Huntingtons Disease Research Paper

Abstract

Background and purpose

The prevalence of Huntington's disease (HD) in the UK is uncertain. Recently, it has been suggested that the prevalence may be substantially greater than previously reported. This study was undertaken to estimate the overall UK prevalence in adults diagnosed with HD, using data from primary care.

Methods

The electronic medical records of patients aged 21 years or more, with recorded diagnoses of HD, were retrieved from the UK's General Practice Research Database. Prevalence was estimated from the number of persons with recorded diagnoses of HD, on 1 July each year, between 1990 and 2010. This number was divided by the total number of persons registered with participating general practices on that same date. These data were also used to estimate both age specific prevalence and prevalence in various regions of the UK.

Results

A total of 1136 patients diagnosed with HD, aged 21 years or more, were identified from the database. The estimated prevalence (expressed per 100 000 population) rose from 5.4 (95% CI 3.8 to 7.5) in 1990 to 12.3 (95% CI 11.2 to 13.5) in 2010. Although an increased prevalence was observed within every age group, the most dramatic was in older patients. Age specific prevalence was highest in the 51–60 year age range (15.8 95% CI 9.0 to 22.3). The prevalence of adult HD was lowest in the London region (5.4 (95% CI 3.0 to 8.9)) and highest in the North East of England (18.3 (95% CI 8.6 to 34.6)) and Scotland (16.1 (95% CI 10.8 to 22.9)).

Conclusions

The prevalence of diagnosed HD is clearly substantially higher in the UK than suggested from previous studies. By extrapolation to the UK as a whole, it is estimated that there are more than 5700 people, aged 21 years or more, with HD. There has also been a surprising doubling of the HD population between 1990 and 2010. Many factors may have caused this increase, including more accurate diagnoses, better and more available therapies and an improved life expectancy, even with HD. There also appears to be a greater willingness to register a diagnosis of HD in patients’ electronic medical records. Such a high prevalence of HD requires more ingenuity and responsiveness in its care. How to appropriately care for, and respond to, so many individuals and families coping with the exigencies of HD demands our greatest resolve and imagination.

Keywords: HUNTINGTON'S

Introduction

Huntington's disease (HD) is a progressive, fatal neurodegenerative disorder causing abnormal movements, psychiatric disturbances and cognitive decline.12 HD segregates as an autosomal dominant trait located on chromosome 4p16.3.3 The HD abnormality is due to an expansion of a polyglutamine (CAG) repeat in exon 1 of the huntingtin protein.2 The size of the CAG repeat is the most critical determinant for the age of onset of HD symptoms.2 Alleles with fewer than 34 CAGs rarely produce symptoms; alleles between 35 and 39 CAGs have variable penetrance; alleles of 40 CAGs or more are fully penetrant if a person lives a normal lifespan; and alleles of 60 CAGs or greater usually result in juvenile onset under 21 years of age. Including all repeat lengths, the size of the CAG repeat accounts for 72% of the variability in age of onset.2 However, 90% of all people with HD worldwide have between 40 and 50 CAGs. For these individuals, the repeat length accounts for only 40% of the variability in age of onset. Of this remaining variability in the age of onset, genetic factors, other than the HD gene, account for 60% and environmental factors for 40%.2 Genetic and environmental modifiers could be playing a role by influencing the prevalence of HD in the UK and globally.

Over the past 60 years there have been many attempts to estimate the prevalence of HD in the UK. Most of these studies attempted to enumerate the numbers of patients by searching general practice, hospital or nursing home records, mainly in specific geographical regions.4–6 Overall, these investigations suggested a prevalence of HD of approximately 6 per 100 000. These estimates have been questioned7 recently because of the apparent disparity between these estimates and the numbers of patients receiving services from the Huntington's Disease Association.

A reliable estimate of the overall prevalence of HD, as well as of regional differences, is important for planning and delivering the appropriate provision of health and social care. The present study was undertaken to obtain a contemporary estimate of the prevalence of diagnosed HD in the UK as a whole, as well as to explore the extent of any regional differences. The incidence and prevalence of the juvenile form of HD is the subject of a separate study.8

Methods

Study design and setting

The General Practice Research Database (GPRD) is the world’s largest computerised database of anonymised longitudinal medical records from primary care. It is now included under the umbrella of the Clinical Practice Research Datalink which brings together data from across the UK's National Health Service. The GPRD is assembled from the electronic health records of patients registered with contributing general practices. Currently over 5 million patients from approximately 625 contributing practices are included. The practices are broadly representative of those in the UK in geographical distribution, practice size, and the age and sex of registered patients. Each individual patient is assigned a unique identification number. No information from medical records allowing identification of patients is included in the database. The data are entirely anonymous to investigators.

