Characterization of the Natural History of LAMA2-RD and Identification of Novel Disease Biomarkers

Characterization of the Natural History of Laminin-Alpha-2-Related Dystrophy (LAMA2-RD) Patients and Identification of Novel Disease Biomarkers

The goal of this observational study is to learn about the natural history and multi-organ involvement of Laminin-Alpha-2-Related Dystrophy (LAMA2-RD) in pediatric and adult patients. The main questions it aims to answer are:

• What is the prevalence and nature of cardiac involvement, and how do this relate to age and muscular phenotype?
• What is the prevalence of peripheral neuropathy, and how do this relate to age and muscular phenotype?
• What is the extent of respiratory, nutritional, skeletal, and cognitive/brain involvement, particularly in adults with more severe vs less severe phenotypes?
• How does quality of life and transition to adulthood occur in individuals with LAMA2-RD?
• Which nomenclature best reflects differences in disease severity and may support future clinical trial design?

Study participants will:

• Undergo retrospective and prospective clinical assessments every 12 months for 2 years across multiple centers.
• A subset of adult participants (n=20) will receive cardiac MRI with contrast enhancement.
• Provide biological samples during routine blood testing for future research.

Background: LAMA2-RD is an autosomal recessive disorder due mutations in the LAMA2 gene. The clinical manifestations of LAMA2-RD range from severe, early-onset congenital muscular dystrophy (CMD) to a milder limb-girdle type muscular dystrophy (LGMDR23). A few promising therapies are getting closer to clinical application, but clinical trial readiness is limited by the paucity of natural history studies. Although some groups have recently shed light on different aspects of the disease, these are usually focused on pediatric populations. A detailed description of the disease in adult patients as well as the importance of specific organs involvement (e.g., heart and peripheral nervous system) are lacking.

Objectives: To describe the natural history of a large cohort of patients affected by LAMA2-RD (n=40-45).

Specifically, the investigators aim 1) to clarify the prevalence and characteristics of cardiac involvement, and to correlate the latter with age and muscular phenotype 2) to clarify the degree of neuropathic involvement 3) to clarify respiratory, nutritional, skeletal, and brain/cognitive involvement, with a focus on adult population 4) to clarify which nomenclature better captures differences in terms of disease severity, to help refine inclusion criteria for trials 5) to understand how quality of life is impacted and transition to adulthood performed 6) to collect biological material for future research Design and methods: This will be a multicenter, retrospective and prospective longitudinal observational study with additional procedures for a subset of patients: cardiac MRI with contrast enhancement and an additional sample handling during routine blood test. Patients will be assessed every 12 months over a period of 2 years. In addition to routine clinical assessments, cardiac MRI will be performed in a selected 20 adult population. The differential involvement of specific organs between LAMA2-RD subpopulations will be analyzed.

INCLUSION

Diagnosis of LAMA2-related dystrophy confirmed via:

1. Two causative mutations in the LAMA2 gene or Muscle biopsy with absence of

2. merosin (laminin-211) and at least one causative mutation in the LAMA2 gene or

   • Consistent phenotype and affected siblings with criteria a) or b) and
   • Ability to participate in study visits at least every 12 months during a 24 months period.
   • Ability to sign informed consent for adults or parents/ legal tutors for children

EXCLUSION

• Lack of a confirmed diagnosis of LAMA2-relate dystrophy
• Inability to participate in study visits at least every 12 months
• Medical fragility which precludes the ability to safely travel to the study site and/or participate in the study assessments