Mutations in the LAMA2 gene affect the production of the α2 subunit of laminin-211 (= merosin) and result in either partial or complete laminin-211 deficiency. Complete merosin deficiency is typically associated with a more severe congenital muscular dystrophy (CMD), clinically manifested by hypotonia and weakness at birth, the development of contractures of large joints, and progressive respiratory involvement. Muscle atrophy and severe weakness typically prevent independent ambulation. Partial merosin deficiency is mostly manifested by later onset limb-girdle weakness and joint contractures so that independent ambulation is typically achieved. Collectively, complete and partial merosin deficiency is referred to as LAMA2-related dystrophies (LAMA2-RDs) and represents one of the most common forms of congenital muscular dystrophies worldwide. LAMA2-RDs are classically characterized by both central and peripheral nervous system involvement with abnormal appearing white matter (WM) on brain MRI and dystrophic appearing muscle on muscle biopsy as well as creatine kinase (CK) levels commonly elevated to >1,000 IU/L. Next-generation sequencing (NGS) has greatly improved diagnostic abilities for LAMA2-RD, and the majority of patients with merosin deficiency carry recessive pathogenic variants in the LAMA2 gene. The existence of multiple animal models for LAMA2-RDs has helped to advance our understanding of laminin-211 and has been instrumental in preclinical research progress and translation to clinical trials. The first clinical trial for the LAMA2-RDs was a phase 1 pharmacokinetic and safety study of the anti-apoptotic compound omigapil, based on preclinical studies performed in the dy^W/dy^W and dy^2J/dy^2J mouse models. This phase 1 study enabled the collection of pulmonary and motor outcome measures and also provided the opportunity for investigating exploratory outcome measures including muscle ultrasound, muscle MRI and serum, and urine biomarker collection. Natural history studies, including a five-year prospective natural history and comparative outcome measures study in patients with LAMA2-RD, have helped to better delineate the natural history and identify viable outcome measures. Plans for further clinical trials for LAMA2-RDs are presently in progress, highlighting the necessity of identifying adequate, disease-relevant biomarkers, capable of reflecting potential therapeutic changes, in addition to refining the clinical outcome measures and time-to-event trajectory analysis of affected patients.

中的突变 拉玛2该基因影响层粘连蛋白211（= merosin）α2亚基的产生，并导致部分或全部层粘连蛋白211缺乏。完全黑素缺乏通常与更严重的先天性肌营养不良（CMD）有关，临床上表现为出生时肌张力低下和虚弱，大关节挛缩的发展以及进行性呼吸受累。肌肉萎缩和严重虚弱通常会阻止独立的运动。一部分黑色素缺乏症主要表现为以后发作的肢带无力和关节挛缩，因此通常可实现独立的下肢活动。总的来说，完全和部分黑素蛋白缺乏症被称为LAMA2相关性营养不良（LAMA2-RDs），代表着全球范围内最常见的先天性肌肉营养不良之一。LAMA2-RDs的典型特征是中枢神经系统和周围神经系统受累，大脑MRI上出现异常出现的白质（WM），肌肉活检时出现营养不良的出现的肌肉以及肌酸激酶（CK）的水平通常升高至> 1,000 IU / L。下一代测序（NGS）大大提高了LAMA2-RD的诊断能力，大多数黑色素缺乏症患者在患者中携带隐性病原体。拉玛2基因。LAMA2-RDs的多种动物模型的存在有助于增进我们对层粘连蛋白211的了解，并且在临床前研究进展和临床试验转化中发挥了作用。LAMA2-RDs的第一个临床试验是抗凋亡化合物omigapil的1期药代动力学和安全性研究，其基础是在临床试验中进行的dy^W /dy^W和dy^2J /dy^2J鼠标模型。这项1期研究能够收集肺部和运动结局指标，也为调查探索性结局指标提供了机会，包括肌肉超声，肌肉MRI和血清以及尿液生物标志物的收集。自然史研究，包括对LAMA2-RD患者的五年前瞻性自然史和比较结局指标研究，有助于更好地描绘自然史并确定可行的结局指标。目前正在进行LAMA2-RDs进一步临床试验的计划，该计划着重于确定适当的，与疾病相关的生物标记物的必要性，这些标记物能够反映潜在的治疗变化，此外还需要完善临床预后指标和事件发生时间轨迹分析受影响的患者。