A 5-year Natural History Study in LAMA2-related Muscular Dystrophy and SELENON-related Myopathy.

A 5-year Natural History Study in LAMA2-related Muscular Dystrophy and SELENON-related Myopathy: the Extended LAST STRONG Study

SELENON-related myopathy (SELENON-RM) and LAMA2-related muscular dystrophy (LAMA2-MD) are congenital neuromuscular disorders presenting with slowly, progressive axial muscle weakness, spinal rigidity, scoliosis and respiratory insufficiency. Currently, no curative treatment options exist, yet promising preclinical trials are ongoing. Clinical trials are expected to start within 5 years. Natural history data and outcome measures for measuring therapy effectiveness were lacking. Therefore, the LAST STRONG Study (a 1.5-year natural history study) started in 2020. With the extended LAST STRONG Study, we aim to further analyze and expand the 1.5-year natural history data on SELENON-RM or LAMA2-MD to provide a detailed clinical description of the Dutch and Flemish cohort. This will enable a smooth transition towards implementation into clinical care and clinical trials.

The extended LAST STRONG Study is a prospective, observational natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM and LAMA2-MD. Patients will be invited to visit our hospital two times (3- and 5-years) after the first visit in the LAST STRONG Study. During both visits, patients will undergo a subset of tests (neurological examination, functional measurements, questionnaires, muscle ultrasound, MRI, pulmonary assessment and accelerometry). All measurements are adapted to the patient's age and functional disabilities.

Rationale: A long-term prospective natural history study in an unselected group of patients including clinical and functional outcome measures is lacking in both SELENON-related myopathy (SELENON-RM) and LAMA2-related muscular dystrophy (LAMA2-MD). Due to the promising ongoing preclinical trials, there is a high need to obtain natural history data in order to reach trial readiness for both diseases. With the extended LAST STRONG study, we aim to further analyze and expand our 1.5-year natural history data on SELENON-RM and LAMA2-MD to provide a detailed clinical description of the Dutch and Flemish cohort. This will enable a smooth transition towards implementation into clinical care and clinical trials that are expected to start within 5 years.

Objective: (1) To collect 3- and 5-year natural history data in patients with SELENON-RM and LAMA2-MD. (2) Implementation of natural history data collection into clinical care and international guidelines, and reach trial readiness.

Study design: This is an observational study. A variety of tests will be performed to get a full impression of the patient's abilities and disabilities (standard medical history, neurological examination, functional measurements, questionnaires, imaging, pulmonary assessment and accelerometry). The tests that the patient undergoes depend on the age/abilities/wishes. The tests are selected based on our previously performed 1.5-year natural history study in LAMA2-MD and SELENON-RM. Each participant will perform these measurements during the two scheduled visits at 3- and 5-year after the first visit during the LAST STRONG Study.

Risk and benefit assessment: This study does not concern any product (medicinal product, food product or medical device). There is a small risk for minor injury, e.g. when a participant falls. However since the investigators use all functional tests using movements to which most participants are familiar (i.e. walking, transfers, etc.), the participant will be able to estimate his/her own risk. The investigators don't include tests in which they push participants to their physical limits. the investigators conclude that this study has a negligible risk. A benefit includes the possibility for participants to get a detailed analysis on their own health. Additionally, participants will contribute to the design of future clinical trials on possible treatment options.

Inclusion Criteria:

• Willing and able to complete (part of) the measurement protocol at the Radboudumc, Nijmegen. If patients do not wish or not able to visit our neuromuscular center, they are offered to participate in our study through home visits.
• Genetic conformation of LAMA2-related muscular dystrophy or SELENON-related myopathy by two recessive (likely) pathologic mutations in the LAMA2 or SELENON gene.
• Typical clinical and histological characteristics combined with genetic confirmation in a first degree relative.
• Dutch speaking

Exclusion Criteria:

• Insufficient understanding of the Dutch language