Novel mutation in optineurin causing aggressive ALS+/-frontotemporal dementia.

Area of Science:

• Neurogenetics
• Neurology
• Molecular Biology

Background:

• Mutations in the optineurin (OPTN) gene are associated with amyotrophic lateral sclerosis (ALS).
• Understanding the genetic basis of ALS in diverse populations is crucial for diagnosis and treatment.
• Previous studies have suggested a role for OPTN mutations in ALS pathogenesis.

Purpose of the Study:

• To screen a Chinese patient cohort for mutations in the optineurin (OPTN) gene.
• To investigate genotype-phenotype associations in patients with OPTN mutations and ALS.
• To determine the contribution of OPTN mutations to ALS in the Chinese population.

Main Methods:

• Targeted next-generation sequencing of all 16 exons of the OPTN gene.
• Screening of 15 familial ALS index cases and 275 sporadic ALS patients of Chinese origin.
• Extensive literature review of previously identified OPTN mutations and their associated phenotypes.

Main Results:

• Identified two known (p.L494W, p.E516Q) and one novel (p.D564H) heterozygous missense OPTN mutations in sporadic ALS patients.
• Patients with p.E516Q and p.D564H mutations presented with aggressive ALS and ALS-frontotemporal dementia (FTD) phenotypes, respectively, with short survival times.
• Literature review revealed heterogeneous clinical phenotypes in OPTN-mutated ALS, ranging from slow progression to aggressive disease courses.

Conclusions:

• OPTN mutations are a contributing factor to ALS in the Chinese population, found in 0.8% of sporadic and 1.5% of familial ALS cases.
• OPTN mutations can lead to aggressive forms of ALS, sometimes accompanied by frontotemporal dementia (FTD).
• Genetic screening for OPTN mutations may aid in diagnosing and understanding the diverse clinical spectrum of ALS.