Late-onset facioscapulohumeral muscular dystrophy defines a distinct clinical subgroup

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) shows marked clinical heterogeneity, partly related to age at onset. We analysed baseline, 12- and 24-month follow-up data from 231 FSHD1 patients enrolled in the ReSolve study (NCT03458832) to compare clinical, genetic, and epidemiological features between adult-onset (n = 190) and late-onset (n = 41) patients. Differences were assessed using generalized linear models and repeated-measures covariance analyses adjusting for demographics and disease duration. Late-onset patients were predominantly female (58.5%, p = 0.039), older (64.8 ± 6.3 vs 47.6 ± 13.5 years; p < 0.001), and carried longer D4Z4 repeats (6.5 ± 1.6 vs 5.7 ± 1.8; p = 0.01). They showed milder facial and upper limb involvement but greater lower limb impairment, evaluated with TUG (2.37 vs 2.11 s, p = 0.001) and 6MWT (329.16 vs 415.22 meters, p = 0.002), despite shorter disease duration. Lower limb weakness was the most frequent initial symptom (30% vs 10.7%, p = 0.0029). After one year, late-onset patients maintained similar characteristics, while facial differences were no longer significant at two years. Disease progression was similar across outcome measures except for the FSHD clinical score, which worsened more in late-onset patients at two years. These findings indicate that late-onset FSHD1 represents a distinct clinical phenotype relevant for outcome measure selection and personalized management strategies.