SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness.

BACKGROUND: SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness. OBJECTIVE: We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care. METHODS: This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry. RESULTS: Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3-42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures. CONCLUSIONS: We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.

Bone Quality in Patients with a Congenital Myopathy: A Scoping Review.

BACKGROUND: Congenital myopathies are rare neuromuscular disorders presenting with a wide spectrum of clinical features, including long bone fractures (LBFs) that negatively influence functional prognosis, quality of life and survival. Systematic research on bone quality in these patients is lacking. OBJECTIVE: This scoping review aims to summarize all evidence on bone quality and to deduce recommendations for bone quality management in congenital myopathies. METHODS: Five electronic databases (Pubmed, Embase, Cochrane, Web of Science, CINAHL) were searched. All studies on bone quality in congenital myopathies were included. Decreased bone quality was defined as low bone mineral density and/or (fragility) LBFs. Study selection and data extraction were performed by three independent reviewers. RESULTS: We included 244 single cases (mean: 4.1±7.6 years; median: 0 years) diagnosed with a congenital myopathy from 35 articles. Bone quality was decreased in 93 patients (37%) (mean: 2.6±6.8 years; median: 0 years). Low bone mineral density was reported in 11 patients (4.5%) (mean: 10.9±9.7; median: 11 years). Congenital LBFs were reported in 64 patients (26%). (Fragility) LBFs later at life were described in 24 patients (9.8%) (mean: 14.9±11.0; median: 14 years). Four cases (1.6%) were reported to receive vitamin D and/or calcium supplementation or diphosphonate administration. CONCLUSION: LBFs are thus frequently reported in congenital myopathies. We therefore recommend optimal bone quality management through bone mineral density assessment, vitamin D and calcium suppletion, and referral to internal medicine or pediatrics for consideration of additional therapies in order to prevent complications of low bone mineral density.