The C9ORF72 expansion mutation: gene structure, phenotypic and diagnostic issues

Area of Science:

• Neurogenetics
• Neurology
• Clinical Diagnostics

Background:

• The 2011 discovery of the C9ORF72 hexanucleotide repeat expansion revealed high prevalence in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).
• This finding spurred research into clinical phenotypes, diagnostic methods, and genetic counseling for FTLD and ALS patients.

Purpose of the Study:

• To review progress in understanding the C9ORF72 expansion's clinical and investigation phenotypes over two years post-discovery.
• To focus on information directly relevant to practicing physicians managing FTLD and ALS patients.

Main Methods:

• Review of global prevalence studies of the C9ORF72 expansion in FTLD, ALS, and other neurological diseases.
• Analysis of clinical phenotype variability, disease risk, and diagnostic investigations (neuroimaging, CSF markers, genetic testing).
• Discussion of diagnostic techniques for quantifying repeat number and associated challenges.

Main Results:

• Summarized global prevalence data, including concurrence with other FTLD/ALS genetic mutations.
• Discussed variability in normal repeat numbers and theories on intermediate/pathological repeat relevance.
• Reviewed clinical features aiding differentiation and diagnostic investigations, including limitations of lab techniques.

Conclusions:

• Accurate clinical and technological diagnosis of C9ORF72-associated FTLD/ALS remains a challenge.
• Future research should focus on improving diagnosis and genetic counseling for affected patients and families.