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Huntington disease

  • Huntington disease (HD) is an autosomal dominant neuropsychiatric disorder.
  • The prevalance of HD in the UK is estimated to be between 4 - 12 per 100,000 people.
  • It causes involuntary movements, cognitive changes, and psychiatric symptoms.
  • Males and females have equal chances of inheriting HD, with no overall sex difference in presentation or clinical course.
  • The clinical features are progressive and median survival time is 15 to 18 years after onset.
  • Mean age of onset is 35 to 44 years, but onset can range from childhood to old age.
  • Each son or daughter of a person with HD has a 50% chance of inheriting it.
  • The DNA alteration causing HD is an expansion of a tri-nucleotide (CAG) repeat in the HD gene.
  • Expansion of the tri-nucleotide repeat may result in genetic anticipation, particularly when a father transmits the condition to a son or daughter.  Anticipation is where the clinical symptoms tend to appear at a younger age or more severely in offspring inheriting the condition, than in the affected parent.

Huntington disease - What are the clinical signs?

Huntington disease - How prevalent is Huntington disease?

Clinical features

There are three general manifestations of HD: movement disorder, cognitive changes and psychiatric disturbances.

Huntington-clinical-features-table

 

Diagnosis

  • A diagnosis of HD is usually first suspected from history (often given by a close relative) and clinical examination in someone who has a known family history of Huntington disease.
  • Where there is no close family history of HD, taking an extended family pedigree may reveal suggestive histories in more distant relatives, or connections with other families known to the relevant regional clinical genetic service.
  • The diagnosis is confirmed or excluded by specific DNA testing, as the only observed DNA alteration mechanism in HD is the expansion of a tri-nucleotide repeat in the HD gene.
  • Since the diagnosis has implications for other family members, diagnostic DNA testing should be accompanied by appropriate anticipatory counselling, and the availability of urgently responsive genetic counselling for the patient and their relatives.

Differential diagnosis

  • Other autosomal dominant neurodegenerative disorders, include:
    • Hereditary cerebellar ataxia
    • Prion Diseases
    • Early-onset familial Alzheimer disease
    • Familial frontotemporal dementia
  • Benign hereditary chorea
  • Creutzfeld-Jakob disease
  • Choreoacanthocytosis (autosomal recessive)
  • Metabolic diseases

Genetic basis

  • HD is an autosomal dominant condition, which means that each son or daughter of someone with HD has a 50% (or 1 in 2) chance of inheriting the gene alteration that causes the condition.
  • The DNA alteration which causes HD is an expansion in the number of copies of a repeated sequence of three bases (CAG), present within the HD (Huntingtin) gene.
  • The number of copies of this tri-nucleotide sequence broadly determines the clinical presentation of HD, as shown in the table below.
  • Huntington disease may demonstrate genetic anticipation leading to symptoms appearing at a younger age or more severely in later generations.  Genetic anticipation is caused by the number of tri-nucleotide repeats tending to increase in subsequent generations, and in HD tends to occur particularly on paternal transmisison.
  • In cases of juvenile HD, the tri-nucleotide expansion is almost exclusively inherited from the father.
  • Very rarely, someone with HD may be homozygous, inheriting a tri-nucleotide expansion from both parents.  This does not seem to give an earlier onset of symptoms than expected for the larger expansion alone, but may be associated with a more rapid disease progression (Squitieri et al. Brain 2003: 126 (4) 946-955).
  • The CAG repeat sequence encodes a 'string' of glutamine amino acids (a poly-glutamine tract).  Expansion of this sequence above a threshold number (approximately 35 repeats) causes the Huntingtin protein to aggregate in brain cells and cause cell death.

