LGMD: EP.177 Clinical and genetic spectrum of a large cohort of delta-sarcoglycan muscular dystrophy.

Abstract

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3-6) that are caused by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent of all sarcoglycanopaphies and it is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic data of a large cohort of LGMDR6 patients and to investigate whether genetic or protein expression data could predict the severity of the disease. We contacted a total of 90 different neuromuscular units/neurology departments over the world and collected demographic, genetic, clinical and remaining protein expression in muscle biopsy data of patients with a genetic confirmed diagnosis of LGMDR6. We contacted more than 90 pediatric and adult neuromuscular units/neurology departments around the world and identified 23 patients from 9 different countries after reviewing genetic data of more than 10.000 patients with a neuromuscular disorder. There was a history of consanguinity in 87% of the patients and 52.2% of patients had another affected relative. Ninety-one percent of the patients were symptomatic at the time of the analysis. Upper and lower limb proximal muscle weakness was the most common presenting symptom. Distal muscle weakness was observed early on the progression of the disease. Cardiac involvement was observed in 5 patients (21.7%) and 4 patients (17.4%) required non-invasive ventilation. Sixty percent of patients were wheelchair-bound since a mean age of 14.6 years old. Patients with an undetectable expression of the sarcoglycan complex measure by muscle immunohistochemistry have a significant early onset of the disease and early age of lost ambulation compared to patients with residual protein expression. This study confirms that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and describes the clinical and molecular data of the largest cohort of patients reported so far. International collaboration has been crucial to collect these data. Our results show that this is a very severe and quickly progressive disease characterized by global muscle weakness affecting proximal and distal muscles of the limbs. As happen with other types of sarcoglycanopathy, there is a correlation between remaining protein expression, age at onset and disease's severity.