also be involved in the pathogenesis of neurodegenerative disorders such as PD. Most strikingly, there are strong in vitro data suggesting that copper interacts with โฃ-synuclein, which is thought to play a key role in the pathogenesis of PD. 2 Therefore, we examined the prevalence of the most frequent mutation in WD, i.e., the H1069Q mutation within the ATP7B gene, in EOPD patients and their unaffected siblings.
Blood samples from consecutive patients with EOPD and their unaffected siblings were ascertained and used for the preparation of chromosomal DNA. Patients were clinically diagnosed according to the U.K. Brain Bank criteria, while available siblings were contacted by phone, subjected to a semistructured interview in order to exclude symptoms suggestive of PD or other movement disorders, and requested to have a blood sample sent to our laboratory. 3 Subsequently, exon 14 of ATP7B was amplified according to previously established protocols. 4 The study was approved by the local ethics committee, and all participants gave written consent before participation. This study was analyzed using descriptive statistics.
One hundred and three German discordant pairs (EOPD: 67 male, 36 female; siblings: 54 male, 49 female) were recruited for this analysis. Sixty-seven pairs featured the same gender, while the remaining 36 pairs had different sexes. The mean age of disease onset in EOPD patients was 41 ฯฎ 6.8 years, while the mean age of their siblings at the time of blood sampling was 52.6 ฯฎ 11.2 years. Ninety-seven patients had a diagnosis of probable EOPD and six patients a diagnosis of possible EOPD. Sixteen of the 103 EOPD patients had a family history of PD. A heterozygous H1069Q mutation was detected in one of the investigated EOPD patients and his unaffected sibling, while all other subjects were homozygous for the wild-type H-allele. The respective EOPD patient (male, 65 years) had a disease onset of 50 years, while his 52-year-old sister did not report any neurological (or hepatic) disease. The patient had the typical features of advanced PD with end-of-dose akinesia and intermittent L-dopa-induced dyskinesias under a predominantly dopaminergic therapy.
The WD gene frequency is approximately 0.56% and the carrier frequency approximately 1:90. Assuming a preponderance of 50% of H1069Q variants within this German cohort, the carrier frequency of the H1069Q mutation can be estimated to be 1:135. We observed a prevalence of 1:103 in both investigated groups. Therefore, these data do not reveal a major impact of the H1069Q mutant in the etiology of EOPD. Interestingly, from the two siblings being heterozygous for the H1069Q mutation, only one suffered from EOPD. This observation supports our assumption that the H1069Q mutation does not play a relevant role in the etiology of PD.
There are several limitations to our analysis. First, the investigated study population was relatively small; in particular, some of the familial cases were possibly caused by a mutation in one of the currently known PD disease genes. 5 Second, it is not possible to rule out entirely the presence of PD in the unaffected siblings by a telephone interview. Third, we cannot exclude the unaffected heterozygous sibling developing PD later in life. Fourth, other mutations in the ATP7B gene than the H1069Q mutation may play a role in the etiology of EOPD. 1 However, in view of the generally very low prevalence of the other known mutations, this seems unlikely. In summary, this study does not provide any strong evidence of an involvement of the H1069Q mutation within ATP7B in EOPD. This result has to be confirmed by larger studies in genetically homogenous populations.