The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.
Background Leucine-rich repeat kinase 2 (LRRK2) is known to harbor highly penetrant mutations linked to familial parkinsonism. However, its full polymorphic variability in relationship to Parkinson’s disease (PD) risk has not been systematically assessed. Methods We examined the frequency pathogenicity of 121 exonic LRRK2 variants in three ethnic series (Caucasian [N=12,590], Asian [N=2,338] and Arab-Berber [N=612]) consisting of 8,611 patients and 6,929 control subjects from 23 separate sites of the Genetic Epidemiology of Parkinson’s Disease Consortium. Findings Excluding carriers of previously known pathogenic mutations, new independent risk associations were found for polymorphic variants in Caucasian (p.M1646T, OR: 1.43, 95% CI: 1.15 – 1.78, P=0.0012) and Asian (p.A419V, OR: 2.27, 95% CI: 1.35 – 3.83, P=0.0011) populations. In addition, a protective haplotype was observed at >5% frequency (p.N551K-p.R1398H-p.K1423K) in the Caucasian and Asian series’, with a similar finding in the small Arab-Berber series that requires further study (combined 3-series OR: 0.82, 95% CI: 0.72 – 0.94, P=0.0043). Of the two previously reported Asian risk variants p.G2385R was found to be associated with disease (OR: 1.73, 95% CI: 1.20 – 2.49, P=0.0026) but no association was observed for p.R1628P (OR: 0.62, 95% CI: 0.36 – 1.07, P=0.087). Also in the Arab-Berber series, p.Y2189C showed potential evidence of risk association with PD (OR: 4.48, 95% CI: 1.33 – 15.09, P=0.012). Of note, two variants (p.I1371V and p.T2356I) which have been previously proposed as pathogenic were observed in patient and control subjects at the same frequency. Interpretation LRRK2 offers an example where multiple rare and common genetic variants in the same gene have independent effects on disease risk. Lrrk2, and the pathway in which it functions, is important in the etiology and pathogenesis of a greater proportion of patients with PD than previously believed. Funding The present study and original funding for the GEO-PD Consortium was supported by grants from Michael J. Fox Foundation. Studies at individual sites were supported by a number of funding agencies world-wide.
This study did not find any difference between the effects of the home-based virtual reality balance training and conventional home balance training. The two training options were equally effective in improving balance, walking, and quality of life among community-dwelling patients with PD.
Aromatic L-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector-mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-[(18)F]fluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.
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