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Povzetek: Background: Amyotrophic lateral sclerosis (ALS) is one of the most devastating fatal motor neuron diseases, characterized by progressive degeneration of motor neurons in the brain and spinal cord. A significant advance in ALS therapy was achieved with the recent European Medicines Agency approval of Tofersen, the first antisense oligonucleotide (ASO) specifically targeting SOD1 mRNA, a key genetic determinant of the disease. Yet, despite its clinical relevance, data on SOD1-ALS in Central Eastern Europe remain scarce. Methods: Here, we present a multicentric study across six countries—Austria, Czechia, Poland, Hungary, Slovakia, and Slovenia—representing approximately 16% of the European Union's population. We report all pathogenic, likely pathogenic, and uncertain SOD1 variants, along with the phenotypic features, including heritability, age, site of onset, and survival. We also assessed the availability of genetic testing, counseling, and access to Tofersen therapy across the region. Results: Out of 1200 patients with confirmed ALS, we identified 24 distinct pathogenic SOD1 variants in a total of 67 patients (median age at onset 47 [40–55] years), of whom 65.7% had familial ALS (fALS) and 34.3% had sporadic ALS (sALS). We characterized the associated phenotypes and reported that 42 patients are currently receiving Tofersen therapy. Conclusion: This study provides the first comprehensive overview of SOD1-ALS in Central Eastern Europe. Our findings underscore the importance of genetic testing and counseling, as well as equitable access to targeted therapies such as Tofersen to advance patient-specific care in this region.
Ključne besede: tofersen amyotrophic lateral sclerosis, Central Eastern Europe, motor neuron disease, SOD1, targeted therapy
Objavljeno v DiRROS: 28.08.2026; Ogledov: 131; Prenosov: 89
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Povzetek: Introduction/Aims Changes in body composition in patients with spinal muscular atrophy (SMA) can cause endocrine abnormalities that are insufficiently studied in adults. We aimed to assess the endocrine profile in a cohort of adults with SMA. Second, we compared body composition and endocrine profiles between nonambulatory and ambulatory patients and between different types of SMA. Methods The cross-sectional study included 29 SMA patients (18 [62.1%] males and 11 [37.9%] females) of median age 44 (IQR 30–51.5) years with type 2, 3, or 4. Body composition was measured by bioimpedance. Morning blood samples were drawn for glycated hemoglobin (HbA1c), lipid profile, testosterone, cortisol, and insulin-like growth factor-1 (IGF-1). Blood glucose, insulin, and beta-hydroxybutyrate (BHB) were measured during a 75 g oral glucose tolerance test. The homeostatic model assessment for insulin resistance index was calculated. Results In total, 75.9% of patients had increased fat mass (FM), with 51.7% having an increase despite normal body mass index. Ambulation was the most important discriminating factor of body composition. 93.1% of patients had metabolic abnormalities, including hyperglycemia, insulin resistance, and dyslipidemia. Increased BHB, a marker of ketosis, was present in more than a third of patients. Functional hypogonadism was present in half of male patients. Testosterone and IGF-1 negatively correlated with FM. Discussion Adult patients with SMA had abnormal body composition and highly prevalent metabolic disturbances that might increase cardiometabolic risk. Because treatments have modified the course of SMA, it is important to investigate whether these observations translate into clinically relevant outcomes.
Ključne besede: spinal muscular atrophy, endocrine manifestations, adults
Objavljeno v DiRROS: 15.06.2026; Ogledov: 267; Prenosov: 242
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Povzetek: The spinal muscular atrophy (SMA) phenotype strongly correlates with the SMN2 gene copy number. However, the severity and progression of the disease vary widely even among affected individuals with identical copy numbers. This study aimed to investigate the impact of genetic variability in oxidative stress, inflammatory, and neurodevelopmental pathways on SMA susceptibility and clinical progression. Genotyping for 31 genetic variants across 20 genes was conducted in 54 SMA patients and 163 healthy controls. Our results revealed associations between specific polymorphisms and SMA susceptibility, disease type, age at symptom onset, and motor and respiratory function. Notably, the TNF rs1800629 and BDNF rs6265 polymorphisms demonstrated a protective effect against SMA susceptibility, whereas the IL6 rs1800795 was associated with an increased risk. The polymorphisms CARD8 rs2043211 and BDNF rs6265 were associated with SMA type, while SOD2 rs4880, CAT rs1001179, and MIR146A rs2910164 were associated with age at onset of symptoms after adjustment for clinical parameters. In addition, GPX1 rs1050450 and HMOX1 rs2071747 were associated with motor function scores and lung function scores, while MIR146A rs2910164, NOTCH rs367398 SNPs, and GSTM1 deletion were associated with motor and upper limb function scores, and BDNF rs6265 was associated with lung function scores after adjustment. These findings emphasize the potential of genetic variability in oxidative stress, inflammatory processes, and neurodevelopmental pathways to elucidate the complex course of SMA. Further exploration of these pathways offers a promising avenue for developing personalized therapeutic strategies for SMA patients.
