RESUMO
OBJECTIVE: To evaluate the frequency and clinical spectrum of the recently identified p.D620N mutation in the VPS35 gene in Parkinson disease (PD) in an international sample. DESIGN: Genetic analysis by DNA sequencing and detailed clinical and neuropsychiatric assessment as well as neuroimaging in mutation carriers. SETTING: Tertiary referral centers in Germany, Serbia, Chile, and the United States. PATIENTS: One thousand seven hundred seventy-four patients with PD. MAIN OUTCOME MEASURE: Frequency of the p.D620N mutation. RESULTS: A single mutation carrier was identified. The mutation carrier was a 60-year-old German man who had tremor-dominant PD since the age of 45 years. Longitudinal follow-up over 13 years revealed a disease progression from Hoehn and Yahr stage 1 to 3. There was evidence of mild cognitive impairment on the Montreal Cognitive Assessment. No abnormalities were observed by multimodal neuroimaging. He had a family history consistent with autosomal dominant inheritance. An affected paternal aunt and 3 reportedly unaffected siblings were also found to be mutation carriers. CONCLUSION: VPS35 mutations are a rare cause of PD in different populations. The clinical phenotype may be indistinguishable from idiopathic PD with the possible exception of an earlier age at onset. Genetic analysis of the extended family revealed incomplete penetrance of the p.D620N mutation.
Assuntos
Predisposição Genética para Doença , Mutação/genética , Doença de Parkinson/genética , Proteínas de Transporte Vesicular/genética , Idoso , Chile , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Saúde da Família , Feminino , Frequência do Gene , Testes Genéticos , Genótipo , Alemanha , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Sérvia , Centros de Atenção Terciária , Estados UnidosRESUMO
BACKGROUND: A common mitochondrial complex I gene polymorphism (10398G) is reported to be inversely associated with the risk of Parkinson disease. We hypothesized that this variant might have a protective effect on the central nervous system and therefore might delay the onset of symptoms in spinocerebellar ataxia type 2 (SCA2). OBJECTIVE: To assess the association of the 10398G polymorphism with age at onset in Cuban patients with SCA2. DESIGN: Genetic association study. SETTING: Holguin, Cuba. PATIENTS: Forty-six Cuban patients with SCA2. MAIN OUTCOME MEASURES: Presence or absence of the 10398G polymorphism was determined in 46 Cuban patients with SCA2 and early or late onset of symptoms, defined as at least 2 SDs lower than or higher than the mean age at onset for patients with a similarly sized triplet repeat expansion. RESULTS: The polymorphism was present in 11 of 27 Cuban patients with SCA2 and early onset (41%) vs 2 of 19 with late onset (11%) (Fisher exact test; P = .04). CONCLUSION: Contrary to our prediction of a later onset of SCA2 in patients with the 10398G polymorphism, we find that this variant is associated with an earlier age at onset in Cuban patients with SCA2.