Identification of TMEM230 mutations in familial Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body-confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.

Amantadine for freezing of gait in patients with Parkinson disease.

BACKGROUND: Freezing of gait (FOG) is a common symptom in patients with advanced Parkinson's disease (PD) representing a major cause of disability and falls. Although the pathophysiology of FOG remains poorly understood, nondopaminergic pathways have been implicated. Treatment studies of levodopa and selegiline have shown limited benefit for FOG. Limited data suggest that amantadine, an N-methyl-D-aspartate receptor antagonist, may be beneficial for FOG in PD. OBJECTIVE: To examine the relationship between treatment with oral amantadine and FOG in patients with PD. METHODS: We conducted a retrospective chart review of PD patients who received amantadine specifically for FOG and had a follow-up assessment of FOG. The primary outcome measure was self-reported effectiveness of amantadine (improvement, worsening, or no change in FOG) based on records from the follow-up assessment. RESULTS: Eleven patients with PD with median age of PD onset of 67 years (range, 51-84 years) and median Hoehn and Yahr stage 3 (range, 2-4) met the study population selection criteria. Ten of 11 patients reported improvement in FOG after initiation of amantadine, whereas FOG worsened in one patient. Median amantadine dosage was 100 mg twice daily, and treatment duration was 20 months (range, 6-66 months). Four patients reported reduction in benefit after 4 months. Three patients reported adverse effects, including blurred vision, visual hallucinations, and peripheral edema; the latter 2 effects resulted in discontinuation of amantadine. CONCLUSION: Amantadine is associated with self-reported improvement in FOG in PD, but this effect may be transient. Further studies, including a randomized placebo-controlled trial, are needed to better evaluate this association.