Heterogeneous phenotype in a family with compound heterozygous parkin gene mutations

Background: Mutations in the parkin gene (PRKN) cause autosomal recessive early-onset Parkinson disease (EOPD). Objective: To investigate the presence of mutations in the PRKN gene in a white family with EOPD and the genotype-phenotype correlations. Design: Twenty members belonging to 3 generations of the EOPD family with 4 affected subjects underwent genetic analysis. Direct genomic DNA sequencing, semi-quantitative polymerase chain reaction, real-time quantitative polymerase chain reaction, and reverse-transcriptase polymerase chain reaction analyses were performed to identify the PRKN mutation. Results: Compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene were identified in 4 patients with early onset (at ages 30-38 years). Although heterozygous T240M and homozygous EX 5_6 del mutations in the PRKN gene have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. The phenotype of patients was that of classic autosomal recessive EOPD characterized by beneficial response to levodopa, relatively slow progression, and motor complications. All heterozygous mutation carriers (T240M or EX 5_6 del) and a 56-year-old woman who was a compound heterozygous mutation carrier (T240M and EX 56 del) were free of any neurological symptoms. Conclusions: Compound heterozygous mutations (T240M and EX 56 del) in the PRKN gene were found to cause autosomal recessive EOPD in 4 members of a large white family. One additional member with the same mutation, who is more than 10 years older than the mean age at onset of the 4 affected individuals, had no clinical manifestation of the disease. This incomplete penetrance has implications for genetic counseling, and it suggests that complex gene-environment interactions may play a role in the pathogenesis of PRKN EOPD.