European journal of neurology · 2025
Clinical and Genetic Characterization of the Largest Cohort of Patients With D3 Limb-Girdle Muscular Dystrophy in an Isolated Uruguayan Population.
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Demicheli Elisa, Zamora Andrea, Sánchez Nury, Colistro Valentina, Vicente Beatriz, Salazar Emilio, Chiesa Mercedes, Santos Anahi, Benvenuto Florencia, Sans Mónica, Vázquez María Cristina
Аннотация
BACKGROUND: Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders characterized by progressive proximal weakness. LGMD D3 is an extremely rare autosomal dominant myopathy caused by pathogenic variants in the HNRNPDL gene encoding a protein related to RNA processing. To date, only six countries and seven families have been reported worldwide: Brazil, China and Italy with the pathogenic variant c.1132G>A p.(Asp378Asn), Uruguay, Argentina and Spain with the pathogenic variant c.1132G>C p.(Asp378His).
METHODS: The study was conducted in the city of Nueva Palmira in Uruguay between March 2019 to August 2024. Forty-nine patients with LGMD D3 and 10 asymptomatic individuals carrying the mutation were examined. Serum CK, electromyography, MRI, and pulmonary function testing results were reviewed when available. Whole exome sequencing and screening test for the mutation were performed. Statistical analysis was done using STATA 16.1.
RESULTS: LGMD D3 in Uruguay presents as a slowly progressive adult-onset scapulo-pelvic-peroneal dystrophy. Pathogenic variant c.1132G>C p.(Asp378His) was confirmed in all participants. Estimated prevalence of LGMD D3 was 3.75/1000 in Nueva Palmira. Mean age of onset differed by sex, with men presenting younger (p = 0.006). Characteristic MRI features were observed.
CONCLUSIONS: LGMD D3 presents with a distinctive scapulo-pelvic-peroneal phenotype. To our knowledge, this is the largest LGMD D3 cluster and the first report of sex-dependent age of onset. Our study illustrates how genetic isolation can lead to high LGMD D3 prevalence in an admixed population and explores its potential origin.
METHODS: The study was conducted in the city of Nueva Palmira in Uruguay between March 2019 to August 2024. Forty-nine patients with LGMD D3 and 10 asymptomatic individuals carrying the mutation were examined. Serum CK, electromyography, MRI, and pulmonary function testing results were reviewed when available. Whole exome sequencing and screening test for the mutation were performed. Statistical analysis was done using STATA 16.1.
RESULTS: LGMD D3 in Uruguay presents as a slowly progressive adult-onset scapulo-pelvic-peroneal dystrophy. Pathogenic variant c.1132G>C p.(Asp378His) was confirmed in all participants. Estimated prevalence of LGMD D3 was 3.75/1000 in Nueva Palmira. Mean age of onset differed by sex, with men presenting younger (p = 0.006). Characteristic MRI features were observed.
CONCLUSIONS: LGMD D3 presents with a distinctive scapulo-pelvic-peroneal phenotype. To our knowledge, this is the largest LGMD D3 cluster and the first report of sex-dependent age of onset. Our study illustrates how genetic isolation can lead to high LGMD D3 prevalence in an admixed population and explores its potential origin.