A 58-year-old man develops rapidly progressive frontotemporal dementia with disinhibition alongside fasciculations and wasting of hand muscles. Family history reveals a brother with a similar combined illness. Which genetic abnormality is the most likely cause?

• A Mutation in the presenilin 1 gene
• B Trinucleotide CAG repeat expansion in the huntingtin gene
• C Hexanucleotide repeat expansion in the C9orf72 gene ✓
• D Expansion of GGC repeat in the NOTCH2NLC gene

Explanation

C GGGGCC hexanucleotide repeat expansion in A9orf72 is the commonest known cause of familial amyotrophic lateral sclerosis and accounts for many familial cases of frontotemporal dementia, with both phenotypes frequently coexisting in one family because they share TDP-43 proteinopathy. Huntingtin expansion causes Huntington chorea, presenilin 1 causes early onset Alzheimer disease, and NOTCH2NLC expansion causes neuronal intranuclear inclusion disease.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.