Vacuolar protein sorting 35 (VPS35) was recently reported to be a pathogenic gene for late-onset autosomal dominant Parkinson's disease (PD), using exome sequencing. To date, VPS35 mutations have been detected only in whites with PD. The aim of the present study was to determine the incidence and clinical features of Asian PD patients with VPS35 mutations. We screened 7 reported nonsynonymous missense variants of VPS35, including p.D620N, known as potentially disease-associated variants of PD, in 300 Japanese index patients with autosomal dominant PD and 433 patients with sporadic PD (SPD) by direct sequencing or high-resolution melting (HRM) analysis. In addition, we screened 579 controls for the p.D620N mutation by HRM analysis. The p.D620N mutation was detected in 3 patients with autosomal dominant PD (1.0%), in 1 patient with SPD (0.23%), and in no controls. None of the other reported variants of VPS35 were detected. Haplotype analysis suggested at least 3 independent founders for Japanese patients with p.D620N mutation. Patients with the VPS35 mutation showed typical tremor-predominant PD. We report Asian PD patients with the VPS35 mutation. Although VPS35 mutations are uncommon in PD, the frequency of such mutation is relatively higher in Japanese than reported in other populations. In VPS35, p.D620N substitution may be a mutational hot spot across different ethnic populations. Based on the clinical features, VPS35 should be analyzed in patients with PD, especially autosomal dominant PD or tremor-predominant PD.
Valosin-containing protein mutations are not rare in Asian patients, and gene analysis should be considered for patients with adult-onset rimmed vacuolar myopathy with neurogenic changes. A wide variety of central and peripheral nervous system symptoms coupled with rare bone abnormalities may complicate diagnosis.
Older age, akinetic-rigid motor subtype, and preexisting hypertension are independent risk factors for supine hypertension. Supine hypertension alone may be associated with milder peripheral sympathetic nervous denervation than orthostatic hypotension alone. As for global cognitive decline, supine hypertension is a far riskier comorbidity of early-stage PD than is orthostatic hypotension.
These results show that latent cardiac and vasomotor sympathetic dysfunction but not parasympathetic dysfunction is already present in early stage de novo PD, even without orthostatic hypotension.
Several studies have reported that olfactory dysfunction is an early neuropathological manifestation of Parkinson's disease (PD). Reduced cardiac meta-iodobenzylguanidine ((123)I-MIBG) uptake may be one of the earliest signs of PD. We studied the relation of olfactory dysfunction to cardiovascular dysautonomia in patients with PD. The study group comprised 66 patients with PD (70.5 years) and 26 controls (70.3 years) for olfactory assessment, 21 controls (72.1 years) for cardiac (123)I-MIBG scintigraphy and heart rate variability (HRV), assessed using the coefficient of variation for RR intervals (HRV), and 23 controls (69.2 years) for orthostatic blood pressure response. Olfactory function was assessed by the odor stick identification test Japan (OSIT-J), and cardiovascular autonomic function was evaluated by (123)I-MIBG scintigraphy of the heart, the fall in orthostatic blood pressure, and HRV. Patients with PD had a significantly lower OSIT-J score than did the controls (4.1 +/- 3.0 vs. 9.9 +/- 1.7, p = 0.001). The OSIT-J score was unrelated to variables other than gender, including age, disease duration, motor score on the unified Parkinson's disease rating scale, score on the mini-mental state examination, motor phenotype, visual hallucinations, and dopaminergic medication on multiple regression and logistic regression analyses. The OSIT-J score was related to the heart/mediastinum ratio of cardiac (123)I-MIBG uptake, the fall in orthostatic blood pressure, and HRV, after adjustment for other clinical variables. Olfactory dysfunction in PD was, thus, significantly related to both cardiac sympathetic and parasympathetic dysfunction, as well as vascular sympathetic dysfunction. As non-motor symptoms of PD, olfactory dysfunction and autonomic network failure appear to be closely related in PD.
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