LAMA2-Related Muscular Dystrophy Across the Life Span: A Cross-sectional Study

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 (NCT04478981, 21 July 2020). The first patient was enrolled in September 2020.

Figure 1. Facial Muscle Weakness and Dysmorphic Features in Patients With LAMA2-MD

(A) neutral position, showing bilateral ptosis. (B) orbicularis oculi weakness. (C) inadequate puckering movements, indicating orbicularis ori weakness. (D) inadequate blowing movements, indicating orbicularis ori weakness. (E) risorius weakness. (F) macroglossia and elongated face. (G) inability of neck flexion indicating rigid spine. (H) scapular winging. (I) spinal and thorax deformities. (J) pseudohypertrophy and hypotrophy of calve muscles, respectively. All identifiable patients provided consent for publication of their pictures. (K) Median muscle strength according to the MRC grading scale in patients with LAMA2-MD. The median muscle strength (MRC) in neck flexor, neck extensor, deltoid, biceps brachii, triceps brachii, wrist flexor, wrist extensor, finger flexor, finger extensor, iliopsoas, gluteus, quadriceps, hamstrings, foot flexor, foot extensor, and toe flexor and extensor hallucis longus muscles.

Figure 2. Scatter Plot

Total MFM-20/32 score (%) against age (years) in patients with decreased merosin expression, absent merosin expression, or an unknown level of merosin expression.

Figure 3. Overview on Echogenicity z Score (Mean) and Heckmatt Score (Median) per Muscle in Patients With LAMA2-MD

The z score of the echogenicity (A) and the median Heckmatt score (B) in the temporalis, sternocleidomastoid, biceps brachii, flexor carpi radialis, rectus abdominis, rectus femoris, vastus lateralis, tibialis anterior, biceps femoris, gastrocnemius medial head, and soleus muscles are shown.