natural history study of children with lama2-related dystrophies

Conditions: Merosin Deficient Congenital Muscular Dystrophy

Summary: the goal of this natural history study is to characterize the disease course, characteristics in paediatric population of lama2-rd (related dystrophies) patients. the aim of the study is to establish a well-described cohort of patients in france with lama2-rd for prospective follow-up and recruitment for future clinical trials. participants will be follow up during a two years period regarding exhaustive aspects of the pathology: * muscular function * respiratory function * cognitive phenotyping * quality of life * growth parameters * biomarkers

the international workshop on lama2-rd, held in 2019 in maastricht, stressed the importance of the identification of lama2-rd patients and the natural history studies worldwide. together with the recent progress in preclinical applications, the road to therapy is paved. however, no effective treatment has currently received market approval. given the phenotype variability in lama2-rd patients, even in very young ones, determining which outcome measure(s) could be the most appropriate to assess the efficacy of potential therapies, and which variables are prognostic of the disease course, is required. in consequence, it is clearly necessary to explore all the aspects of the pathology: physiological, clinical/motor, biological, aligning with current or future international studies though collaboration. unlike results obtained through a retrospective study, data from a prospective natural history will be less subject to bias and error. control of the studied population will also lead to reduce the variability of the results. the different variables explored during this study aim to cover all aspects of the disease and appear to be relevant candidates as outcomes. the aim of the study is to focus on the clinical phenotyping and to establish a well-described cohort of patients in france with lama2-rd for prospective follow-up and recruitment for future clinical trials. one other objective is to validate the use of a large subset of outcome measures in lama2-rd. adding an electrophysiological data will give more insight to the neuropathology of the disease and enlarge the scope of futures therapies. an exploratory part will test if denaturation profiling of plasma from patients can be used to follow disease progression. finally, serum and plasma samples from patients will also be stored for future studies focused on searching and validating novel biomarkers in lama2-rd.

Eligibility criteria:
inclusion criteria: * signed informed consent by the legal authority responsible and/or assent by the subject (starting from 6 years old) * subject must be * supportive clinical phenotype and diagnosis of lama2-rd, confirmed by: * two pathogenic variants in the lama2 gene (via a diagnostic laboratory included on an approved list of genetic testing laboratories (annex 1)) or * muscle biopsy with absence of merosin (laminin-211) and at least one pathogenic variant in the lama2 gene * absence of another confirmed neurological genetic disease * willingness to maintain current exercise and/or physical therapy regimen for the duration of the clinical study * willingness to comply with the study protocol, including all the mandatory study procedures and visits * affiliated to or a beneficiary of a french or acknowledged in france, social security scheme exclusion criteria: * developmental quotient less than 70 and/or behavioral disorder requiring general anesthesia to perform an mri * acute medical illness or hospitalization within 30 days prior to informed consent * participation in a previous trial of any investigational agent for lama2-rd, or use of any other investigational therapy within 30 days prior to informed consent, or participation in other clinical studies, within 30 days (or 5 half-lives, whichever is longer) prior to informed consent, which, in the opinion of the pi, may potentially confound results from this study * other significant medical condition and/or overall fragility of medical status, which in the opinion of the investigator may confound interpretation of the clinical course of lama2-rd * pregnant or breastfeeding women

Keywords: lama2 congenital muscular dystrophy natural history