The GPRD aims to include complete diagnostic and prescribing information for each registered patient. When patients newly register with a contributing practice, major past and existing diseases are recorded in their medical records and are included in the research database. However, the dates of onset and dates of past diagnoses are not always accurately recorded. Some diagnoses that occurred in the past may be recorded without a date or as occurring at the date of registration. Morbidity in UK primary care is recorded using Read codes Clinical Terms V.3.9 At both practice and individual patient levels the data are subject to a range of quality checks prior to being made available for research purposes.10 The quality of the data has been found to be high in a large number of independent validation studies.11

Ethics approval for the study was obtained from the GPRD's Independent Scientific Advisory Committee and from the London School of Hygiene and Tropical Medicine's Research Ethics Committee. The potential funders of the study played no part in its design, analysis or interpretation.

Participants and variables

The source population is all patients aged 21 years or more who registered with general practices contributing to the GPRD during the period 1990–2010. Eligible cases are defined as persons with one or more recorded diagnoses of HD or Huntington's chorea anywhere in their medical records. The Read codes used to identify cases of HD were F134.00 (Huntington's chorea) and Eu02200 (dementia in HD).

For each general practice, the observation period for the study began as the later of two dates: either the study start date, 1 January 1990, or the date at which the practice started contributing research standard data to the GPRD. The end of the observation period was the earlier of two dates: the last date for which the practice contributed data to the GPRD or the study end date, 31 December 2010. Individual patients were included in denominators only during times within the observation period that they were registered with a practice contributing data to the GPRD.

Bias

The records of patients diagnosed with rheumatic and Sydenham's chorea (Read codes G02.00, GO2.11, GO20.00, GO21.00 and GO2z.00), ‘drug induced chorea’ (135 200) and ‘other choreas’ (F135z00 and F135.00) were reviewed to assess the extent to which recorded diagnoses of other forms of chorea might represent possible cases of HD. An approximate 20% random sample of the full records of cases with ‘other choreas’ was examined in detail. They were categorised independently as ‘not HD’, ‘possibly HD’, ‘probably HD’ and ‘definite HD’ by the authors (NSW, SJT and MDR).

Statistical methods

Prevalence was estimated from the ratio of number of persons with a recorded diagnosis of HD on 1 July each year, between 1990 and 2010, divided by the total number of persons in the database, on that same date. Binomial CIs were calculated. In estimating the prevalence in age bands, and among various geographical regions of the UK, annual point prevalence estimates were averaged and approximate (binomial) 95% CIs calculated. All prevalence rates are expressed per 100 000 of the population.

Results

Participants

A total of 1136 patients aged 21 years or more with a diagnosis of HD were identified in the database. Of those with recorded diagnoses, 592 were women and 544 were men.

Main findings

Between 1990 and 2010, the average prevalence of HD was 10.0 (95% CI 8.8 to 11.3). Prevalence was similar in women (10.4, 95% CI 8.7 to 12.3) and men (9.4, 95% CI 7.8 to 11.4). However, the prevalence of HD (table 1) more than doubled over the two decades, from 5.4 (95% CI 3.8 to 7.5) in 1990 to 12.3 (11.2 to 13.5) in 2010. All age groups had an increase in prevalence. This was most pronounced among older patients (table 2). The average prevalence rates of HD in different age bands, across the whole period, are shown in table 3. As expected, prevalence was low in younger age groups. It rises to a peak between the ages of 51 and 65 years.

Table 1

Point prevalence rates of Huntington's disease by calendar year (per 100 000)

Table 2

Average prevalence rates of Huntington's disease, 1990–2010, by 7 year periods (per 100 000 population)

Table 3

Average prevalence rates, 1990–2010, of recorded diagnoses of Huntington's disease by age group (per 100 000)

The regional prevalence rates of recorded diagnoses of HD showed substantial heterogeneity (table 4). The highest rates were in Scotland and North East England. The lowest rates were in London.

