PDF(Pubmed)
Abstract：
BACKGROUND: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA)≥250 and (GAA)200-249 expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine.
METHODS: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial.
RESULTS: Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA)≥250 expansion. FGF14 (GAA)200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2191; OR, 15.20; 95% CI, 7.52-30.80; p < 0.0001). The phenotype of patients carrying a (GAA)200-249 allele closely mirrored that of patients carrying a (GAA)≥250 allele. Patients carrying a (GAA)≥250 or a (GAA)200-249 allele had a significantly greater clinician-reported (80%, 33/41 vs 31%, 5/16; RR, 2.58; 95% CI, 1.23-5.41; Fisher\'s exact test, p = 0.0011) and self-reported (59%, 32/54 vs 11%, 2/19; RR, 5.63; 95% CI, 1.49-21.27; Fisher\'s exact test, p = 0.00033) response to 4-aminopyridine treatment compared to patients carrying a (GAA)<200 allele. Placebo-controlled video-oculography data, available for four patients carrying an FGF14 (GAA)≥250 expansion, showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo.
CONCLUSIONS: This study confirms that FGF14 GAA expansions are a frequent cause of DBN syndromes. It provides preliminary evidence that (GAA)200-249 alleles might be pathogenic. Finally, it provides large real-world and preliminary piloting placebo-controlled evidence for the efficacy of 4-aminopyridine in GAA-FGF14 disease.
BACKGROUND: This work was supported by the Clinician Scientist program \"PRECISE.net\" funded by the Else Kröner-Fresenius-Stiftung (to CW, AT, and MSy), the grant 779257 \"Solve-RD\" from the European\'s Union Horizon 2020 research and innovation program (to MSy), and the grant 01EO 1401 by the German Federal Ministry of Education and Research (BMBF) (to MSt). This work was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) N° 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575 (to MSy, BB and-as associated partner-SZ), the NIH National Institute of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to SZ), the Fondation Groupe Monaco (to BB), and the Montreal General Hospital Foundation (grant PT79418 to BB). The Care4Rare Canada Consortium is funded in part by Genome Canada and the Ontario Genomics Institute (OGI-147 to KMB), the Canadian Institutes of Health Research (CIHR GP1-155867 to KMB), Ontario Research Foundation, Genome Quebec, and the Children\'s Hospital of Eastern Ontario Foundation. The funders had no role in the conduct of this study.
METHODS: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial.
RESULTS: Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA)≥250 expansion. FGF14 (GAA)200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2191; OR, 15.20; 95% CI, 7.52-30.80; p < 0.0001). The phenotype of patients carrying a (GAA)200-249 allele closely mirrored that of patients carrying a (GAA)≥250 allele. Patients carrying a (GAA)≥250 or a (GAA)200-249 allele had a significantly greater clinician-reported (80%, 33/41 vs 31%, 5/16; RR, 2.58; 95% CI, 1.23-5.41; Fisher\'s exact test, p = 0.0011) and self-reported (59%, 32/54 vs 11%, 2/19; RR, 5.63; 95% CI, 1.49-21.27; Fisher\'s exact test, p = 0.00033) response to 4-aminopyridine treatment compared to patients carrying a (GAA)<200 allele. Placebo-controlled video-oculography data, available for four patients carrying an FGF14 (GAA)≥250 expansion, showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo.
CONCLUSIONS: This study confirms that FGF14 GAA expansions are a frequent cause of DBN syndromes. It provides preliminary evidence that (GAA)200-249 alleles might be pathogenic. Finally, it provides large real-world and preliminary piloting placebo-controlled evidence for the efficacy of 4-aminopyridine in GAA-FGF14 disease.
BACKGROUND: This work was supported by the Clinician Scientist program \"PRECISE.net\" funded by the Else Kröner-Fresenius-Stiftung (to CW, AT, and MSy), the grant 779257 \"Solve-RD\" from the European\'s Union Horizon 2020 research and innovation program (to MSy), and the grant 01EO 1401 by the German Federal Ministry of Education and Research (BMBF) (to MSt). This work was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) N° 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575 (to MSy, BB and-as associated partner-SZ), the NIH National Institute of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to SZ), the Fondation Groupe Monaco (to BB), and the Montreal General Hospital Foundation (grant PT79418 to BB). The Care4Rare Canada Consortium is funded in part by Genome Canada and the Ontario Genomics Institute (OGI-147 to KMB), the Canadian Institutes of Health Research (CIHR GP1-155867 to KMB), Ontario Research Foundation, Genome Quebec, and the Children\'s Hospital of Eastern Ontario Foundation. The funders had no role in the conduct of this study.
摘要：
背景：GAA-FGF14疾病/脊髓小脑共济失调27B是一种最近描述的神经退行性疾病，由成纤维细胞生长因子14（FGF14）基因（GAA）≥250个扩增引起，但是它的表型谱，致病阈值，和基于证据的治疗仍有待建立。我们报告了特发性眼球震颤（DBN）患者中FGF14（GAA）≥250和（GAA）200-249扩张的频率及其对4-氨基吡啶的反应。
方法：170例特发性DBN患者的回顾性队列研究，包括4-氨基吡啶治疗反应的深入表型分析和评估，包括对之前一项随机双盲4-氨基吡啶试验的安慰剂对照视频眼图治疗反应数据的再分析.
