site mutations, nonsense mutations, missense mutations, deletions, and insertions have also been described [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33].…”