CONGENITAL MUSCULAR DYSTROPHIES: EP.69 LAST STRONG: LAMA2 and SELENON to study trial readiness, outcome measures and natural history

Abstract

SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset rigidity of the spine and respiratory insufficiency. Patients with mutations in LAMA2 gene causing merosin-deficient congenital muscular dystrophy (LAMA2-MD) have a similar clinical phenotype, with a heterogenous disease spectrum ranging from a severe, early-onset congenital (complete laminin α2 deficiency) to a mild, childhood-onset limb-girdle type muscular dystrophy (partial laminin α2 deficiency). For both SELENON-RM and LAMA2-MD, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data. Appropriate clinical and functional outcome measures need to be selected to reach trial readiness. We are performing a natural history study in Dutch-speaking patients diagnosed with SELENON-RM (n=10, mean age=18 (3-50) years, F=3, M=7) and LAMA2-MD (n=20, mean age=19 (3-50) years, F=15; M=5). Patients have four visits over a period of 1.5 year, with an interval of six months. At all visits, they undergo standard neurological examination, hand-held dynamometry (age≥5 years), functional measurements, questionnaires (patient report and/or parent proxy; age≥2 years), muscle ultrasound including ultrasound of the diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age≥5 years), and accelerometry for eight days; at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography), X-ray of the spine (age≥2 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age≥2 years) and full body magnetic resonance imaging (MRI) (age≥10 years). Hereby we aim to describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD and to select outcome measures for future clinical trials. Our natural history study is an essential step to reach trial readiness.