title: Potential relationship between genotype and clinical outcome in propionic acidaemia patients.
abstract: Propionic acidaemia (PA) is an autosomal recessive disorder caused by mutations in either of the PCCA or PCCB genes which encode the alpha and beta subunits, respectively, of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). In this work we have examined the biochemical findings and clinical outcome of 37 Spanish PA patients in relation to the mutations found in both PCCA and PCCB genes. We have detected 27 early-onset and 101 late-onset cases, showing remarkably similar biochemical features without relation to either the age of onset of the disease or the defective gene they have. Twenty-one of the patients have so far survived and three of them, now adolescents, present normal development. Different biochemical procedures allowed us to identify the defective gene in 9 PCCA deficient and 28 PCCB deficient patients. Nine putative disease-causing mutations accounting for 77.7% of mutant alleles were identified among PCCA deficient patients, each one carrying a unique genotypic combination. Of PCCB mutant alleles 98% were characterised. Four common mutations (ins/del, E168K, 1170insT and A497V) were found in 38/52 mutant chromosomes investigated, whereas the remainder of the alleles harbour 12 other different mutations. By examining the mutations identified both in PCCA and PCCB genes and the clinical evolution of patients, we have found a good correlation between certain mutations which can be considered as null with a severe phenotype, while certain missense mutations tend to be related to the late and mild forms of the disease. Expression studies, particularly of the missense mutations identified are necessary but other genetic and environmental factors probably contribute to the phenotypic variability observed in PA.
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Pérez-Cerdá
authors.forename: B
authors.initials: B
authors.lastname: Merinero
authors.forename: P
authors.initials: P
authors.lastname: Rodríguez-Pombo
authors.forename: B
authors.initials: B
authors.lastname: Pérez
authors.forename: L R
authors.initials: LR
authors.lastname: Desviat
authors.forename: S
authors.initials: S
authors.lastname: Muro
authors.forename: E
authors.initials: E
authors.lastname: Richard
authors.forename: M J
authors.initials: MJ
authors.lastname: García
authors.forename: J
authors.initials: J
authors.lastname: Gangoiti
authors.forename: P
authors.initials: P
authors.lastname: Ruiz Sala
authors.forename: P
authors.initials: P
authors.lastname: Sanz
authors.forename: P
authors.initials: P
authors.lastname: Briones
authors.forename: A
authors.initials: A
authors.lastname: Ribes
authors.forename: M
authors.initials: M
authors.lastname: Martínez-Pardo
authors.forename: J
authors.initials: J
authors.lastname: Campistol
authors.forename: M
authors.initials: M
authors.lastname: Pérez
authors.forename: R
authors.initials: R
authors.lastname: Lama
authors.forename: M L
authors.initials: ML
authors.lastname: Murga
authors.forename: T
authors.initials: T
authors.lastname: Lema-Garrett
authors.forename: A
authors.initials: A
authors.lastname: Verdú
authors.forename: M
authors.initials: M
authors.lastname: Ugarte
mesh_terms: D000328:Adult; D001710:Biotin / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002262:Carboxy-Lyases / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D005816:Genetic Complementation Test; D005838:Genotype; D006801:Humans; D008297:Male; D043586:Methylmalonyl-CoA Decarboxylase; D010641:Phenotype; D013030:Spain; D016896:Treatment Outcome; D014316:Tritium
chemical_list: D014316:Tritium; D001710:Biotin; D002262:Carboxy-Lyases; D043586:Methylmalonyl-CoA Decarboxylase