KIF5A p.Pro986Leu Risk Variant and Accelerated Progression of Amyotrophic Lateral Sclerosis.

Area of Science:

• Genetics
• Neuroscience
• Neurology

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease.
• Genetic factors contribute to ALS heterogeneity.
• KIF5A gene variants have been implicated in ALS pathogenesis.

Purpose of the Study:

• To investigate the impact of the KIF5A rs113247976 (p.Pro986Leu) risk allele on phenotypic variability in ALS.
• To determine if this specific KIF5A variant influences disease progression.
• To validate findings in independent ALS cohorts.

Main Methods:

• Analysis of two Italian ALS cohorts (n=865 and n=1174).
• Genotyping for the KIF5A rs113247976 polymorphism.
• Comparison of disease progression rates (ALSFRS-R preslope) between wild-type and heterozygous carriers.
• Multiple linear regression to identify predictors of disease progression.

Main Results:

• The minor allele (T) frequency for rs113247976 was 0.015.
• Heterozygous carriers of the p.Leu986 variant exhibited a faster disease progression rate.
• These findings were consistent and validated across both discovery and replication cohorts.
• Age at onset and the KIF5A p.Leu986 variant were identified as significant predictors of faster ALS progression.

Conclusions:

• Heterozygous carriers of the KIF5A p.Leu986 variant show accelerated ALS progression.
• This genetic marker is associated with increased phenotypic variability in ALS.
• The KIF5A p.Leu986 variant warrants consideration for genetic screening in ALS clinical trials and patient stratification.