Coexisting Parkinson’s and Wilson’s Disease: Chance or Connection?

• Published in: Canadian journal of neurological sciences 2017-03, Vol.44 (2), p.215-218
• Main Authors: Gasca-Salas, Carmen, Alonso, Angel, González-Redondo, Rafael, Obeso, José A.
• Format: Article
• Language: English
• Subjects: Age; Aged; Asymptomatic; Biopsy; Comorbidity; Copper; Dopamine; Dystonia; Female; Hepatolenticular Degeneration - diagnosis; Hepatolenticular Degeneration - genetics; Humans; Letters to the Editor; Liver; Metabolism; Mutation; Parkinson Disease - diagnosis; Parkinson Disease - diagnostic imaging; Parkinson Disease - physiopathology; Parkinson's disease; Patients
• ISSN: 0317-1671; 2057-0155
• DOI: 10.1017/cjn.2016.327

DISCUSSION We report a patient with a clinical presentation and evolution typical of YOPD, and an abnormal copper metabolism with a genetic confirmation for WD. Previous in vitro studies of its biochemical properties found diminished but significant copper transport activity.15 Although computational (in silico) models do not clearly predict a deleterious effect of the gene, the multiple independent submissions to the refSNP cluster (rs121907998) (http://www.ncbi.nlm.nih.gov/sites/entrez?db=snp), its extremely low frequency in control general populations (1000 Genomes Project, Exome Aggregation Consortium), and its co-segregation with the disease (even in the homozygous status),14 meet the criteria required to classify it as “pathogenic” under the guidelines for the interpretation of sequence variants provided by the American College of Medical Genetics and Genomics.16 The evidence supporting the pathogenicity of the P768L variant is even stronger: in silico tools predict it to be deleterious, and it has been linked to WD in the homozygous status.17 Patients with ATP7B mutations are typically heterozygous, and unlike homozygote patients, where there is no phenotype-genotype correlation showing entirely different phenotypes in the same mutation,18 heterozygotes have a hepatic presentation or are presymptomatic, but do not have a neurological presentation.12,13,19 To our knowledge compound M645R/P768L heterozygosity has never been reported in other families before, so the associated described phenotype would probably need to be confirmed in other patients with the same genetic alteration. In WD there is typically no levodopa responsiveness to parkinsonian signs, probably due to a post-synaptic deficit of dopaminergic neurotransmission in addition to a pre-synaptic deficit.24 We cannot totally rule out that copper metabolism abnormalities caused nigro-striatal neurodegeneration or triggered the pathological process of PD, since decreased serum ceruloplasmin levels have been shown to be associated with nigral iron deposition and could be a potential risk factor for PD.25 Moreover, on the basis of a single study of three elderly patients with late onset parkinsonism levodopa responsive heterozygotes for a 15bp nucleotide deletion at the 5’UTR region of the ATP7B gene, it has been hypothesized that a single mutated ATP7B allele may act as a risk factor for late-onset parkinsonism. [...]these subjects were older than our patient and were not diagnosed with WD bas