Imagine that the UNC13A gene is like a weather vane for amyotrophic lateral sclerosis (ALS). It’s not only linked to shorter survival after the disease sets in, but it also seems to indicate how strong the winds of upper motor neuron involvement may blow. This study looked at the impact of the UNC13A gene on various clinical features of ALS patients, including cognitive and behavioral profiles, motor neuron scores, disease progression rate, age and site of onset, and overall survival. The researchers found that carriers of the risk genotype associated with UNC13A had shorter median survival compared to those without the risk genotype. Additionally, patients with the risk genotype displayed more severe upper motor neuron involvement. However, no significant associations were found between UNC13A and other clinical parameters. These findings support earlier research demonstrating the role of UNC13A in determining survival outcomes and suggest a potential link between this gene and upper motor neuron damage in ALS. To learn more about this exciting study, check out the full article!

BackgroundThe UNC13A gene is an established susceptibility locus for amyotrophic lateral sclerosis (ALS) and a determinant of shorter survival after disease onset, with up to 33.0 months difference in life expectancy for carriers of the rs12608932 risk genotype. However, its overall effect on other clinical features and ALS phenotypic variability is controversial.MethodsGenotype data of the UNC13A rs12608932 SNP (A–major allele; C–minor allele) was obtained from a cohort of 972 ALS patients. Demographic and clinical variables were collected, including cognitive and behavioral profiles, evaluated through the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) – Italian version and the Frontal Behavioral Inventory (FBI); upper and lower motor neuron involvement, assessed by the Penn Upper Motor Neuron Score (PUMNS) and the Lower Motor Neuron Score (LMNS)/Medical Research Council (MRC) scores, respectively; the ALS Functional Rating Scale Revised (ALSFRS-R) score at evaluation and progression rate; age and site of onset; survival. The comparison between the three rs12608932 genotypes (AA, AC, and CC) was performed using the additive, dominant, and recessive genetic models.ResultsThe rs12608932 minor allele frequency was 0.31 in our ALS cohort, in comparison to 0.33–0.41 reported in other Caucasian ALS populations. Carriers of at least one minor C allele (AC + CC genotypes) had a shorter median survival than patients with the wild-type AA genotype (−11.7 months, p = 0.013), even after adjusting for age and site of onset, C9orf72 mutational status and gender. Patients harboring at least one major A allele (AA + AC genotypes) and particularly those with the wild-type AA genotype showed a significantly higher PUMNS compared to CC carriers (p = 0.015 and padj = 0.037, respectively), thus indicating a more severe upper motor neuron involvement. Our analysis did not detect significant associations with all the other clinical parameters considered.ConclusionOverall, our findings confirm the role of UNC13A as a determinant of survival in ALS patients and show the association of this locus also with upper motor neuron involvement.

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