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

<b>Background</b>: 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 <i>C9orf72</i> 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 <i>C9orf72</i> repeat expansions and potential modifying roles of <i>APOE</i>, <i>ATXN1</i>, and <i>ATXN2</i> in Serbian ALS/FTD patients. <b>Methods</b>: Our study included an ALS/FTD cohort (<i>n</i> = 22) and healthy controls (n = 94). Repeat sizing in <i>C9orf72, ATXN1</i> and <i>ATXN2</i> was performed by fluorescent polymerase chain reaction (PCR) and capillary electrophoresis, while repeat-primed PCR was used to confirm <i>C9orf72</i> expansions. <i>APOE</i> genotyping was conducted using real-time PCR assays targeting SNPs rs429358 and rs7412. <b>Results</b>: In the ALS/FTD cohort, 31.82% of the patients had heterozygous <i>C9orf72</i> repeat expansion. The most common <i>APOE</i> genotype among patients was ε3/ε3 (72.73%). Intermediate-length <i>ATXN1</i> alleles (32-44 repeats) were detected in 13.64% of patients and <i>ATXN2</i> intermediate-length alleles (27-33 repeats) were found in 9% of patients. No significant differences were observed between ALS/FTD patients and controls in <i>APOE ε4</i> frequency or intermediate <i>ATXN1/ATXN2</i> repeats. <b>Conclusions</b>: 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.