Genetic and clinical insights into ALS8: exploring the impact of VAPB pathogenic variants in familial amyotrophic lateral sclerosis

TL;DR

This study explores the genetic and clinical features of ALS8, a rare form of familial ALS caused by the VAPB P56S variant, focusing on its prevalence and slower progression in Brazilian families.

Contribution

The study identifies three new cases of the VAPB P56S variant in Brazilian families and highlights its distinct clinical and genetic characteristics.

Findings

Three patients were found to carry the VAPB P56S pathogenic variant associated with ALS8.

ALS8 cases showed symptom onset in the lower limbs and slower disease progression compared to typical ALS.

A large family with 11 affected members demonstrated autosomal dominant inheritance and variable survival rates.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to progressive muscle weakness and paralysis. Approximately 10% of ALS cases are familial (FALS), with the
VAPB
gene's P56S pathogenic variant being notably prevalent in Brazilian families, contributing to the rare ALS8. This variant progresses more slowly than typical ALS, with distinct clinical features.

To identify
VAPB
gene pathogenic variants in Brazilian FALS patients, particularly the P56S pathogenic variant associated with ALS8 and explore its clinical presentation and progression.

Twelve FALS patients from 12 unrelated families in Rio de Janeiro were included in the study between 2023 and 2024. Clinical, laboratory, and electrophysiological data were reviewed. Collection of DNA samples happened via oral swabs, and
VAPB
gene sequencing was performed to identify pathogenic variants, specifically the P56S variant linked to ALS8.

There were 3 cases of the P56S pathogenic variant, all presenting ALS8 with symptom onset in the lower limbs and slower disease progression. A family with 11 affected members across four generations showed an autosomal dominant inheritance pattern, with varying survival rates, highlighting its clinical variability.

The present study underscores the importance of genetic screening for ALS subtypes, particularly ALS8, in Brazil. Identifying the P56S pathogenic variant enhances our understanding of ALS's genetic diversity and clinical presentation, offering a foundation for improved diagnostic practices and personalized care.

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