Table 4

Average prevalence rates of Huntington's disease, for 1990 to 2010, by UK region (per 100 000)

Other choreiform diagnoses

In addition to people with a recorded diagnosis of HD, 866 patients had a recorded diagnosis of rheumatic or Sydenham's chorea, 566 had a diagnosis of other chorea and 12 had a diagnosis of drug induced chorea. The median year of birth of patients with recorded diagnoses of rheumatic or Sydenham's chorea was 1941. Of these, 148 (17%) were born after 1960. In only 31 instances were diagnoses of rheumatic or Sydenham's chorea subsequently revised to HD and all these are included in the estimates for HD reported here. From the detailed examination of the records of a sample (n=115) of ‘other choreas’, the adjudication indicated that 101 patients had no evidence to support a diagnosis of HD and 14 were possible cases. Of the people with medical codes for chorea in whom we found no evidence of HD, 52 had a diagnosis of ‘other chorea’ in childhood or adolescence yet were all alive and well decades later. We are confident these records represent rheumatic chorea in childhood or adolescence. The 49 remaining people with medical codes for chorea had other likely underlying causes such as cerebrovascular disease or thyrotoxicosis. In four records the diagnosis of ‘other chorea’ was subsequently revised to some other movement disorder, such as Parkinson's disease. The 14 possible cases of HD had ‘other chorea’ recorded together with psychiatric symptoms, mainly depression and/or anxiety. These cases might reflect an underlying diagnosis of HD or, alternatively, an HD phenocopy disorder.12

Discussion

In 2010, our estimate of the prevalence of diagnosed adult HD was 12.3 per 100 000 people (table 1). Other studies undertaken in the UK between 1970 and 1995 showed an estimated prevalence of HD of approximately 6 per 100 000, with some suggestions of geographical variation.4 The most recent published estimate,6 based on data from 2004 to 2007, suggested prevalence rates ranging from 6.4 to 6.6 per 100 000. Our substantially larger estimate of the prevalence of HD in the UK is closer to that recently suggested based on the numbers of people receiving services from the voluntary sector.7

The prevalence estimates reported here relate to diagnosed HD as recorded in primary care health records. Given the rarity of the disorder, and the expertise needed to diagnose it, specialists would have made the recorded diagnoses. The GPRD records do not include reports of individual patient's CAG repeat lengths. However, we are confident that genetic tests will have been consistently used by UK specialists since the mid-1990s in order to diagnose HD. Consequently, we do not consider that our results will have been confounded by the inclusion of patients with HD phenocopy syndromes.12 It is therefore extremely unlikely that our results overestimate the true prevalence. We accept that we might have failed to capture all cases and our current prevalence figure probably still represents an underestimate.

Our analysis of the data derived from GPRD documents a dramatic and significant increase in the prevalence of HD over the past two decades (table 1). Many explanations can account for this increase. Since the mid-1990s, genetic testing has been routinely used in the UK to definitively confirm the presence of the expanded allele in the HD gene. Patients presenting with atypical manifestations of HD are now being correctly diagnosed. These include patients with so-called ‘senile chorea’. Very elderly patients, even those presenting in their 80s or 90s, are now being diagnosed with HD. In addition, patients with no family history, and those with new mutations, are being correctly diagnosed using the HD genetic test.

Our data are also compatible with a genuine rise in prevalence.13 Many factors influence patient longevity. Effective symptomatic treatments can help extend life. Tetrabenazine can reduce chorea and minimise the risks of falls and choking. Antidepressants and antipsychotic treatments may reduce suicide rates which are 7–12 times more common in HD.2 Attention to good nutrition is also critical because patients need to consume as much as 5000 calories daily to maintain their weight. Pureed foods and other forms of nutritional support, swallowing therapy and enterogastrostomy feeding can add years to peoples’ lives. Measures that increase the longevity of the population as a whole, such as those reducing the risk of cardiovascular disease, may also contribute to an increase in life expectancy of those with HD.

HD has been heavily stigmatised globally for over a century. We know that some UK patients request that their hospital specialists refrain from informing their general practitioners of their HD diagnosis. Some diagnoses of HD made by specialists, and communicated to general practitioners, may not be recorded in their records due to fears with respect to issues of confidentiality. A confirmed diagnosis of HD in one family member has genetic consequences for the rest of the family, who may not realise that they are at risk. Individuals diagnosed with HD may lose the capacity to obtain life insurance or a mortgage. Many unanticipated and adverse consequences for patients and families may appear, just from a recorded diagnosis of HD. However, over the two decades of our study, there may have been less reluctance to conceal a diagnosis of HD. This may lead to a more accurate reporting of the true prevalence over time. At every age group, there was an increased recording of HD diagnoses. However, the increase was most marked in the later age groups.

