A 5-year natural history study in LAMA2-related muscular dystrophy and SELENON-related myopathy: the Extended LAST STRONG study.

Background: SELENON-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive axial muscle weakness, rigidity of the spine, scoliosis, and respiratory insufficiency. Laminin-a2-related muscular dystrophy (LAMA2-MD) has a similar clinical phenotype, which ranges from severe, early-onset congenital muscular dystrophy type 1A (MDC1A) to milder forms presenting as childhood- or adult-onset limb-girdle type muscular dystrophy. The first 1.5-year natural history follow-up showed that 90% of the patients had low bone quality, respiratory impairments were found in all SELENON-RM and most of the LAMA2-MD patients, and many had cardiac risk factors. However, further extensive knowledge on long-term natural history data, and clinical and functional outcome measures is needed to reach trial readiness. Therefore, we extended the natural history study with 3- and 5-year follow-up visits (Extended LAST STRONG).

Methods: The Extended LAST STRONG is a long-term natural history study in Dutch-speaking patients of all ages diagnosed with genetically confirmed SELENON-RM or LAMA2-MD, starting in September 2023. Patients visit our hospital twice over a period of 2 years to complete a 5-year follow up from the initial LAST-STRONG study. At both visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, muscle ultrasound, respiratory assessments (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years), X-ray of the left hand (age ≤ 17 years), lower extremity MRI (age ≥ 10 years), accelerometry for 8 days (age ≥ 2 years), and questionnaires (patient report and/or parent proxy; age ≥ 2 years). All examinations are adapted to the patient's age and functional abilities. Disease progression between all subsequent visits and relationships between outcome measures will be assessed.

Discussion: This study will provide valuable insights into the 5-year natural history of patients with SELENON-RM and LAMA2-MD and contribute to further selecting relevant and sensitive to change clinical and functional outcome measures. Furthermore, this data will help optimize natural history data collection in clinical care and help develop clinical care guidelines.

Trial registration: This study protocol including the patient information and consent forms has been approved by medical ethical reviewing committee ('METC Oost-Nederland'; https://www.ccmo.nl/metcs/erkende-metcs/metc-oost-nederland , file number: 2023-16401). It is registered at ClinicalTrials.gov (NCT06132750; study registration date: 2023-10-05; study first passed date: 2023-11-15).