结果：特发性DBN患者FGF14（GAA）≥250个扩张的频率为48％（82/170）。在100％（82/82）和43％（35/82）的FGF14（GAA）≥250扩张的患者中观察到小脑性共济失调。与对照组(0.87%;19/2191;OR,15.20；95%CI，7.52-30.80；p<0.0001）。携带（GAA）200-249等位基因的患者的表型与携带（GAA）≥250等位基因的患者的表型密切相关。携带（GAA）≥250或（GAA）200-249等位基因的患者的临床医生报告（80％，33/41vs31%，5/16；RR，2.58；95%CI，1.23-5.41；Fisher精确检验，p=0.0011)和自我报告(59%，32/54vs11%，2/19；RR，5.63；95%CI，1.49-21.27；Fisher精确检验，p=0.00033）与携带（GAA）<200等位基因的患者相比，对4-氨基吡啶治疗的反应。安慰剂控制的视频眼图数据，可用于四名携带FGF14（GAA）≥250扩展的患者，显示4-氨基吡啶的DBN慢相速度显着降低，但不是安慰剂。
结论：本研究证实FGF14GAA扩张是DBN综合征的常见原因。它提供了初步证据，（GAA）200-249个等位基因可能是致病性的。最后,它为4-氨基吡啶在GAA-FGF14疾病中的疗效提供了大量的真实世界和初步试验安慰剂对照证据.
背景：这项工作得到了由ElseKröner-Fresenius-Stiftung（给CW，AT,和MSY），来自欧盟地平线2020研究与创新计划（对MSY）的授予779257“Solve-RD”，以及德国联邦教育与研究部（BMBF）（对MSt）的拨款01EO1401。这项工作也得到了DeutscheForschungsgemeinschaft(DFG，德国研究基金会）N°441409627，作为EJPRD框架下PROSPAX财团的一部分，欧洲罕见疾病联合计划，根据EJPRDCOFUND-EJPN°825575(至MSY，BB和-作为关联合作伙伴-SZ)，美国国立卫生研究院国家神经系统疾病和中风研究所（授予SZ2R01NS072248-11A1），摩纳哥基金会（BB），和蒙特利尔综合医院基金会（授予BBPT79418）。Care4Rare加拿大联盟部分由加拿大基因组和安大略省基因组学研究所（KMBOGI-147）资助，加拿大卫生研究院（CIHRGP1-155867，KMB），安大略省研究基金会，魁北克基因组,以及东安大略省基金会儿童医院。资助者在这项研究的进行中没有任何作用。
方法：170例特发性DBN患者的回顾性队列研究，包括4-氨基吡啶治疗反应的深入表型分析和评估，包括对之前一项随机双盲4-氨基吡啶试验的安慰剂对照视频眼图治疗反应数据的再分析.
结果：特发性DBN患者FGF14（GAA）≥250个扩张的频率为48％（82/170）。在100％（82/82）和43％（35/82）的FGF14（GAA）≥250扩张的患者中观察到小脑性共济失调。与对照组(0.87%;19/2191;OR,15.20；95%CI，7.52-30.80；p<0.0001）。携带（GAA）200-249等位基因的患者的表型与携带（GAA）≥250等位基因的患者的表型密切相关。携带（GAA）≥250或（GAA）200-249等位基因的患者的临床医生报告（80％，33/41vs31%，5/16；RR，2.58；95%CI，1.23-5.41；Fisher精确检验，p=0.0011)和自我报告(59%，32/54vs11%，2/19；RR，5.63；95%CI，1.49-21.27；Fisher精确检验，p=0.00033）与携带（GAA）<200等位基因的患者相比，对4-氨基吡啶治疗的反应。安慰剂控制的视频眼图数据，可用于四名携带FGF14（GAA）≥250扩展的患者，显示4-氨基吡啶的DBN慢相速度显着降低，但不是安慰剂。
结论：本研究证实FGF14GAA扩张是DBN综合征的常见原因。它提供了初步证据，（GAA）200-249个等位基因可能是致病性的。最后,它为4-氨基吡啶在GAA-FGF14疾病中的疗效提供了大量的真实世界和初步试验安慰剂对照证据.
背景：这项工作得到了由ElseKröner-Fresenius-Stiftung（给CW，AT,和MSY），来自欧盟地平线2020研究与创新计划（对MSY）的授予779257“Solve-RD”，以及德国联邦教育与研究部（BMBF）（对MSt）的拨款01EO1401。这项工作也得到了DeutscheForschungsgemeinschaft(DFG，德国研究基金会）N°441409627，作为EJPRD框架下PROSPAX财团的一部分，欧洲罕见疾病联合计划，根据EJPRDCOFUND-EJPN°825575(至MSY，BB和-作为关联合作伙伴-SZ)，美国国立卫生研究院国家神经系统疾病和中风研究所（授予SZ2R01NS072248-11A1），摩纳哥基金会（BB），和蒙特利尔综合医院基金会（授予BBPT79418）。Care4Rare加拿大联盟部分由加拿大基因组和安大略省基因组学研究所（KMBOGI-147）资助，加拿大卫生研究院（CIHRGP1-155867，KMB），安大略省研究基金会，魁北克基因组,以及东安大略省基金会儿童医院。资助者在这项研究的进行中没有任何作用。
