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Huntington's disease

What's in this article:

 · How Huntington's disease presents to GPs

 · The genetic causes of Huntington's

 · How Huntington's will affect a patient

 · Potential advances in genetics could lead to disease prevention

Potential advances in genetics could lead to disease prevention

Is neuro-imaging, such as SPECT scanning, part of the diagnostic work-up?

An MRI scan can be useful by demonstrating a characteristic striatal atrophy and by excluding other conditions which may present in a similar manner. SPECT scanning is not routinely used, but positron emission tomography can demonstrate characteritic hypo-perfusion in the striatum and the anterior cerebral cortex even in pre-clinical HD in apparently asymptomatic gene carriers.

What support is available for patients and for their families?

The Huntington's Disease Association can provide information and support for patients and families. It employs several HD care workers throughout the country who can liaise with health professional services. All genetic centres are experienced in counselling and some can offer an ongoing support for patients and families not only when they are first given the genetic diagnosis gene, but also when they become symptomatic.

Generally, once symptomatic the patients are under the care of neurology and psychiatric services with input from physiotherapists, speech therapists, occupational therapists and social workers. Ideally they should be seen in a specialist multidisciplinary clinic.

What does the future hold?

During the last decade there has been enormous progress towards unravelling the molecular pathology of HD. One important observation comes from a transgenic mouse model carrying the human HD gene with a large CAG repeat expansion, which can be experimentally switched on and off.

In this model, switching off the expression of HD stops accumulation of abnormal huntingtin in neurones and allows them to get rid of its deposits. This has been associated with reversal of pathological changes in the brain, arrest of disease progression and even some functional improvement.

Theoretically, if we could manipulate the expression of the HD gene by selectively targeting it and switching it off early in life, we might be able to prevent the disease. It is also possible that once the reasons for selective neurodegeneration are understood we can devise a neuroprotective strategy operating 'downstream' of the genetic defect.

How Huntington's will affect a patient

How do you approach telling a patient about the diagnosis once it seems a possibility?

This is a complex issue because of the implications of the diagnosis for the patient and the family. Each offspring of the index case has a 50 per cent chance of being a gene carrier. If the patient is already symptomatic and presents to a neurologist (or psychiatrist), a possibility of HD should be raised with the patient and a referral to the clinical genetics service should be discussed and offered.

The molecular genetic test on a patient's blood sample can be carried out after a full assessment and counselling. Asymptomatic patients with a

positive family history of HD who request predictive testing should

also be referred to the regional genetic centre.

This diagnosis must place an overwhelming stress on a family.

Yes. Even symptomatic patients may decide against having the test. The attitudes towards predictive testing in asymptomatic family members are often very polarised. Some wish to have a predictive test and some not, and there may be a conflict of interests. Generally a clinical geneticist is best placed to handle these complex issues.

The regional genetics centres keep a register of affected families and this is very important. Difficulties may arise when HD develops in a child, including problems with parental consent for testing and implications of a positive test for one of the parents if he or she is still asymptomatic.

One problem that one may encounter is an apparently negative family history of HD. It is important to establish how much history is actually known due to family breakdown or adoption, and consider an early death of the affected parent or uncertain paternity.

Is suicide a common feature in these cases?

Yes, suicide rates are increased not only in the population of patients with HD, but also in people with a positive family history of HD.

Is treatment of the psychiatric aspects of this illness simply symptomatic?

Yes, it is. Anxiety, affective and psychotic disorders are managed symptomatically in the usual way. Mood swings, which are quite common in HD, usually respond well to sodium valproate as a mood-stabilising agent. There have been reports of general improvement of the motor and neuropsychiatric condition on a combination of sodium valproate and an atypical neuroleptic ­ eg, olanzepine.

The genetic causes of Huntington's

Are any subtle signs present in gene carriers?

It has been reported that careful neuropsychology testing can reveal mild cognitive problems in people at risk of HD who are otherwise thought to be completely asymptomatic. Since the manifestations of HD may be very subtle, some 'presymptomatic' patients requesting predictive testing for HD mutation are not aware that they already are symptomatic. For example, they may have a minor degree of chorea or eye movement abnormalities, or have a history of neuropsychiatric problems.

How long does it take, from first presentation to death?

The natural course of HD from diagnosis to death is about 15, sometimes 20, years. It is not known when the actual neurodegenerative process starts, presumably many years before the clinical onset.

What is the nature of the genetic defect in HD?