Ključne besede: inflammation, neurodegeneration, neurodevelopment, oxidative stress, single nucleotide polymorphism, spinal muscular atrophy
Objavljeno v DiRROS: 04.06.2026; Ogledov: 285; Prenosov: 257
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Povzetek: Disease-modifying therapies have significantly influenced the clinical course of spinal muscular atrophy (SMA), yet objective biomarkers for monitoring disease progression and treatment remain limited. We profiled four muscle-specific miRNAs (myomiRs), ten bioinformatically predicted mRNA targets, two functionally associated lncRNAs, and SMN transcripts in whole blood from 50 adults with SMA types II-IV. Using RT-qPCR, we assessed associations between baseline RNA expression and demographic and clinical parameters, including SMA type, ambulatory status, motor and respiratory function, and explored longitudinal changes during nusinersen (24 months) and risdiplam (6/12 months) treatment. At baseline, miR-206 was higher in type III than in type II and in ambulatory compared to non-ambulatory patients, while it correlated positively with motor and respiratory function and with SMN mRNA variants (total, FL, and ∆7). SMN transcript levels were higher in patients with more SMN2 copies and in ambulatory patients and showed positive correlations with motor and respiratory function. miR-133a-3p and miR-133b correlated negatively with upper limb and respiratory function, and sex-related differences were observed for miR-133a-3p, FGFR1, ANXA2, and LINCMD1. During nusinersen treatment, we observed a decrease in miR-206, LINCMD1, and lnc-GJA1-2, alongside modest reductions in SMN-∆7 and total SMN. In contrast, risdiplam induced a peripheral splicing shift: SMN-FL and the FL/∆7 ratio increased, while SMN-∆7 decreased; miR-133a-3p also decreased at 6 months. By integrating muscle-derived RNAs, particularly miR-206, with blood SMN2 splicing changes, we propose a composite, blood-based biomarker approach for assessing SMA status and treatment-associated molecular changes and highlight myomiR-lncRNA-mRNA networks that suggest disease-relevant mechanisms.
Ključne besede: SMN2 splicing, biomarkers, spinal muscular atrophy, IncRNA, miR-206, myomiR
Objavljeno v DiRROS: 15.05.2026; Ogledov: 325; Prenosov: 305
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Povzetek: Background: Late-onset Pompe disease (LOPD), a rare autosomal recessive multisystemic disorder, substantially impacts patients’ day-to-day activities, outcomes, and health-related quality of life (HRQoL). The PROPEL trial compared cipaglucosidase alfa plus miglustat (cipa+mig) with alglucosidase alfa plus placebo (alg+pbo) in adult patients with LOPD over 52 weeks and showed improved motor and respiratory function in patients switching treatment from standard-of-care enzyme replacement therapy (ERT) to cipa+mig at baseline. This study evaluated the impact of cipa+mig on patient-reported outcomes (PROs), including HRQoL in ERT-experienced patients, using data from PROPEL. Methods: PROs evaluated included the Subject’s Global Impression of Change (SGIC), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a, PROMIS Fatigue Short Form 8a, Raschbuilt Pompe-specific Activity (R-PAct), and European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L). The proportions of responders in the cipa+mig arm and the alg+pbo arm were compared via chi-squared or Fisher’s exact test (patient-level responder analysis), and least squares (LS) mean differences were calculated for change from baseline at Week 52 of the PRO measures (group-level analysis). Results: At Week 52, patient-level SGIC responder and group-level SGIC analyses favored cipa+mig compared with alg+pbo across all SGIC domains (e.g. 90 vs. 59% responders in the cipa+mig vs. the alg+pbo group for SGIC ability to move around; P=0.0005; and LS mean difference 0.385; P=0.02). Similarly, PROMIS Physical Function and Fatigue domains numerically favored cipa+mig in both analyses (e.g. 50 vs. 40% responders in the cipa+mig vs. alg+pbo arm for PROMIS Physical Function; P=0.37; and LS mean difference 3.1; P=0.11). R-PAct for both treatment groups was similar in the patient-level responder analysis, but numerically favored alg+pbo in the group-level analysis (35% responders in both arms; P=0.95; and LS mean difference −0.8; P=0.48). Self-care, usual activities, and depression anxiety domains of EQ-5D-5L numerically favored cipa+mig in both analyses (e.g. 20 vs. 12% responders in the cipa+mig vs. alg+pbo arm for EQ-5D-5L self-care; P=0.54; and LS mean difference −0.108; P=0.52). Conclusions: Overall, switching treatment from alglucosidase alfa to cipa+mig positively impacted PRO measurements during the double-blind period of PROPEL.
Ključne besede: Pompe disease, patient-reported outcomes, health-related quality of life, SARS-Cov-2
Objavljeno v DiRROS: 26.02.2026; Ogledov: 546; Prenosov: 294
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