In all respects, our data are internally valid. The proportion of affected men and women were similar. Prevalence was highest in patients aged 51–65 years. There was no evidence to suggest that individuals with diagnoses of rheumatic or Sydenham's chorea had underlying HD. It is possible that a small number of the 14 patients, out of the 121 records subjected to close scrutiny with recorded diagnoses of ‘other choreas’ and categorised by us as ‘possible’ cases, actually had HD. If we include these individuals, our prevalence estimates increase by approximately 6%.

We noted marked regional variation in prevalence across the UK (table 4). This may partly be due to random error but may also reflect genuine regional differences. Previous studies4 have suggested higher prevalence rates in Scotland. No studies have been reported from North East England. The lower rates in London may be the result of the net effects of migration.

The recent study by Sackley and colleagues6 of the prevalence of HD in the UK as a whole was based on an analysis of the THIN (The Health Improvement Network) database.14 Their estimate, for the years 2004 to 2007, ranged from 6.0 to 6.5 per 100 000. It is unclear why these prevalence estimates are so much lower than the ones reported using GPRD. While differences between the data sources (such as quality checks and the specification of periods of follow-up from contributing practices) may have made a small contribution to the differences in prevalence in our study, compared with that of Sackley and colleagues,6 it is likely that issues of methodological design explain most of the discrepancy. Sackley and colleagues6 adjusted their prevalence estimates of HD by including all patients with a diagnosis of ‘chorea’ as well as half of those with a family history of HD. Using this approach, their revised ‘total’ prevalence estimates, between 2004 and 2007, ranged from 9.6 to 10.3 per 100 000, which is still less than the prevalence reported in the present study. Although it is possible that some patients with a diagnosis of ‘chorea’ did indeed have HD, Sackley et al's revised estimate neglects the fact that ‘chorea’ is a symptom of many other conditions. From our data it would have been inappropriate to have made any adjustments to our estimates of prevalence by including other diagnoses of chorea.

Sackley and colleagues6 included half of those people who had a recorded family history of HD in their revised number of cases. However, they do not specify if a family history of HD means that the person had an affected parent or grandparent. They assumed that half of those at risk will develop symptoms of HD, which is not true. They also make the egregious mistake of including these at risk individuals as already diagnosed in their yearly prevalence calculations of diagnosed HD patients. When estimating the prevalence of patients with diagnosed HD, it is inappropriate to include individuals who are merely at risk. Nor should prevalence estimates include people whose genetic testing reveals an expanded CAG repeat. Having an expanded CAG repeat is not synonymous with a clinical diagnosis of HD.

There are 46 638 400 people over the age of 21 years in the UK population.15 Applying our current prevalence estimate of 12.3 per 100 000 argues for more than 5700 people in the UK with diagnosed HD. A much larger population of people16 carrying expanded CAG repeats are destined to follow the relentless, irrevocable and destructive attack on body and mind that HD presents. The misery and suffering HD brings to patients and families and the growing scale of the problem behoves us to provide the best health and social care. It is also important to replace our current trial and error use of symptomatic treatments with therapies that are fit for purpose. We must develop new symptomatic therapies aimed at the myriad motor, cognitive and psychiatric problems that HD represents. And even more urgent is our task to create innovative treatments and cures aimed at stopping the abnormal protein through gene silencing or repairing the expanded repeat. The fact that the HD mutation is the same worldwide gives us hope that alleviation of suffering with new therapies and cures will lift a global burden.

Acknowledgments

The authors are grateful to the Hereditary Disease Foundation and the Huntington's Disease Association for their support for this study.

References

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Huntington's disease: a clinical review

1Department of Neurology K5Q112, LUMC PO Box 9600, 2300RC Leiden The Netherlands

Corresponding author.

Raymund AC Roos: ln.cmul@soor.c.a.r

Author information ►Article notes ►Copyright and License information ►

Received 2009 Oct 21; Accepted 2010 Dec 20.

Copyright ©2010 Roos; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<url>http://creativecommons.org/licenses/by/2.0</url>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC.

Abstract

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington's disease; JHD). The classic sign is chorea that gradually spreads to all muscles. All psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required. The progression of the disease leads to a complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide.

