BACKGROUND: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. OBJECTIVE: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. METHODS: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. RESULTS: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. CONCLUSIONS: Moderate single-nucleotide polymorphism-based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- MeSH
- celogenomová asociační studie * MeSH
- dospělí MeSH
- dystonické poruchy genetika MeSH
- dystonie * genetika MeSH
- genetická predispozice k nemoci * genetika MeSH
- jednonukleotidový polymorfismus * genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- rizikové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments. OBJECTIVES: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL. RESULTS: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups. CONCLUSIONS: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- MeSH
- činnosti denního života MeSH
- dvojitá slepá metoda MeSH
- Hallervordenův-Spatzův syndrom * farmakoterapie genetika MeSH
- kyselina pantothenová analogy a deriváty MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
