LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials.
LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials.
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DOI：
10.1002/acn3.51709
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发表时间：
2023-02
影响因子：
5.3
通讯作者：
Weihl, Conrad C.
中科院分区：
文献类型：
--
作者：
Findlay, Andrew R.;Robinson, Sarah E.;Poelker, Stephanie;Seiffert, Michelle;Bengoechea, Rocio;Weihl, Conrad C.
描述D1型肢体带状肌营养不良症(LGMDD1型)的完整表型谱和自然病史。通过系统的文献和图表回顾，我们提取了与LGMDD1疾病负担相关的临床事件的年龄。手动肌肉测试和定量测力数据被用来估计年化变化率。我们还使用先前经过验证的患者报告结果评估(ACTIVLIM，PROIS-57)和新的LGMDD1问卷进行了一项横断面观察性研究。一些人在1.5年和2.5年 时接受了重复的ACTIVLIM和LGMDD1问卷评估。共有122名来自14个不同国家的LGMDD1患者纳入研究。我们发现了两个新的变异体(p.E54K和p.V99A)。体外检测和分离支持它们的致病性。平均发病年龄29.7 岁。基因分型似乎影响患者的发病年龄、虚弱类型和失去活动的中位时间(34 年)。吞咽困难是最常见的异常(51.4%)。三角肌、二头肌、握力、髂腰肌和腿筋力量下降(0.5-1百万磅/年)。横断面ACTIVLIM和LGMDD1问卷得分与发病年限相关。纵向上，只有LGMDD1问卷在1.5年和2.5年 年都发现了显著的进展。治疗试验将需要62名患者(1.5年 年)或30名患者(2.5年 年)才能检测到LGMDD1量表的进展减少70%。这项研究是迄今为止对LGMDD1患者进行的最大规模的描述，并强调了需要前瞻性验证的潜在的基因依赖差异。未来的临床试验在选择结果指标和招募患者时，将需要考虑这些关键表型特征的可变性。
To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle testing and quantitative dynamometry data were used to estimate annualized rates of change. We also conducted a cross‐sectional observational study using previously validated patient‐reported outcome assessments (ACTIVLIM, PROMIS‐57) and a new LGMDD1 questionnaire. Some individuals underwent repeat ACTIVLIM and LGMDD1 questionnaire assessments at 1.5 and 2.5 years. A total of 122 LGMDD1 patients were included from 14 different countries. We identified two new variants (p.E54K, p.V99A). In vitro assays and segregation support their pathogenicity. The mean onset age was 29.7 years. Genotype appears to impact onset age, weakness pattern, and median time to loss of ambulation (34 years). Dysphagia was the most frequent abnormality (51.4%). Deltoids, biceps, grip, iliopsoas, and hamstrings strength decreased by (0.5‐1 lb/year). Cross‐sectional ACTIVLIM and LGMDD1 questionnaire scores correlated with years from disease onset. Longitudinally, only the LGMDD1 questionnaire detected significant progression at both 1.5 and 2.5 years. Treatment trials would require 62 (1.5 years) or 30 (2.5 years) patients to detect a 70% reduction in the progression of the LGMDD1 questionnaire. This study is the largest description of LGMDD1 patients to date and highlights potential genotype‐dependent differences that need to be verified prospectively. Future clinical trials will need to account for variability in these key phenotypic features when selecting outcome measures and enrolling patients.
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影响因子：
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通讯作者：
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