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Familial frontotemporal dementia — MRCPsych Paper A MCQ

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HardGeneticsFamilial frontotemporal dementiaMRCPsych Paper A

A 59-year-old man develops a 2-year history of progressive disinhibition, loss of empathy, stereotyped behaviour and non-fluent speech. MRI shows predominant frontal and anterior temporal atrophy. His father developed motor neurone disease with behavioural change in his early 60s, and his paternal grandfather had a progressive language-led dementia. Which genetic mechanism most likely accounts for this pedigree?

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Correct answer: A — Autosomal dominant inheritance due to MAPT or GRN variants, or a C9orf72 repeat expansion

Explanation lettering: B = shown as A · A = shown as B · D = shown as C · E = shown as D · C = shown as E

B is correct. The presentation is consistent with frontotemporal dementia, while affected individuals in three successive paternal generations indicate vertical transmission. Direct transmission from an affected father to his son strongly supports autosomal dominant inheritance and excludes mitochondrial and X-linked mechanisms. The principal genetic causes of autosomal dominant FTD are pathogenic variants in MAPT or GRN and the C9orf72 hexanucleotide repeat expansion; the association with motor neurone disease particularly raises C9orf72. Recessive TREM2-associated disease would more typically produce a horizontal pedigree, such as affected siblings, rather than successive affected generations. A paternal 15q11–q13 deletion causes Prader–Willi syndrome, not late-onset familial FTD. Although UBQLN2 variants can cause an ALS–FTD spectrum disorder, direct male-to-male transmission is incompatible with X-linked inheritance.

Reference: Convery R, Mead S, Rohrer JD. Review: Clinical, genetic and neuroimaging features of frontotemporal dementia. Neuropathology and Applied Neurobiology. 2019;45(1):6–18. https://pubmed.ncbi.nlm.nih.gov/30582889/