Common mutations of interest in the diagnosis of amyotrophic lateral sclerosis: how common are common mutations in ALS genes?

ABSTRACT

Introduction

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease predominantly affecting upper and lower motor neurons. Diagnosis of this devastating pathology is very difficult because the high degree of clinical heterogeneity with which it occurs and until now, no truly effective treatment exists.

Areas covered

Molecular diagnosis may be a valuable tool for dissecting out ALS complex heterogeneity and for identifying new molecular mechanisms underlying the characteristic selective degeneration and death of motor neurons. To date, pathogenic variants in ALS genes are known to be present in up to 70% of familial and 10% of apparently sporadic ALS cases and can be associated with risks for ALS only or risks for other neurodegenerative diseases. This paper shows the procedure currently used in diagnostic laboratories to investigate most frequent mutations in ALS and evaluating the utility of involved molecular techniques as potential tools to discriminate ‘common mutations’ in ALS patients.

Expert opinion

Genetic testing may allow for establishing an accurate pathological diagnosis and a more precise stratification of patient groups in future drug trials.

KEYWORDS:

• Amyotrophic lateral sclerosis
• genes
• genetic tests
• diagnosis
• mutations

Article highlights

• The enormous progress made in both technology and genetics over the past 20 years has led to the discovery of the first genetic mutation that causes ALS and the identification of more than 100 ALS-related genes.

• Four main genes (SOD1, C9ORF72, TARDBP, and FUS) are commonly tested and common mutations are detected in different populations.

• Some patients appear to carry more than one rare disease-causing mutation – ALS is an oligogenic disease.

• The identified genetic variants hint to specific pathways involved in ALS etiology but, there are no specific therapies for any of the genetic variants, until today.

• Future whole-genome and -exome sequencing studies are expected to identify several additional susceptibility loci pointing to the existence of a molecular taxonomy for ALS.

• Genetic testing may allow for establishing a definitive diagnosis and a better stratification of patients for clinical trials.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.