Introduction

• FKRP-related LGMDR9 is an autosomal recessive limb-girdle muscular dystrophy, a class of genetic muscle diseases characterized by progressive weakness predominantly in proximal limb muscles.
• LGMDR9 is highly variable in presentation, as patients can either present a severe weakness with rapid deterioration and loss of ambulation in their teens or a later onset with milder disease evolution. The average age at diagnosis is 30 years.
• Patients with LGMDR9 are prone to respiratory involvement and dilated cardiomyopathy.
• Some ambulant patients may require non-invasive ventilation (NIV) with the earliest sign of involvement being diaphragmatic and a drop in their forced vital capacity (FVC).
• To reinforce published data on the natural history of LGMDR9 and expand the geographic outreach, Genethon launched a natural history study (NHS) in three European countries (NCT03842878), which will function as a non-concurrent control group for the gene therapy trial (NCT05224505) sponsored by Atamyo.
• Atamyo coordinated discussions with experts ensuring that the selection of parameters measured in the NHS and the gene therapy trial are robust and clinically meaningful.

Background & Aim

• Limb-girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive rare neuromuscular disorder caused by a mutation in the fukutin-related protein gene FKRP. Respiratory and cardiac involvement is common and can occur independently of skeletal muscle involvement. The disease is heterogeneous with age of onset, degree of severity and rate of progression, which was earlier confirmed by assessment of muscle fat fraction (FF) using quantitative magnetic resonance imaging (MRI).
• Quantitative MRI-based outcome measures, including FF, water T2 and water T1 (which reflect disease activity mechanisms such as inflammation/edema/…) are used in many longitudinal studies in neuromuscular diseases. Besides skeletal muscle MRI, MRI-based cardiac outcome measures are also assesed in muscle diseases with cardiac involvement.
• Here, we investigated preliminary MRI data in skeletal and cardiac muscle in the Généthon natural history study in LGMD R9.

Introduction

LGMD-R9 is due to mutations in the FKRP gene, encoding the Fukutin Related Protein.

FKRP is involved in α-dystroglycan (αDG) glycosylation: In this complex multi-step process, the precise function of FKRP is the addition of a ribitol-5-phosphate in the sugar chain being formed, in the Golgi apparatus. Glycosylation defects of αDG disrupt its proper binding to extra-cellular matrix (ECM) components, and therefore the link between the cytoskeleton and the ECM. Muscle fibers become less resistant to muscle contractions.