Introduction

The first description by Waters, of a patient with what we now call Huntington's chorea, dates from 1842. But it was not until 1872, after the lecture and description of the disease by George Huntington, that it became known as Huntington's chorea. It is a neurodegenerative disorder passing within families from generation to generation with onset in middle age and characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia [1] For many decades its name remained unchanged, until the nineteen-eighties when, fully aware of the extensive non-motor symptoms and signs, the name was changed to Huntington's disease (HD). In 1983, a linkage on chromosome 4 was established and in 1993 the gene for HD was found [2]. That period marked a tremendous increase in interest in HD and neurogenetic disorders. For the first time, actual premanifest diagnoses could be made and as more diseases involving trinucleotide repeats of CAG were found, HD served as a model for many studies in medicine. CAG (cytosine (C), adenine (A), and guanine (G)), is a trinucleotide, the building stone of DNA. CAG is the codon for the amino acid glutamic. Finding the gene opened new research lines, new models and for the first time a real rationale on the way to treat this devastating disease. Many symptomatic treatments are now available, but there is a need for better, modifying drugs.

Epidemiology

Huntington's disease is a rare neuropsychiatric disorder with a prevalence of 5-10 per 100,000 in the Caucasian population. In Japan, a much lower prevalence of about one-tenth of prevalence of the Caucasion population is described [3]. Recently, several phenocopies have been described, all of which have an even lower prevalence (see paragraph on differential diagnosis).

Clinical description

The nuclear symptoms and signs of Huntington's disease (HD) consist of motor, cognitive and psychiatric disturbances. Other less well-known, but prevalent and often debilitating features of HD include unintended weight loss, sleep- and circadian rhythm disturbances and autonomic nervous system dysfunction. The mean age at onset is between 30 and 50 years, with a range of 2 to 85 years. The mean duration of the disease is 17-20 years. The progression of the disease leads to more dependency in daily life and finally death. The most common cause of death is pneumonia, followed by suicide.

The motor symptoms and signs

The characteristic motor changes are involuntary, unwanted movements. Initially, the movements often occur in the distal extremities such as fingers and toes, but also in small facial muscles. For bystanders these muscle twitches are often invisible or can be explained as nervousness. In daily life, walking becomes unstable and the person can look as if he/she is slightly drunk. Gradually the unwanted movements spread to all other muscles from distal to more proximal and axial. Choreatic movements are present all the time the patient is awake. No single pattern exists, but facial choreatic movements can lead to a continuous movement of facial muscles where for instance an eyebrow is lifted, an eye closed, the head is bent or turned while the tongue is protruded with the lips pouting. The most prominent are the extension movements of the long back muscles. Talking and swallowing gradually become more problematic leading to choking at any time in some patients. In later stages the patient even becomes mute. Dysarthria and dysphagia become very prominent during the course of the disease. All patients develop hypokinesia, akinesia, and rigidity leading to a slower pace of all activities (bradykinesia: slowness of movement) and a severe hesitation in embarking on a movement (akinesia: difficulty in starting movemevents)). The balance between chorea and hypokinesia is determined individually. The extremes are on the one hand the younger patient with an overwhelming rigidity (Westphal variant) and on the other hand the very old patient severely affected in the last stage of the disease with a long duration of illness, bed-bound with rigidity and flexion contractures in the extremities. Dystonia is characterized by slower movements with an increased muscle tone leading to abnormal posture, for instance torticollis, but also rotation of the trunk or limbs. Dystonia (for instance torticollis) can be the first motor sign in Huntington's disease. Other unwanted movements include tics, comparable to the ones seen in Tourette syndrome, but these are fairly rare. Cerebellar signs can appear sporadically, similar to the presence of hypo- and hypermetria. Walking is often described as 'drunk' or 'cerebellar ataxia'-like. Distinguishing between choreatic and ataxic walking is very difficult. Pyramidal signs (Babinski sign) are present incidentally.

The influence of motor disturbance on activities of daily life progresses over time. The presence of hyperkinesia and hypokinesia results in difficulties in walking and standing, and frequently leads to an ataxic gait and frequent falls. Furthermore, daily activities such as getting out of bed, taking a shower, dressing, toileting, cleaning the house, cooking and eating become more and more difficult. Depending on the kind of work the patient does, motor signs will sooner or later interfere with performance, even if psychiatric and cognitive changes are still in the background.

