Department of Pediatrics and Neurology, DMD Program, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Clinical Translational Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
J Cachexia Sarcopenia Muscle. 2023 Dec;14(6):2804-2812. doi: 10.1002/jcsm.13357. Epub 2023 Oct 25.
Mutations in the 79 exons of the dystrophin gene result in muscle wasting and weakness of varying clinical severity, ranging from severe/typical Duchenne muscular dystrophy (DMD) to intermediate DMD and mild Becker muscular dystrophy (BMD), depending on the frameshift of the mutation. We previously reported that males with DMD have progressively declining appendicular lean mass (ALM) and ALM index (ALMI) with age and worsening functional motor ability compared with healthy controls. These indices have not been studied in patients with intermediate DMD and BMD phenotypes and across DMD genotypes. In this study, we compared age-related trajectories of ALM and ALMI of patients who had (1) BMD without functional mobility deficits with patients who had DMD at different stages of disease and healthy controls; (2) a DMD intermediate phenotype with patients who had a typical DMD phenotype; and (3) DMD categorized by genotype.
We conducted a retrospective review of ALM and ALMI data from 499 patients (ages 5-23 years) with DMD (466 typical and 33 intermediate) and 46 patients (ages 5-21 years) with BMD (without functional mobility deficits and functional mobility score of 1). Patients were grouped according to age reflecting disease stage (ages 5 to <7, 7 to <10, 10 to <14, and 14 to <20 years) and genotype (mutations in exons 1-30, 31-44, 45-62, and 63-79).
ALM and ALMI trajectories of patients with BMD paralleled those of healthy controls until adolescence, in contrast to patients with DMD. ALMI Z-scores of patients with BMD remained within ±2 SD without decline while those of patients with DMD fell below -2 SD around age 12 years. Patients with BMD had increasing ALM and ALMI with age, with peak accrual between ages 10 to <14 years. ALMI declined after age 14 years for those with intermediate DMD compared with 10 years for patients with typical DMD. Patients with mutations in exons 63-79 had a greater decline in ALMI as compared with those with other genotypes after age 10 years.
Age-related changes in ALMI in patients with BMD and intermediate DMD differ from those with typical DMD, reflecting their clinical phenotypes. ALM and ALMI should be further studied in patients with BMD and DMD subtypes for their potential value as surrogate markers to characterize the severity of BMD and DMD and inform clinical care decisions and clinical trial designs.
肌营养不良蛋白基因突变发生在 79 个外显子中，导致肌肉消耗和不同临床严重程度的虚弱，从严重/典型杜氏肌营养不良症（DMD）到中间型 DMD 和轻度贝克肌营养不良症（BMD）不等，具体取决于突变的移码。我们之前报道过，与健康对照组相比，患有 DMD 的男性随着年龄的增长，四肢瘦体重（ALM）和四肢瘦体重指数（ALMI）逐渐下降，运动功能能力恶化。这些指标尚未在中间型 DMD 和 BMD 表型患者以及不同 DMD 基因型患者中进行研究。在这项研究中，我们比较了（1）无运动功能障碍的 BMD 患者与不同疾病阶段的 DMD 患者和健康对照组的 ALM 和 ALMI 的年龄相关性轨迹；（2）中间型 DMD 表型患者与典型 DMD 表型患者；以及（3）按基因型分类的 DMD。
我们对 499 名 DMD 患者（年龄 5-23 岁）（466 名典型患者和 33 名中间型患者）和 46 名 BMD 患者（年龄 5-21 岁）（无运动功能障碍，运动功能评分 1）的 ALM 和 ALMI 数据进行了回顾性分析。根据年龄反映疾病阶段（5-<7 岁、7-<10 岁、10-<14 岁和 14-<20 岁）和基因型（外显子 1-30、31-44、45-62 和 63-79 的突变）对患者进行分组。
与 DMD 患者相反，BMD 患者的 ALM 和 ALMI 轨迹与健康对照组相似，直到青春期。BMD 患者的 ALMI Z 评分在没有下降的情况下保持在±2SD 范围内，而 DMD 患者的 ALMI Z 评分在 12 岁左右降至-2SD 以下。BMD 患者的 ALM 和 ALMI 随年龄增长而增加，峰值在 10-<14 岁之间。与典型 DMD 患者的 10 岁相比，中间型 DMD 患者的 ALMI 在 14 岁后下降。与其他基因型相比，63-79 外显子突变的患者在 10 岁后 ALMI 下降更为明显。
BMD 和中间型 DMD 患者的 ALMI 与典型 DMD 患者的年龄相关性变化不同，反映了他们的临床表型。应进一步研究 BMD 和 DMD 亚型患者的 ALM 和 ALMI，以评估其作为 BMD 和 DMD 严重程度的替代标志物的潜在价值，并为临床护理决策和临床试验设计提供信息。
