The CAPN3 p.Lys 254del variant is not always associated with dominant CAPN3‐related muscular dystrophy

Author:

Valls Andrea12,Gutiérrez‐Gutiérrez Gerardo234,Martínez Agustín5,Ruiz‐Roldán Cristina12,Camaño Pilar126,López de Munain Adolfo12789,Sáenz Amets12ORCID

Affiliation:

1. Neurosciences Area Biodonostia Health Research Institute San Sebastian Spain

2. CIBERNED, CIBER, Spanish Ministry of Science & Innovation, Carlos III Health Institute Madrid Spain

3. Department of Neurology Hospital Universitario Infanta Sofía Madrid Spain

4. Neuromuscular Diseases Unit Universidad Europea de Madrid Madrid Spain

5. Hospital Público da Mariña–Burela Burela Spain

6. Molecular Diagnostics Platform, Biodonostia Health Research Institute San Sebastian Spain

7. Department of Neurology Donostialdea Integrated Health Organisation, Osakidetza San Sebastian Spain

8. Department of Neurosciences University of the Basque Country UPV‐EHU San Sebastian Spain

9. Faculty of Medicine University of Deusto Bilbao Spain

Abstract

AbstractIntroduction/AimsLimb‐girdle muscular dystrophy R1 (LGMDR1) calpain 3‐related usually presents as a recessively transmitted weakness of proximal limb‐girdle muscles due to pathogenic variants in the CAPN3 gene. Pathogenic variants in this gene have also been found in patients with an autosomal dominantly inherited transmission pattern (LGMDD4). The mechanism underlying this difference in transmission patterns has not yet been elucidated. Camptocormia, progressive limb weakness, myalgia, back pain, and increased CK levels are common clinical features associated with dominant forms. The p.Lys254del pathogenic variant was associated with camptocormia in two LGMDD4 families. This study aimed to present carriers found in recessively transmitted LGMDR1 families bearing the p.Lys254del variant that do not show muscle weakness.MethodsDNA sequencing was performed on exon 5 of CAPN3 in family members to establish the carrier status of the pathogenic variant. They were evaluated clinically and MRI was performed when available.ResultsTwo families presented with the p.Lys254del pathogenic variant in a homozygous or compound heterozygous state. Family members carrying only the pathogenic variant in the heterozygous state did not demonstrate the myopathic characteristics described in dominant patients. Camptocormia and other severe clinical symptoms were not observed.DiscussionWe conclude that the p.Lys254del pathogenic variant per se cannot be solely responsible for camptocormia in dominant patients. Other undisclosed factors may regulate the phenotype associated with the dominant inheritance pattern in CAPN3 pathogenic variant carriers.

Funder

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas

Publisher

Wiley

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