X 连锁肌小管肌病：一项前瞻性国际自然病史研究。
X-linked myotubular myopathy: A prospective international natural history study.
机构信息
From I-Motion (M.A., C.L., T.G., E.G., V.C., L.S.), Institute of Myology, Paris, France; Paediatric Neurology and Neuromuscular Center (U.S., A.G.), University of Essen, Germany; Unit of Neuromuscular and Neurodegenerative Disorders (A. D'Amico), Department of Neurosciences, Bambino Gesu Children's Research Hospital IRCCS, Rome, Italy; Division of Neurology and Program for Genetics and Genome Biology (J.J.D.), Hospital for Sick Children, Toronto, Canada; Boston Children's Hospital (B.T.D.), MA; Centre de Référence Neuromusculaire (A. Daron), CHR La Citadelle, Liège, Belgium; UCI Pediatrica (A.H.), Hospital Puerta del Mar, Cadiz, Spain; Centre de Référence Maladies Neuromusculaires Adulte (C.d.L.), Hôpital de la Croix-Rousse, Hospices Civils de Lyon; Service de Réanimation Polyvalente (J.-M.A.), Hôpital Sainte Musse, Toulon; Centre de Référence des Maladies Neuromusculaires d'Ile de France-Nord et Est (M.M.), Hôpital Armand Trousseau, Paris; Service de Neuropédiatrie Hôpital Roger Salengro (J.-M.C.), CHRU, Lille; Service de Rééducation Pédiatrique "L'Escale" (C.V., S.F.), Hôpital Mère Enfant, CHU-Lyon, France; CeRCa (R.B.), Hôpital Pierre-Zobda-Quitman, CHU de Martinique, Fort-de-France, Martinique; Laboratoire Diagnostic Génétique (V.B.), Nouvel Hôpital Civil, Strasbourg; Genethon (A.B.-B.), UMR S951 Inserm, Univ Evry, Université Paris Saclay, Evry; Neuromuscular Investigation Center (J.-Y.H.), Institute of Myology, Paris, France; and Valerion Therapeutics (H.L.), Concord, MA.
出版信息
Neurology. 2019 Apr 16;92(16):e1852-e1867. doi: 10.1212/WNL.0000000000007319. Epub 2019 Mar 22.
OBJECTIVES
Because X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcome measures.
METHODS
We designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored.
RESULTS
Forty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti-adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10.
CONCLUSIONS
Our data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population.
CLINICALTRIALSGOV IDENTIFIER
NCT02057705.
目的
由于 X 连锁肌小管肌病（XLMTM）是一种由基因突变引起的罕见神经肌肉疾病，具有较大的表型异质性，为确保临床试验准备就绪，有必要更好地量化疾病负担并确定最佳结果测量指标。
方法
我们设计了一项针对 XLMTM 患者的国际前瞻性和纵向自然史研究，并在随访的第一年评估肌肉力量以及运动和呼吸功能。还监测了针对腺相关病毒血清型 8 的体液免疫。
结果
2014 年 5 月至 2017 年 5 月期间共纳入 45 名年龄 3.5 个月至 56.8 岁的男性患者。13 名患者表现为轻度表型（无需通气支持），7 名患者表现为中度表型（每天通气支持时间少于 12 小时），25 名患者表现为重度表型（每天通气支持 12 小时或更长时间）。即使是非常虚弱的患者，也能进行大多数力量和运动功能评估。运动功能测量 32 总评分、握力和捏力、用力肺活量、第一秒用力呼气量和峰值咳嗽流量测量可区分 3 组患者。病史显示数名患者出现运动里程碑丧失。37 名患者的纵向数据显示，运动功能测量 32 总评分显著下降 2%。在评估的 38 名患者中，26%检测到抗腺相关病毒 8 中和活性，其中 2 名患者的抑制滴度>1:10。
结论
我们的数据证实，无论表型如何，男性幸存者的 XLMTM 均呈缓慢进展，为该人群的临床开发提供了结果验证和自然史数据。
临床试验.gov 标识符：NCT02057705。
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