Data from: Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints

Objective: Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years. Methods: Twenty‐three participants with LGMD R9, previously assessed over a 1‐year period, were re‐enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups. Results: At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1‐year follow‐up study. In direct contrast to the 1‐year follow‐up, the 6‐min walk test, 10‐m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1‐ and 6‐year studies. Interpretation: These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.

研究目的：肢带型肌营养不良R9型（Limb girdle muscular dystrophy type R9, LGMD R9）是一种常染色体隐性遗传性肌肉疾病，目前尚无针对其病因的治疗方案。针对这类缓慢进展的疾病，开发候选疗法需要敏感的结局指标以支持临床试验开展。本研究针对LGMD R9队列人群展开为期6年的随访，拓展了功能评估与磁共振成像（Magnetic Resonance Imaging, MRI）肌肉脂肪分数检测的应用场景。
研究方法：23名此前已接受1年随访评估的LGMD R9患者，在随访满6年时重新入组。本次研究开展了标准化功能评估，项目包括肌力检测、计时类测试与肺量测定；同时采用定量MRI技术检测下肢骨骼肌群的脂肪分数。
研究结果：随访6年时，本次研究纳入评估的全部14个肌群均出现脂肪分数显著升高，而此前1年随访研究中仅8个肌群存在该变化。与1年随访结果截然不同的是，本次6年随访中，6分钟步行试验、10米步行/跑步试验、计时起立行走试验、登梯试验、下梯试验与坐椅起立试验均显示功能显著下降。在所有功能测试项目中，仅用力肺活量（Forced Vital Capacity, FVC）在1年与6年随访中均出现显著降低。
研究解读：本研究结果进一步支持将脂肪分数检测与功能评估共同作为临床试验的主要结局指标。其中最适宜的单块肌肉为股外侧肌、股薄肌（gracilis）、缝匠肌与腓肠肌；采用小腿肌群、大腿肌群或小腿三头肌（triceps surae）复合组进行检测时，可获得较高的标准化反应均值（Standardized Response Mean, SRM）。相较于功能测试，为期6年的定量脂肪分数检测展现出更高的标准化反应均值，提示其对疾病进展的响应性更强。