 Huntington-genetic-basis-table

Clinical management

  • For an individual who is concerned by symptoms, refer to a neurologist for diagnosis and ongoing management.
  • Symptomatic drug treatment of HD is available for the movement disorder and some psychiatric complications.
  • Ancillary care advice can be sought from physiotherapy, occupational therapy, speech therapy, dietetics and psychosocial support services, with nursing and respite care support as required.
  • In many centres there are specialist multidisciplinary clinics held for patients with HD; see 'UKGTN Guide to centres with specialist expertise for rare genetic disorders'.
  • There is currently no treatment to retard the progression of the disease, although there are a number of therapies under research investigation including alternatives for route of administration.

For someone concerned about their chance of inheriting HD, and unaware of any symptoms, or for someone concerned about genetic risk to offspring, refer to clinical genetics.  A list of UK genetic centres can be found on the British Society for Genetics Medicine (BSGM) website.

Huntington disease - What treatments are available?

Huntington disease - What research is taking place?

Genetic testing

  • DNA testing in HD is based on there being only one gene involved (Huntingtin gene on chromosome 4), and only one mechanism of DNA alteration observed: expansion of the number of copies of a tri-nucleotide (CAG) repeat.

Genetic testing can be used for:

  • Diagnostic testing: to confirm or exclude the diagnosis in a person with symptoms.  This would normally be requested only by a neurologist or psychiatrist, or through Clinical Genetics.
  • Predictive testing: to provide information for an asymptomatic relative about their genetic status in relation to HD.  Predictive test requests are normally only accepted through Clinical Genetic centres (see BSGM website for a list of UK centres).
  • Prenatal testing: in pregnancy, to determine the genetic status of the fetus, provided that the diagnosis of HD in the family has been confirmed.  The clinical management of prenatal testing in HD should normally be co-ordinated through Clinical Genetics.
  • Preimplantation genetic diagnosis (PGD): to enable selection and reimplantation of fertislised eggs/blastocysts which have a very low chance of inheriting the HD gene alteration.

Two ways of testing the DNA:

  • Within families, DNA testing for HD can be a definitive direct test for the CAG repeat expansion, or a test based on DNA markers from within and surrounding the Huntingtin gene.
  • The definitive direct DNA test is used for all diagnostic and predictive testing, and for prenatal diagnosis or PGD when one parent is already known to have inherited HD.
  • In PGD, since the DNA is amplified from a single cell, direct testing for the CAG repeat expansion is backed up by DNA marker tests.  These show how patterns of the markers are passed down the family, thereby tracking the different copies of the HD gene, but they require DNA samples to be available from at least two generations.
  • The DNA marker tests also form the basis of a subset of prenatal or PGD tests where a grandparent is proven to be affected but the at-risk parent does not wish to undergo a predictive test on themself.  This is referred to as an exclusion test, since it is able to distinguish between a result which shows a fetus would have a very low chance for inheriting HD, from a result where this chance would be 50%.

All genetic testing for HD should be accompanied by supportive genetic counselling:

  • For diagnostic tests, this can ensure that there is prior awareness of the consequent genetic implications for family members.
  • For predictive tests there are established protocols involving genetic counselling to ensure that prediction is undertaken only as a fully formed and considered decision, taking into account personal, reproductive, financial, insurance and career implications.
  • Prenatal testing and PGD also require careful counselling, particularly if one of the parents is clinically asymptomatic and has not already undergone predictive genetic testing.

 Genetic testing in childhood:

  • Asymptomatic predictive testing is normally only available above an accepted age of autonomous consent.  This is usually considered to be age 18 years, in line with certain other minimum legal ages.
  • Genetic testing for HD in a child with neurological or psychiatric symptoms should involve Clinical Genetics and Paediatric Neurology assessment for child and family management reasons and to minimise the risk of inadvertent prediction of a later-onset presentation.
  • The principles of autonomy and informed reflective consent governing DNA testing in HD have relevance for many other adult-onset genetic disorders.  The principles of DNA testing in childhood are set out in: 'Genetic Testing of Children' - Report of a working party of the British Society for Human Genetics 2010

This information is intended for educational use and was current in August 2013. For clinical management, it is recommended that local guidelines and protocols are used.