Behaviour and psychiatric symptoms and signs

Psychiatric symptoms are very frequently present in the early stage of the disease, often prior to the onset of motor symptoms. The percentage of patients with psychiatric signs varies between 33% and 76% depending on the methodology of the study[4]. Because of their impact on daily life, these symptoms and signs usually have a highly negative impact on functioning and on the family [5]. The most frequently occurring sign is depression. The diagnosis is difficult because weight loss, apathy and inactivity also occur in HD. Usually there is low self-esteem, feelings of guilt and anxiety. Apathy is related to disease stage, whereas anxiety and depression are not. Suicide occurs more frequently in early symptomatic individuals and also in premanifest gene carriers. Around the time of the gene test and the stage when independence diminishes are the most risky periods for suicide. Anxiety also occurs frequently (34-61%), sometimes in relation to uncertainty about the start and or the course of the disease. Obsessions and compulsions can disturb the patient's life and also lead to irritability and aggression. Irritability is often the very first sign, in retrospect, but in fact occurs during all stages of the disease [4]. The way irritability is expressed varies enormously from serious disputes to physical aggression. A loss of interest and increasing passive behaviour are seen as part of the apathy syndrome. It can be difficult to discriminate apathy from depression. Pychosis may appear, mainly in the later stages of the disease. In most cases this goes together with cognitive decline. The complete clinical picture is comparable to schizophrenia with paranoid and acoustic hallucinations. In the early stages, hyper-sexuality can cause considerable problems in a relationship. In the later stages hypo-sexuality is the rule.

Dementia

Cognitive decline is the other main sign of HD and can be present long before the first motor symptoms appear, but can also be very mild in far advanced stages of the disease. The cognitive changes are particularly in relation to executive functions. In normal conditions, cognitive and motor behaviour is goal-directed and planned. Normally individuals are able to distinguish what is relevant and what can be ignored, but patients with HD lose this capability. The patients are no longer able to organise their life or to plan things which in the past were simple. They lose flexibility of mind, and can no longer make mental adjustments. Misjudgements lead to complicated situations, with patients no longer reacting as they did in the past or in a way that the environment expects. Language is relatively spared. Memory certainly becomes impaired, although the semantic memory can be spared to a certain extent. All psychomotor processes become severely retarded [3].

Secondary symptoms and signs

From early on, an unintended weight loss has been reported in all patients. As more attention is now paid to this phenomenon, the loss seems to be a little less severe, the cause being diverse. Although it seems logical to think that chorea should play the main role in weight loss, it has been shown that there is no relation between weight loss and chorea or other movement disorders. A relation with the length of the CAG repeat has been described [6]. More practical issues, such as slower functioning, decreased appetite, difficulty handling food and swallowing certainly play a role. But hypothalamic neuronal loss is also a causative factor [7,8].

Attention has only recently been focused on sleep- and circadian rhythm disturbances of patients with HD [9]. Autonomic disturbances can result in attacks of profuse sweating.

Juvenile Huntington's disease

If the first symptoms and signs start before the age of 20 years, the disease is called Juvenile Huntington's disease (JHD). Behaviour disturbances and learning difficulties at school are often the first signs. Motor behaviour is often hypokinetic and bradykinetic with dystonic components. Chorea is seldom seen in the first decade and only appears in the second decade. Epileptic fits are frequently seen. The CAG repeat length is over 55 in most cases. In 75% of the juveniles the father is the affected parent [10].

Development of the disease

The course of the life of a person with one parent with Huntington's disease can be divided into an at-risk, a preclinical (A) and a clinical (B) stage. The at-risk stage comes to an end when it is determined whether the person carries the increased CAG repeat on chromosome 4. If he does carry the gene, then he will go through the preclinical and clinical stages until the end.

The clinical course is roughly divided into three parts (Table ​1), indicating a decrease in independence and increase in the need for care. The clinical stage with clear manifest signs is preceded by the premanifest gene positive stage, and the transition or phenoconversion phase, when more and more doubt about manifestations of signs emerges. During periods of stress, irrespective of whether this is physical or psychological, it is not uncommon for clinical symptoms or signs to become manifest. These signs can fade away temporarily when the circumstances normalize. In the past, the first symptom was always a motor sign. Dependent on the family's and the doctor's experience with the disease, a diagnosis was suggested. However, over the last 20 years it has become clear [11,12] that psychiatric as well as cognitive changes can be the first signs, many years before motor signs become visible. If the non-motor signs are less specific, it can be very difficult to make a diagnosis. In retrospect, many patients mention a gradual change in behaviour and performance at work. They stayed home for some time with a 'burn-out' or a 'depression'. These signs are rather non-specific and often have a plausible explanation. With improved knowledge about the genetic status and the course of the disease it has become clear that these signs can be the first manifestation of Huntington's disease.

