Mutations in either the PCCA or PCCB genes are responsible for propionic 
acidemia (PA), one of the most frequent organic acidemias inherited in autosomal 
recessive fashion. Most of the mutations detected to date in both genes are 
missense. In the case of PCCA deficient patients, a high number of alleles 
remain uncharacterized, some of them suspected to carry an exonic deletion. We 
have now employed multiplex ligation probe amplification (MLPA) and long-PCR in 
some cases to screen for genomic rearrangements in the PCCA gene in 20 patients 
in whom standard mutation detection techniques had failed to complete genotype 
analysis. Eight different deletions were found, corresponding to a frequency of 
21.3% of the total PCCA alleles genotyped at our center. Two of the exonic 
deletions were frequent, one involving exons 3-4 and another exon 23 although in 
the first case two different chromosomal breakpoints were identified. Absence of 
exons 3 and 4 which is also the consequence of the novel splicing mutation 
c.231+1g>c present in two patients, presumably results in an in-frame deletion 
covering 39 aminoacids, which was expressed in a eukaryotic system confirming 
its pathogenicity. This work describes for the first time the high frequency of 
large genomic deletions in the PCCA gene, which could be due to the 
characteristics of the PCCA gene structure and its abundance in intronic 
repetitive elements. Our data underscore the need of using gene dosage analysis 
to complement routine genetic analysis in PCCA patients.