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.

BackgroundAim. Common features of tuberous sclerosis complex (TSC) arise from the formation of hamartomas both in the brain and multiple organ systems, mainly due to a mutation in one of two genes, TSC1 or TSC2, with well described inter- and intrafamilial different phenotypic outcomes. The aim of this work was to make a synthesis of the patients data with diagnosed tuberous sclerosis in order to better understand the disease in our environment. Methods. We reviewed retrospectively the clinical records of all patients with TSC, diagnosed and regularly followed at the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade, Serbia during the period of more than two decades. Statistical analyses were performed using descriptive statistics as well as the Fisher?s exact test. Results. Cohort of 44 patients with the diagnosis of definitive TSC were included. The mean age at last follow-up was 19.4 years [age range 1?58, standard deviation (SD) 11.8]. Family history for TSC was noted in 25% of patients. Dermatological manifestations were described in 93.2%, retinal astrocytoma and cardiac rhabdomyomas was found in 36.4% each, nephrological manifestations in 34.1% and lymphangioleiomyomatosis was diagnosed in two female patients. All patients presented with the structural lesions of central nervous system; epilepsy was diagnosed in 88.6%, out of whom 59 % of patients had seizure onset in the first year of life. The West syndrome was diagnosed in 27.3% of patients. Complete seizure control was achieved in 30.8%, in a majority with valproic acid or cabamazepine, but also with topiramate, lamotrigine and vigabatrin. At least two antiepileptic drugs were administered in 82% of patients. Mental retardation was noted in 50% of patients. Psychiatric manifestations were found in 40.9%, with attention deficit hyperactivity disorder diagnosed in 27.3%, autism spectrum disorder in 13.6 %, and psychosis and depression observed in 11.4% each. Conclusion. This kind of synthesis of the data certainly contributes to better understanding of the disease in our environment, as TSC, although well-known disease, still remains diagnostic and therapeutic challenge in daily clinical practice.

Duchenne muscular dystrophy is the most common inherited muscle disease in childhood, which has a progressive clinical course with a fatal outcome that most often occurs between the second and fourth decade of life. The disease is inherited X-linked, recessively, and in two-thirds of patients, it is transmitted from the mother, while in the remaining third of patients, it is a de novo mutation. Mutations in the dystrophin gene (DMD gene) such as deletions, duplications and small mutations can be found throughout the entire length of the gene. The disease begins between the third and fifth year of life, and the initial muscle weaknesses are clinically manifested as slower running, difficulty climbing stairs or difficulty getting up from squats. Sometimes, accidentally discovered, elevated keratin kinase values or delayed early psychomotor development milestones in a child with hypertrophic calves can initiate a diagnostic procedure in the direction of Duchenne muscular dystrophy. The disease usually has a uniform clinical course and implies a clear time sequence of events. Muscle weakness leads to loss of ambulation, then the function of the upper extremities, to complete immobility, with the evolution of dilated cardiomyopathy and respiratory insufficiency, which are the main causes of death. Certain patients show deviations from the above in terms of longer functionality and later loss of independent ambulation, later cardiomyopathy and respiratory insufficiency and vice versa. It is believed that in addition to the application of modern standards of care and treatment of patients, the clinical course is influenced by genes independent of the causal DMD gene, which affects processes in dystrophic muscle, primarily inflammation, fibrosis and fatty infiltration, through specific signaling pathways. So far, six genes have been described whose variants modify the course of Duchenne muscular dystrophy. The secreted phosphoprotein 1 (SPP1) is the first described gene whose G allele in the variant rs28357094 is associated with an earlier age of gait loss. In addition, variants in the genes described are LTBP4 (latent transforming growth factor-b binding protein 4), CD40, ACTN3 (actinin 3), THBS1 (thrombospondin 1) and TCTEX1D1 (Tctex1 domain containing 1). The aim of this paper is to present already-known genes that modify Duchenne muscular dystrophy and their influence on the clinical course of the disease.