Background: Clinical course variability in Duchenne muscular dystrophy (DMD) is partially explained by the mutation location in the DMD gene and variants in modifier genes. We assessed the effect of the SPP1, CD40, and LTBP4 genes and DMD mutation location on loss of ambulation (LoA). Methods: SNPs in SPP1-rs28357094, LTBP4-rs2303729, rs1131620, rs1051303, rs10880, and CD40-rs1883832 were genotyped, and their effect was assessed by survival and hierarchical cluster analysis. Results: Patients on glucocorticoid corticosteroid (GC) therapy experienced LoA one year later (p = 0.04). The modifying effect of SPP1 and CD40 variants, as well as LTBP4 haplotypes, was not observed using a log-rank test and multivariant Cox regression analysis. Cluster analysis revealed two subgroups with statistical trends in differences in age at LoA. Almost all patients in the cluster with later LoA had the protective IAAM LTBP4 haplotype and statistically significantly fewer CD40 genotypes with harmful T allele and “distal” DMD mutations. Conclusions: The modifying effect of SPP1, CD40, and LTBP4 was not replicated in Serbian patients, although our cohort was comparable in terms of its DMD mutation type distribution, SNP allele frequencies, and GC-positive effect with other European cohorts. Cluster analysis may be able to identify patient subgroups carrying a combination of the genetic variants that modify LoA.

Myotonic dystrophy type 1 (DM1) is caused by an expansion of CTG repeats in the DMPK gene. In a proportion of patients, the expanded allele contains variant repeats, which have been associated with later disease onset and different clinical presentation, although their full impact remains incompletely defined. We compared sociodemographic, neuromuscular, and multisystem clinical features between DM1 patients with pure CTG expansions (n = 66) and those with variant repeats (n = 9), who formed a consecutive cohort of unrelated index cases evaluated at the age of diagnosis in routine clinical practice. Patients with variant repeats were nine years older at diagnosis than patients with pure repeat expansions (p = 0.025), had more years of formal education (p = 0.024), and showed reduced muscle strength in proximal lower limbs (p = 0.049). No childhood or juvenile forms were observed among patients with variant repeats. Sex, disease duration, and most other clinical parameters, including multisystem involvement, did not differ between groups. The results of our exploratory study support variant repeats as disease modifiers in both age at onset and pattern of muscle involvement, and imply a two-sequential-component hypothesis in DM1 pathogenesis.