Genetics · MU Sofia

39. Hereditary Diseases Caused by Dynamic Mutations: Huntington’s Disease, Myotonic Dystrophy, Fragile X (Martin–Bell) Syndrome

Explains how unstable expansions of short trinucleotide repeats cause anticipation, variable expressivity and parent-of-origin effects, then covers Huntington's disease, myotonic dystrophy and fragile X syndrome in turn. For each it gives the gene, repeat, pathophysiology, clinical features, diagnosis and management, with repeat-length classification tables for Huntington's and fragile X and a table of myotonic dystrophy types.

Inside: 10 sections · 8 labelled pictures · 3 tables · 14 flashcards · 4 min

Topic 39 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 10 sections, about 566 words (4 min of reading), with 14 flashcards.

In this note

  1. Hereditary Diseases Caused by Dynamic Mutations: Huntington’s Disease, Myotonic Dystrophy, Fragile X (Martin–Bell) Syndrome
  2. General Mechanism of Dynamic Mutations
  3. I. HUNTINGTON’S DISEASE (HD)
  4. II. MYOTONIC DYSTROPHY (DM)
  5. III. FRAGILE X (MARTIN–BELL) SYNDROME
  6. CGG Repeat Categories
  7. Pathophysiology
  8. Clinical Features
  9. Diagnosis
  10. Management

Hereditary Diseases Caused by Dynamic Mutations: Huntington’s Disease, Myotonic Dystrophy, Fragile X (Martin–Bell) Syndrome

Dynamic mutations are caused by unstable expansion of short nucleotide repeats (most commonly trinucleotide repeats) within specific genes. Unlike classical mutations, the repeat length can increase across generations, leading to:

  • anticipation (earlier onset and increased severity),
  • variable expressivity,
  • parent-of-origin effects.

The most common repeats involved are:

  • CAG → polyglutamine expansion
  • CTG → toxic RNA effects
  • CGG → gene silencing

General Mechanism of Dynamic Mutations

  • Normal individuals carry a stable number of repeats.
  • Expansion beyond a pathogenic threshold disrupts gene function.
  • Repeat length often increases during meiosis, especially in one parent (paternal or maternal bias depending on disease).

I. HUNTINGTON’S DISEASE (HD)

Huntington’s disease is an autosomal dominant, progressive neurodegenerative disorder characterized by:

  • movement abnormalities (chorea),
  • psychiatric disturbances,
  • cognitive decline and dementia.

Genetic and Molecular Basis

  • Gene: HTT (Huntingtin gene)
  • Chromosome: 4p16.3
  • Repeat involved: CAG trinucleotide repeat
  • Protein effect: polyglutamine expansion in huntingtin protein

CAG Repeat Lengths

  • Anticipation: more pronounced with paternal transmission.

Pathophysiology

  1. 1. Expanded CAG repeats produce mutant huntingtin protein with long polyglutamine tract.
  2. 2. Mutant protein misfolds and aggregates in neurons.
  3. 3. Preferential degeneration of GABAergic neurons in the striatum (caudate and putamen).
  4. 4. Loss of inhibitory control of motor pathways → chorea.
  5. 5. Progressive cortical and subcortical neuronal loss → dementia and psychiatric symptoms.

Clinical Features

  • Age of onset: usually 30–50 years (earlier with larger repeats).

Neurological

  • Chorea (involuntary, jerky movements).
  • Dystonia, rigidity in late stages.
  • Gait disturbance.

Psychiatric

  • Depression, irritability, anxiety.
  • Personality changes.
  • Psychosis in some cases.

Cognitive

  • Progressive dementia.
  • Impaired executive function and memory.

Diagnosis

  • Clinical features + family history.
  • Genetic testing showing expanded CAG repeats.
  • Brain imaging: caudate nucleus atrophy with enlarged lateral ventricles.

Management

  • No curative therapy.
  • Symptomatic treatment:
  • Tetrabenazine for chorea.
  • Antipsychotics and antidepressants.
  • Genetic counseling essential.

Continue reading free

The whole note, all 10 sections, is free with an AceMed account, with its 14 flashcards. Premium adds flashcard recall, highlights and Ask AI.

Start freeAlready a member? Open the note