LAMA2 -Related Muscular Dystrophy Across the Life Span

Abstract

Background and Objectives LAMA2 -related muscular dystrophy ( LAMA2 -MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. No curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data, and appropriate clinical and functional outcome measures are needed. We aim for deep clinical phenotyping, establishment of a well-characterized baseline cohort for prospective follow-up and recruitment for future clinical trials, improvement of clinical care, and selection of outcome measures for reaching trial readiness. Methods We performed a cross-sectional, single-center, observational study. This study included neurologic examination and functional measurements among others the Motor Function Measure 20/32 (MFM-20/32) as primary outcome measure, accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electrocardiography and echocardiography, and dual-energy X-ray absorptiometry. Results Twenty-seven patients with genetically confirmed LAMA2 -MD were included (21 ± 13 years; M = 9; ambulant = 7). Axial and proximal muscle weakness was most pronounced. The mean MFM-20/32 score was 42.0% ± 29.4%, with domain 1 (standing and transfers) being severely affected and domain 3 (distal muscle function) relatively spared. Physical activity as measured through accelerometry showed very strong correlations to MFM-20/32 (Pearson correlation, −0.928, p < 0.01). Muscle ultrasound showed symmetrically increased echogenicity, with the sternocleidomastoid muscle most affected. Respiratory function was impaired in 85% of patients without prominent diaphragm dysfunction and was independent of age. Ten patients (37%) needed (non)invasive ventilatory support. Cardiac assessment revealed QRS fragmentation in 62%, abnormal left ventricular global longitudinal strain in 25%, and decreased left ventricular ejection fraction in 14% of patients. Decreased bone quality leading to fragility fractures was seen in most of the patients. Discussion LAMA2 -MD has a widely variable phenotype. Based on the results of this cross-sectional study and current standards of care for congenital muscular dystrophies, we advise routine cardiorespiratory follow-up and optimization of bone quality. We propose MFM-20/32, accelerometry, and muscle ultrasound for assessing disease severity and progression. For definitive clinical recommendations and outcome measures, natural history data are needed. Clinical Trials Registration This study was registered at [clinicaltrials.gov][1] ([NCT04478981][2], 21 July 2020). The first patient was enrolled in September 2020. 6MWT= : 6-Minute Walk Test; 10MWT= : 10-Meter Walk Test; BMI= : body mass index; CIS= : Checklist Individual Strength; DEXA= : dual-=energy X-ray absorptiometry; DMD= : Duchenne muscular dystrophy; EK2= : Egen Klassifikation version 2; ECG= : electrocardiogram; FEV1%= : percentage of predicted forced expiratory volume in 1 second; FVC%= : percentage of predicted forced vital capacity; FVC= : forced vital capacity; GLS= : global longitudinal strain; GTFT= : Graded and Timed Function Tests; HFMS= : Hammersmith Functional Motor Scale; HHD= : Handheld dynamometry; INQoL= : Individualized Neuromuscular Quality of Life; IPA= : Impact on Participation and Autonomy; LAMA2-MD= : LAMA2-related muscular dystrophy; LVEF= : left ventricular ejaction fraction; MDC1A= : merosin-deficient congenital muscular dystrophy type 1A; MEP= : Maximum Expiratory Pressure; MFM-20/32= : Motor Function Measure 20/32; miniBEST= : Mini Balance Evaluation Systems Test; MIP= : Maximum Inspiratory Pressure; MRC= : Medical Research Council; PBS= : Pediatric Balance Scale; PCF= : peak cough flow; PedsQL= : Pediatric Quality of Life Inventory; PedsQL NMM= : Pediatric Quality of Life Inventory Neuromuscular Module; PedsQL MFS= : Pediatric Quality of Life Inventory Multidimensional Fatigue Scale; RAND-36= : Research and Development-36; SNIP= : Sniff Nasal Inspiratory Pressure; SVMgs= : the gravity subtracted sum of vector magnitudes; TUG= : Timed Up and Go Test; TDI= : tissue Doppler imaging; TTE= : transthoracic echocardiography; VC= : vital capacity [1]: http://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04478981&atom=%2Fnng%2F9%2F5%2Fe200089.atom