Limb Girdle Muscular Dystrophy Associated With TRIM32 Variants: A National Cohort Study

LGMDR8 is a very rare autosomal recessive limb-girdle muscular dystrophy caused by variants in the TRIM32 gene. To date, 92 cases have been reported, mainly in the Hutterite population with a founder effect. This study aimed to describe a cohort of European origin and to investigate genotype-phenotype correlations.

We conducted a retrospective, multicenter study of 14 French patients with genetically confirmed LGMDR8. Clinical, histological, electrodiagnostic, imaging, and genetic data were collected and compared with those from previously published cases.

Patients showed a slowly progressive disease course, with a mean age at onset of 25.1 years (range 7.5-40.0). The main presenting symptom was proximal lower limb weakness (n = 13). At last follow-up, all patients had proximal lower limb weakness, 10/14 had upper limb involvement, and 10/14 had distal lower limb weakness. Six patients lost ambulation (mean disease duration: 27.3 years). No cardiac or respiratory involvement was observed. Mean creatine kinase levels were mildly elevated (4.5× upper limit of normal). Muscle biopsies exhibited dystrophic features. Ragged-red and COX-negative fibers were observed in two patients. Muscle magnetic resonance imaging revealed symmetrical involvement predominantly affecting posterior thigh muscles. Fourteen distinct pathogenic variants were identified, including eight new ones. Six variants were located in the C-terminal domain. LGMDR8 was estimated to account for 0.9% of the LGMD cases in France. No clear genotype-phenotype correlation was found.

LGMDR8 is very rare in non-Hutterite patients. Age of onset is highly variable. Variants are distributed across most protein domains and did not predict clinical severity.