title: 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-1per 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.
authors.affiliation: Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Service of Neonatology, Department of Pediatrics, Hospital Clínico Universitario de Santiago, Health Research Institute of Santiago de Compostela (IDIS), CIBERER, Santiago de Compostela, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Couce
authors.affiliation: Unit of Metabolism, Department of Pediatrics, Hospital de Cruces, Group of Metabolism, Biocruces Health Research Institute, Barakaldo, Spain.
authors.forename: Luís
authors.initials: L
authors.lastname: Aldamiz-Echevarría
authors.affiliation: Metabolic Disorders, Dietetics and Nutrition Unit, Virgen del Rocío University Hospital, Sevilla, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Bueno
authors.affiliation: Pediatric Gastroenterology, Hospital San Pedro de Alcantara, Cáceres, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Barros
authors.affiliation: Nutrition and Metabolic Unit, Service of Pediatrics, Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: Amaya
authors.initials: A
authors.lastname: Belanger-Quintana
authors.affiliation: Gastroenterology, Hepatology and Child Nutrition Unit, Carlos Haya University Hospital, Málaga, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Blasco
authors.affiliation: Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: María-Teresa
authors.initials: MT
authors.lastname: García-Silva
authors.affiliation: Unit of Pediatric Gastroenterology and Metabolic Diseases, Hospital Materno Infantil de Badajoz, Badajoz, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Márquez-Armenteros
authors.affiliation: Unit of Metabolopathies, Hospital Universitario la Fe, Valencia, Spain.
authors.forename: Isidro
authors.initials: I
authors.lastname: Vitoria
authors.affiliation: Gastroenterology Unit, Pediatric Service, Virgen de la Arrixaca University Hospital, Murcia, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Vives
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Universidad Autónoma de Madrid, IdiPaz, CIBERER, ICIII, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Navarrete
authors.affiliation: Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Service of Neonatology, Department of Pediatrics, Hospital Clínico Universitario de Santiago, Health Research Institute of Santiago de Compostela (IDIS), CIBERER, Santiago de Compostela, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández-Marmiesse
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Universidad Autónoma de Madrid, IdiPaz, CIBERER, ICIII, Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Universidad Autónoma de Madrid, IdiPaz, CIBERER, ICIII, Madrid, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Pérez-Cerdá
mesh_terms: D000208:Acute Disease; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D058070:Asymptomatic Diseases; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D005998:Glycine / Q000031:analogs & derivatives* / Q000652:urine; D045782:Hemiterpenes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D050769:Isovaleryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D010421:Pentanoic Acids / Q000097:blood; D010641:Phenotype; D015995:Prevalence; D013030:Spain / Q000453:epidemiology
chemical_list: D045782:Hemiterpenes; D010421:Pentanoic Acids; C008216:isovaleric acid; C005916:N-isovalerylglycine; C027333:3-methylbutyrylcarnitine; D003404:Creatinine; D050769:Isovaleryl-CoA Dehydrogenase; D002331:Carnitine; D005998:Glycine