The genetic abnormality in HD is an expansion and instability of a CAG (cytosine-adenine-guanine) trinucleotide repeat within the coding portion of the IT15 (huntingtin) gene on chromosome 4. Patients with HD have in excess of 36 CAG repeats. This CAG repeat encodes a polyglutamine domain near the N-terminal of the protein gene product called huntingtin. The function of huntingtin is still unknown; it is present not only in the brain but also in various other tissues. In mutant huntingtin, the polyglutamine stretch is abnormally long which completely alters its properties.

This leads to abnormal interactions of mutant huntingtin with other cellular proteins and ultimately leads to degeneration of neurones. There is an inverse correlation between the number of CAG repeats and the age of onset of HD: the longer the repeat, the earlier the age of onset. This is particularly clear in patients with long CAG expansions and as a rule patients with more than 60 repeats develop HD in childhood.

Several other neurodegenerative diseases, for example autosomal dominant spinocerebral ataxias, share the same basic molecular mechanism.

How is this genetic defect expressed in the nervous system?

The pathological changes of HD are manifest only in the brain and include loss of neurones and tissue shrinkage. They are earliest and most severe in the caudate nucleus and putamen, that is collectively called the neostriatum.

The second most affected region is the cerebral cortex of the frontal, temporal and anterior parietal lobes. This regional selectivity of neurodegeneration remains an unsolved mystery. It is not due to a regionally selective expression of the abnormal huntingtin, which is ubiquitously present throughout the brain, and there must be other factors.

There is only one 'non-neurological' feature of HD, namely a striking weight loss in more advanced stages of the disease. It seems to reflect an increased metabolic rate rather than an excessive expenditure of energy due to chorea.

Does the very specific geography of the pathological changes in HD give us any therapeutic hope?

Maybe. In animal models of HD, attempts to replace the degenerated striatal neurones by grafted embryonic cells have met with some success. Similar studies are now under way in HD patients. They involve transplantation of embryonic human striatal neurones into the patient's striatum. The initial reports seem to be encouraging, but there are complex ethical issues, as well as problems with tissue availability.

The latter problem might be bypassed by stem cell transplantation. But the clinical outcome would presumably depend on at least partial functional integration between the graft and the host's brain.

It has to be appreciated that the striatum has very complex internal and external connections, receives inputs from all regions of the cortex, and sub-serves not only motor, but also cognitive and limbic functions.

Therefore this is a major challenge. Moreover, the cognitive and psychiatric manifestations of HD have a complex substrate involving the cerebral cortex as well. It remains to be seen which deficits, and for how long, can be corrected.

How Huntington's disease presents to GPs

What is Huntington's disease (HD) and how often will a GP encounter it?

Huntington's disease is a progressive and ultimately fatal neurodegenerative disease of the brain characterised by chorea, dementia and various neuropsychiatric disorders.

The HD gene is an autosomal dominant and has full penetrance. In most cases the onset of the disease is delayed until around the age of 40, although it can present in all ages including children and the elderly.

Its prevalence is highest in white Caucasian populations of Europe and North America (three-seven per 100,000) and lower in black African and Asian populations (one per 100,000).

So an average GP might see a case every few years. How does the clinical picture present in the early days?

The onset of HD is insidious and often difficult to pin down. Approximately two-thirds of patients develop chorea first. Other involuntary movements, such as dystonia or myoclonus, may follow.

In others the disease begins with a progressive cognitive decline and various neuropsychiatric problems, such as changes in personality and behaviour, anxiety, affective and psychotic disorders. If the family history of HD is not known, or actively concealed, the diagnosis in such cases may initially be difficult.

In fact, the motor and cognitive deficits of HD develop more or less in parallel, but may initially be subtle and require more sophisticated methods of assessment, for example careful neuropsychology testing.

A patient with early chorea gives the impression of being fidgety or restless but can, to some extent, suppress involuntary movements or 'disguise' them by purposeful gestures. The impairment of eye movements is an early motor sign.

Despite its dramatic appearance, chorea is often not disabling to the patient. It is a gradually worsening motor control, including inability to plan and sequence movements, poor balance, dysarthria and dysphagia, that is the main source of physical disability. With disease progression, chorea becomes less severe and is replaced by slowness and paucity of voluntary movements and muscle rigidity.

Some patients with adult-onset HD from the beginning present with an akinetic-rigid syndrome similar to parkinsonism. The dementia is progressive and includes inflexibility and slowness of mental processes, impairment of memory and executive dysfunction.

It has to be remembered that up to 10 per cent of patients present before the age of 20. This group, particularly young children, typically presents with behavioural and cognitive problems, and a declining performance at school.

Epilepsy is quite common. On the other hand, chorea is absent or minimal, and the clinical picture is dominated by a profound impairment of motor control and muscle rigidity.

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