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 α and 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 10 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.

Molecular analysis of PCCB gene in Korean patients with propionic acidemia

“…Recently in one study, the correlation was described in PCCB homozygotes presenting with early onset form [20]. It is not surprising that the homozygotes with two mutations, T428I and 1527del3, in our study also presented with early onset and had null enzyme activities.…”

“…In Perez-Cerda's study, four common mutations were found in 38/52 mutant chromosomes investigated, whereas the remainder of the alleles harbors 12 other different mutations [20]. The most frequent mutation in Spanish patients with PCCB gene defect is ins/del mutation, which replaces 14 bp in the coding sequence with 12 bp, unrelated to this region of the gene, followed by 1170insT, the second most common allele [21].…”

Expansion of the Phenotypic Spectrum of Propionic Acidemia with Isolated Elevated Propionylcarnitine

“…In virtually all reported cases of PA including atypical and mild ones, the diagnosis is supported by concurrent abnormal acylcarnitine profile and urine organic acids that identify the disease-specific 2-MCA and 3-OHP (AlDirbashi et al 2014;Weisfeld-Adams et al 2010;Pérez-Cerdá et al 2000). In this report, two individuals with compound heterozygous mutations in PCCA/PCCB present with significant C3 elevations in the absence of or only modest elevation in 2-MCA or 3-OHP, escaping the classic biochemical hallmarks for the PA diagnosis.…”

Nutritional and Pharmacological Management during Chemotherapy in a Patient with Propionic Acidaemia and Rhabdomyosarcoma Botryoides

“…During acute intermittent illnesses, high-energy feeds without the precursor amino acids are required to prevent metabolic decompensation (Ogier de Baulny et al 2005;McDonald et al 2007;Deodato et al 2006). The prognosis of PA has been improving in the last years, with a larger amount of patients reaching adult life (Martín-Hernández et al 2009;Pérez-Cerdá et al 2000;Baumgartner et al 2007;Williams et al 2009). …”