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Huntington’s & Trinucleotide Disorders | MRCP Part 1

TL;DR

Trinucleotide Repeat Disorders (Huntington’s) are a high-yield neurogenetics topic for MRCP Part 1, centred on CAG repeat expansion causing progressive neurodegeneration. Focus on anticipation, repeat thresholds, caudate atrophy, and the movement–cognitive–psychiatric triad. Exam questions commonly test inheritance patterns and differentiating Huntington’s from other repeat disorders. Mastering these concepts can secure straightforward marks in genetics and neurology stations.


Why this matters

For MRCP Part 1, neurogenetics is tested through pattern recognition rather than obscure detail. Trinucleotide Repeat Disorders (Huntington’s) is a classic exam topic: predictable inheritance, well-defined molecular basis, and characteristic clinical features.

Candidates often lose marks by confusing repeat types or missing early psychiatric features. Strengthen your foundation using the MRCP Part 1 overview and consolidate with Free MRCP MCQs.


Core sections

1) What are trinucleotide repeat disorders?

These are genetic conditions caused by expansion of repeating DNA triplets within specific genes. When repeat numbers exceed a threshold, they disrupt normal protein function.

Key mechanisms:

  • Gain-of-function toxicity (e.g., Huntington’s disease)

  • Gene silencing (e.g., Fragile X syndrome)

2) Huntington’s disease — genetics you must recall

  • Gene: HTT (chromosome 4)

  • Repeat sequence: CAG (polyglutamine expansion)

  • Inheritance: Autosomal dominant

  • Anticipation: Present, especially paternal transmission

Repeat length thresholds (frequently tested):

  • <26 → Normal

  • 27–35 → Intermediate (no disease, risk to offspring)

  • 36–39 → Reduced penetrance

  • ≥40 → Full penetrance

3) Clinical features — the classic triad

  1. Movement disorder: chorea (early), rigidity (late)

  2. Cognitive decline: executive dysfunction → dementia

  3. Psychiatric features: depression, irritability, psychosis

Exam pearl: Psychiatric symptoms often precede motor signs.

4) Neuroanatomy and imaging

  • Degeneration of caudate nucleus and putamen

  • MRI/CT: enlarged frontal horns → “boxcar ventricles”

This explains the hallmark choreiform movements via basal ganglia dysfunction.

5) Key comparison table (high-yield)

Disorder

Repeat

Inheritance

Key feature

Huntington’s

CAG

AD

Chorea, dementia

Fragile X

CGG

X-linked

Intellectual disability, macroorchidism

Myotonic dystrophy

CTG

AD

Myotonia, cataracts

Friedreich’s ataxia

GAA

AR

Ataxia, cardiomyopathy

Spinocerebellar ataxias

CAG

AD

Cerebellar ataxia

6) Five most tested subtopics

  1. Repeat length vs disease severity

  2. Anticipation (paternal bias)

  3. Early psychiatric manifestations

  4. Imaging findings (caudate atrophy)

  5. Genetic counselling implications

7) Pathophysiology made simple

Expanded CAG repeats produce abnormal polyglutamine proteins, which aggregate and cause neuronal death—particularly in the striatum.

8) Diagnosis and management

  • Diagnosis: Confirmed by genetic testing

  • Treatment: No cure

Symptomatic management:

  • Tetrabenazine → chorea

  • Antipsychotics → behavioural symptoms

  • SSRIs → depression

Medical student revising neurogenetics and Huntington’s disease for MRCP Part 1 exam preparation

Practical examples / mini-cases

MCQ:A 42-year-old man presents with involuntary jerky movements and progressive behavioural changes. His father died young with similar symptoms. Genetic testing shows 41 CAG repeats.

Most likely diagnosis? A. Fragile X syndromeB. Huntington’s diseaseC. Myotonic dystrophyD. Friedreich’s ataxia

Answer: B. Huntington’s disease

Explanation:

  • Autosomal dominant inheritance

  • ≥40 CAG repeats → full penetrance

  • Classic triad with family history confirms diagnosis

Common pitfalls (5 bullets)

  • Confusing repeat types (CAG vs CGG vs CTG)

  • Ignoring reduced penetrance range (36–39)

  • Missing psychiatric symptoms as early clue

  • Misidentifying inheritance pattern

  • Assuming disease-modifying therapy exists


Practical study-tip checklist

  • Memorise repeat types + inheritance patterns

  • Associate Huntington’s with CAG + AD + chorea

  • Visualise caudate atrophy → ventriculomegaly

  • Practise threshold-based MCQs

  • Revise all repeat disorders together

Boost your exam readiness with Start a mock test and reinforce recall using Free MRCP MCQs.


FAQs

1) What is anticipation in Huntington’s disease?

Anticipation refers to earlier onset and increased severity in successive generations due to repeat expansion, especially via paternal inheritance.

2) What repeat causes Huntington’s disease?

A CAG trinucleotide repeat expansion in the HTT gene. ≥40 repeats typically cause disease.

3) Which brain region is affected first?

The caudate nucleus, leading to characteristic movement and imaging findings.

4) Is Huntington’s disease curable?

No. Management is supportive and symptom-based.

5) How is Huntington’s different from Fragile X?

Huntington’s is autosomal dominant with CAG repeats and chorea, whereas Fragile X is X-linked with CGG repeats and intellectual disability.


Ready to start?

For structured preparation, start with the MRCP Part 1 overview and integrate daily practice using Free MRCP MCQs. Simulate real exam conditions with a Start a mock test. Suggested sibling reading: Parkinson’s vs Huntington’s comparison (neurodegenerative disorders).


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