Autosomal recessive limb‐girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients

Abstract

Abstract In this retrospective study, we conducted a clinico‐genetic analysis of patients with autosomal recessive limb‐girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3 , DYSF , SGCG , SGCA , SGCB , SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand‐dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3‐5/LGMD2C‐E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR‐LGMD and MMD in the Netherlands amounted to 14.4 × 10 −6 . Thirty‐three novel mutations were identified. A wide range in age of onset (0‐72 years) and loss of ambulation (5‐74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non‐invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.