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Contains fulltext : 229267.pdf (Publisher’s version ) (Open Access) OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 10(9) ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.

Formation of toxic α-synuclein oligomers appears to be a key underlying pathological mechanism of synucleinopathies such as Parkinson's disease or multiple system atrophy (MSA). Given that Epigallocatechin-gallate has been shown to inhibit α-synuclein aggregation, it might represent a causal treatment option. Therefore, we set out to evaluate the safety, tolerability and a potential disease-modifying effect of Epigallocatechin-gallate in patients with MSA after 48 weeks of treatment. Power calculation was performed on existing natural history data on the progression of the Unified MSA Rating Scale as primary readout parameter. To assess the efficacy of Epigallocatechin-gallate versus placebo regarding the reduction of disease progression measured during the study period (80 % power, 5 % p level, 50 % effect size) 36 patients per group are needed. Considering a drop-out rate of 20 % a total of 86 patients will be recruited in this multicentre study. These data provide a solid rationale to investigate whether supplementation of Epigallocatechin-gallate can delay the progression of the MSA-related disability.

Ziel der prospektiven diagnostischen Studie war es, das Risikopotenzial der akustischen Reizstimuli, welche bei VEMP-Untersuchungen verwendet werden, für die Cochlea abzuschätzen. Hierzu wurden 30 gesunde erwachsene Probanden im Alter von 20 bis 35 Jahren mit klinischen Standardeinstellungen (tone burst, 500 Hz, 133 dB SPL, Stimulusrate 200) auf cervicale vestibuläre myogene Potenziale (cVEMP) untersucht. Vor, unmittelbar nach und 24 Stunden nach der VEMP-Testung wurde die kochleäre Funktion mittels Tonschellenaudiogramm und Distorsionsproduktemissionsmessung (DPOAE) bestimmt. Zusätzlich wurden die Probanden nach Ohrsymptomen befragt. Bei allen Probanden konnten cVEMP abgeleitet werden. 8 (27%) Testpersonen berichteten über Ohrsymptome unmittelbar nach der Untersuchung, die sich innerhalb von 24 Stunden zurückbildeten. Die Hörschwellen verschlechterten sich nicht. Die DPOAE Level fielen im Hochfrequenzbereich (4.000–6.000 Hz) unmittelbar nach Exposition auf dem beschallten Ohr ab. Bei Probanden mit subjektiven Ohrsymptomen war der Abfall stärker ausgeprägt. Innerhalb von 24 Stunden kam es zu einer Erholung der DPOAE-Level. Akustische Stimuli, wie sie zur VEMP-Messung eingesetzt werden, können als Nebenwirkung die kochleäre Funktion beeinflussen. Ein klinisch relevanter Abfall der Hörschwelle ließ sich nicht nachweisen. Subjektive auditorische Symptome waren innerhalb von 24 Stunden rückläufig. Um das Nebenwirkungsrisiko zu minimieren, sollten die Reizstärke und die Wiederholungsraten so gering wie möglich gehalten werden. Der Erstautor gibt keinen Interessenkonflikt an., GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; 11:Doc216; ISSN 1865-1038