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QuestionChoice
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).
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CTG triplet repeat with anticipation through spermatogenesis
QuestionChoice
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.
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CAG triplet repeat with anticipation through spermatogenesis
QuestionChoice
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.
52881
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CCTG repeat with anticipation through spermatogenesis
QuestionChoice
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.
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CTG repeat with anticipation through oogenesis
QuestionChoice
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.
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CAG triplet repeat with anticipation through oogenesis
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Hematoma Hallux
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# Summary

Huntington's disease is an autosomal dominant neurodegenerative disorder characterized by choreoathetosis and dementia. Diagnosis is confirmed by genetic testing, and management involves a multidisciplinary approach to symptomatic relief and patient support. The disease progression is inevitable and usually leads to mortality due to complications from physical decline or suicide.

# Definition

Huntington's disease is a genetic disorder that causes progressive breakdown of nerve cells in the brain. It is characterised by motor, cognitive, and psychiatric abnormalities.

# Epidemiology

As the most common hereditary neurodegenerative disorder, the prevalence of Huntington's disease is estimated to be between 1 in 10,000 and 1 in 20,000 individuals.

# Aetiology

Huntington’s disease is caused by an autosomal dominant mutation involving an excessive repetition of the CAG trinucleotide (>38 repeats) in the huntingtin gene, which encodes the huntingtin protein. 

The number of CAG repeats is directly correlated with disease severity and age of onset, with **anticipation** observed in families—meaning that symptoms often present earlier in successive generations due to an increase in the number of repeats.

The pathogenesis is closely related to the gradual degeneration of specific brain regions, particularly the **caudate nucleus and putamen**, which are key components of the basal ganglia. This degeneration leads to the characteristic motor, cognitive, and psychiatric symptoms of the disease.

# Signs and Symptoms

Huntington's disease presents with a characteristic triad of symptoms:

- Choreoathetosis: Unpredictable, flowing, and writhing movements
- Cognitive impairment: Dementia, often marked by problems with judgment, memory, and other cognitive functions
- Psychiatric abnormalities: Depression, irritability, apathy, and sometimes psychosis

# Differential Diagnosis

Huntington's disease should be differentiated from other disorders presenting with similar symptoms, such as:

- **Parkinson's disease**: Characterized by bradykinesia, resting tremor, rigidity, and postural instability
- **Wilson's disease**: Presents with liver disease, Kayser-Fleischer rings in the eye, and neurological symptoms such as dystonia, tremor, and dysarthria
- **Huntington's disease-like disorders (HDL1, HDL2, HDL3, and HDL4)**: Present with a similar clinical picture but have different genetic backgrounds
- **Neuroacanthocytosis syndromes**: Characterized by movement disorders and spiculated red blood cells (acanthocytes)

# Investigations

Investigations in Huntington's disease include:

- **Neuroimaging**: MRI and CT scans may show loss of striatal volume and an enlarged frontal horn of the lateral ventricles in moderate to severe disease stages
- **Genetic testing**: Confirmatory, and also allows for predictive testing in at-risk family members with pre-test genetic counseling 

# Management

Although no treatments can halt disease progression, management strategies aim at symptomatic relief and supporting the patient and their family:

- **Chorea management**: Medications such as tetrabenazine are commonly used, with the most evidence base
- **Depression management**: Selective serotonin reuptake inhibitors (SSRIs) are typically the first-line treatment
- **Psychosis management**: Antipsychotics, preferably newer atypical agents, are used due to lower rates of extrapyramidal side effects
- **Supportive care**: This includes a significant amount of physical and emotional support from a multidisciplinary team

# Prognosis

The prognosis for Huntington's disease is poor, with an invariable decline in physical and cognitive abilities. Death usually occurs due to complications related to physical decline such as pneumonia, while suicide is the second most common cause of death.

# References

[Click here for more on Huntington's Disease](https://patient.info/doctor/huntingtons-disease-pro#nav-0)
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Huntington's disease
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Neurology
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Huntington's disease is an autosomal dominant disorder caused by CAG repeat expansion in the HTT gene, leading to progressive neurodegeneration.
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?
a