A 27-year-old man presents to the Neurology Clinic with a 1-year history of progressive difficulty with concentrating, issues with coordination and irritability. Six months ago, he was admitted after a suicide attempt. He does not know his biological parents because he was adopted at a young age but he has been told that one of his biological parents had previously tried to kill themselves and are currently being reviewed by the memory clinic aged 45.

What is the genetic basis of his underlying diagnosis?

Options:
explanation: Huntington's disease is an autosomal dominant disorder with observed genetic anticipation through spermatogenesis. It is caused by expansion of the triplet repeat, CAG encoding glutamine, in the huntingtin gene (*HTT*) on chromosome 4. Around 37+ CAG repeats are needed to develop the disease. In the earliest stages, the symptoms and signs are nonspecific, including low mood, difficulties with concentrating, coordination problems and irritability. As the disease progresses, chorea (involuntary jerking or dancing movements) and dementia occur. Anticipation is the process whereby expansion of a pathological repeat sequence, in this case CAG repeats, are observed after each generation. In the case of Huntington's disease, this is more notable with paternal inheritance. The longer the repeat sequence, the earlier the onset of the disorder. In this case, there has likely been inheritance from the paternal side due to earlier onset of the disorder being illustrated in the son and father's past medical history.
name: CAG triplet repeat with anticipation through spermatogenesis
label: a
answer: yes
explanation: In Huntington's disease, there are pathological expansions in CAG repeats, with paternal inheritance being associated with higher genetic instability and therefore expansion. CTG repeats are the underlying cause for myotonic dystrophy type I, which is also autosomal dominant and exhibits anticipation. The other notable group of diseases that have pathological CAG repeats are the spinocerebellar ataxias (SCAs).
name: CTG triplet repeat with anticipation through spermatogenesis
label: c
answer: no
explanation: In Huntington's disease, there are pathological expansions in CAG repeats, with paternal inheritance being associated with higher genetic instability and anticipation. CCTG repeat is the pathological basis behind myotonic dystrophy type II.
name: CCTG repeat with anticipation through spermatogenesis
label: e
answer: no
explanation: CAG repeat expansions and anticipation are the cause of the early presentation of this patient's Huntington's disease. However, anticipation in Huntington's is observed through spermatogenesis and paternal transmission and not oogenesis/maternal transmission.
name: CAG triplet repeat with anticipation through oogenesis
label: b
answer: no
explanation: In Huntington's disease, there are pathological expansions in CAG repeats, with paternal inheritance being associated with higher genetic instability and therefore expansion. CTG repeats are the underlying cause for myotonic dystrophy type I, which is also autosomal dominant and exhibits anticipation. The other notable group of diseases that have pathological CAG repeats are SCAs.
name: CTG repeat with anticipation through oogenesis
label: d
answer: no

Correct answer: a


Learning point: Huntington's disease is an autosomal dominant disorder caused by CAG repeat expansion in the HTT gene, leading to progressive neurodegeneration.