Genetic and Clinical Insights into ALS/FTD: Profiling a Rare Cohort to Explore Spectrum Heterogeneity

Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are recognized as a spectrum of neurodegenerative disorders with overlapping clinical, pathological, and genetic features. The identification of C9orf72 hexanucleotide repeat expansion as the most common genetic cause of both conditions has prompted further investigation of genetic modifiers that may contribute to disease heterogeneity. We aimed to analyze the frequency of C9orf72 repeat expansions and potential modifying roles of APOE, ATXN1, and ATXN2 in Serbian ALS/FTD patients. Methods: Our study included an ALS/FTD cohort (n = 22) and healthy controls (n = 94). Repeat sizing in C9orf72, ATXN1 and ATXN2 was performed by fluorescent polymerase chain reaction (PCR) and capillary electrophoresis, while repeat-primed PCR was used to confirm C9orf72 expansions. APOE genotyping was conducted using real-time PCR assays targeting SNPs rs429358 and rs7412. Results: In the ALS/FTD cohort, 31.82% of the patients had heterozygous C9orf72 repeat expansion. The most common APOE genotype among patients was ε3/ε3 (72.73%). Intermediate-length ATXN1 alleles (32-44 repeats) were detected in 13.64% of patients and ATXN2 intermediate-length alleles (27-33 repeats) were found in 9% of patients. No significant differences were observed between ALS/FTD patients and controls in APOE ε4 frequency or intermediate ATXN1/ATXN2 repeats. Conclusions: Larger, population-specific studies and meta-analyses are needed to better understand the role of genetic modifiers in ALS/FTD pathogenesis and their influence on clinical heterogeneity. By integrating genetic and clinical data, this study represents a step toward the development of precision medicine strategies for ALS/FTD.