Huntington’s Disease
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Introduction

Huntington’s disease – HD – (aka Huntington’s chorea, named after George Huntington [1872]) is an autosomal dominant disorder that shows full penetrance. It is a progressive neurodegenerative disorder that causes a distinct phenotype (set of symptoms) including chorea, dystocia, reduced coordination, reduced cognitive function and behavioural changes.
The mean age of onset is 30-50.
It is associated with loss of brain tissue particularly in the basal ganglia and cortex.
Genetically – it is caused by a long triplet repeat in the Huntingtin gene (HTT).

Treatment is supportive only. No known treatment can alter disease progression. 

Epidemiology and Aeitiology

Affects approximately 5-10 per 100 000 individuals

  • Incidence highest in those of western European descent, and lowest in Black Africans
  • It is the most common inherited neurodegenerative disorder
  • Men and women affected equally
  • Symptoms usually begin at between age 20-50, but ins one circumstances can occur before the age of 20 – Juvenile Huntington’s disease (JHD) can affect children

Genetics & Pathology

Repeating CAG gene sequence in Huntington's disease
Repeating CAG gene sequence in Huntington’s disease

Sufferers carry a defect in chromosome 4 on the Huntgingtin gene (HTT). The normal Huntingtin gene codes for the amino acid glutamine. The gene contains a trinucleotide repeat sequence (CAG). In normal individuals, the repeat is not problematic. As the repeat becomes longer, it may reach a threshold. Once the repeat has surpassed the threshold, then Huntington’s disease results.

  • At 36-40 repeats, the disease exists with reduced penetrance
  • At >40 repeats, the disease exists with full penetrance
  • Some sufferers may have hundreds of repeats. In such severe disease, onset may be before the age of 20 (7% of cases), and may be referred to as juvenile HD

The length of this repeat sequence determines the onset and severity of the disease. The longer the repeat, the greater the severity and earlier the onset
The repeat can lengthen with subsequent generations leading to a worse phenotype over time, within the same family.
The protein produced by the defective HTT gene causes increased neuronal damage via unknown mechanisms.
 Genetic testing is available to asses if an individual is affected. Patients will also usually receive genetic counselling. As symptoms don’t typically present until after child bearing age, families may already have children and grandchildren who may/may not wanted to be tested – if 1 parent is affected, there is a 50% risk of an affected child
Pathology

  • There is cerebral and caudate nucleus/corpus striatum atrophy due to the loss of GABA-nergic and cholinergic neurons. – the caudate nucleus is located within the corpus striatum. The corpus striatum is located just beneath the lateral ventricles, either side of the thalamus, and divided into the caudate nucleus (which projects into the ventricle) and the lenticular nucleus, external to the ventricles).
  • Imaging (MRI / CT) is often performed to rule out alternative diagnosis. HD will show squaring off of the ventricle edges – boxcar ventricles where the caudate nucleus has atrophied.
MRI of the brain showing reduction in brain tissue volume - consistent with Huntington's disease
MRI of the brain showing reduced brain tissue volume – consistent with Huntington’s disease

Presentation

Age of onset typically 30-50.
Initially symptoms may be sporadic, but then become progressive. Behavioural symptoms are often noted first. THese may cause social issues (such as martial breakdown and relationship conflict) may years before the other symptoms begin.

Other symptoms occur typically in the order:

  • Chorea Agitation Dementia ± seizures Death
  • Symptoms may also present simultaneously
  • Antisocial behaviour disorders (including bi-polar and schizophtrenia) may also exist
  • Motor signs  – Chroea – these typically include involuntary short sharp muscle movements, gait problems, grimacing, dystonia and motor impersistence whereby muscle contractions cannot be sustained (e.g. as demonstrated by protrusion of the tongue)
  • Progression – ultimately, patients will have difficulty walking and swallowing and will suffer from severe dementia.

Investigations

  • In later disease, CT and MRI changes may be seen – in the form of loss of volume and increased size of the lateral ventricles
  • Consider testing for alternative causes – SLE, anti-phospholipid syndrome, thyroid disorders and Wilson’s disease

Genetic Testing

Genetic testing is available in specialist centres. There are four classifications:

  • < 27 repetitions of CAG on HTT gene – normal
  • 27-35 repetitions – small chance that repeat can increase in future generations. Patient will not develop Huntington’s disease
  • 36-39 repetitions – small chance of developing Huntington’s disease later in life
  • 40+ repetitions – likely to develop Huntington’s disease

The test is not able to determine the likely age of onset, but is predictive of the age of death. The greater the number of repeats – the shorter the life expectancy.

Treatment

Is typically only supportive. Treatments do not affect disease progression.

  • Antipsychotics (e.g. chlorpromazine, haloperidol) can be useful to reduce chorea and agitation, but do not alter disease progression. They are usually titrated up to the maximum tolerable dose.
    • Atypical antipsychotics are preferable due to the lower risk of extra pyramidal side effects
  • Tetrabenazine may be useful to treat chorea symptoms
  • Depression should be recognised and treated with SSRIs
    • There is a significantly higher prevalence of suicidal ideation (up to 20%) and suicide (up to 2%) than the general population
  • GABA affecting treatments have been proven ineffective. Experimental therapies are looking at NMDA receptors and enhancing mitochondrial energy production.

Counseling to both patient and family, and the offer of genetic testing are important.

Death is usually due to a confounding illness – such as pneumonia.

References

  • Huntington’s Disease – patient.info
  • Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
  • Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F
  • Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

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Dr Tom Leach

Dr Tom Leach MBChB DCH EMCert(ACEM) FRACGP currently works as a GP and an Emergency Department CMO in Australia. He is also a Clinical Associate Lecturer at the Australian National University, and is studying for a Masters of Sports Medicine at the University of Queensland. After graduating from his medical degree at the University of Manchester in 2011, Tom completed his Foundation Training at Bolton Royal Hospital, before moving to Australia in 2013. He started almostadoctor whilst a third year medical student in 2009. Read full bio

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