Table 1

Stages during the life of a Huntington's disease patient

Assessments

The clinical assessment of the symptoms and signs of HD is important for patient, family and care-givers. To follow the patient systematically, mainly for research purposes, several scales have been developed. The best known are the Shoulson and Fahn capability scale [13] and the Unified Huntington Disease Rating Scale (UHDRS) [14,15]. The UHDRS consists of a motor, behaviour, cognitive and functional part, preceded by a history and medication scheme. For the behaviour signs a new scale was developed by Craufurd: the Problem Behaviour Scale (PBS)[16]. Other scales, for instance for the quality of life, are also in use. In the European Network for Huntington disease (EHDN: website [17]) a whole set of assessment scales has been devised, which are now in use for over 6,000 patients in Europe.

Aetiology

Huntington's disease is an autosomal dominantly inherited disease caused by an elongated CAG repeat on the short arm of chromosome 4p16.3 in the Huntingtine gene [2]. This gene codes for the huntingtin protein and, on exon 1, contains the CAG tract. The wild-type contains a CAG repeat, coding for a polyglutamine stretch in the protein at that site in the range 6 to 26. Huntington's disease is associated with 36 repeats or more. Definite clinical manifestation will occur if the number of repeats exceeds 40. The range 36-39 leads to an incomplete penetrance of the disease or to a very late onset. The range between 29 and 35, the so-called intermediate alleles, is unstable, which means that these alleles are prone to changes during reproduction. Copying the gene may lead to mistakes and very often leads to elongation and seldom to shortening. This phenomenon is mainly seen in the male line of reproduction [18].

An inverse correlation has been described between the length of the repeat and the age at onset, determined by the first motor manifestation. The longer the CAG repeat, the earlier the onset. When the disease starts before the age of 20 years, so-called juvenile Huntington's disease (JHD), the repeat often exceeds 55 [5]. The length of the repeat determines about 70% of the variance in age at onset and gives no indication at all about the initial symptom, the course, or the duration of illness. The only correlation now described is the faster weight loss associated with a longer CAG repeat [6]. Anticipation phenomenon is seen in Huntington families in the paternal line of inheritance.

The normal wild-type Huntingtin protein plays a role in synaptic function, is necessary in the post-embryonic period, possibly has an anti-apoptotic function and is possibly protective against the toxic mutant, huntingtin [19]. There is evidence that the mutant form leads to a gain of function as well as to a loss of function. The role of the mutation has been studied in many models: cells, fibroblasts, C. Elegans, drosophila, mice, rat, sheep and monkey. Mice models (more than 10 available) are most commonly used. As neuronal intranuclear and intracytoplasmic inclusions are found, it is still not clear what role they play. Are the inclusions pathogenic in themselves or are they only a side-product of other mechanisms? The inclusions are present in many areas of the brain. The overall pathology, brain atrophy, particularly in the striatum with extensive neuronal loss, is well known [20,21].

Diagnosis

The diagnosis is based on the clinical symptoms and signs in a person with a parent with proven HD. First, it is obligatory to take a precise history from the person with symptoms followed by a detailed family history. When all information has been obtained the diagnosis is not very difficult, although non-specific clinical pictures can be misleading. Also when the parent is not known or has died due to another cause at a young age, the clinical picture can be difficult to recognise. It is often necessary to request old information in the form of medical records and autopsy reports. The current gold standard is DNA determination, showing a CAG-repeat of at least 36 on the huntingtin gene on chromosome 4. Before 1993, a family history with clinical and morphological verification in at least one of the parents or grandparents was obligatory.

The clinical criteria currently necessary are still motor changes with or without psychiatric or cognitive changes. However, in most cases a combination of the three main signs is present. The combination with the family history is sufficient for diagnosis. No imaging, general blood tests or other diagnostic tools are helpful. For all diagnostic tests, it is necessary to obtain informed consent from the patient. This is important because if that person is given a diagnosis of Huntington's disease, then probably many more individuals around the patient will be confronted with an increased risk of Huntington's disease. Extensive studies are underway to detect biomarkers (clinical, blood, MRI) and hence the transition determining parameters [22].

Several studies are now focussing on changes in function and changes in brain imaging (MRI) before clinical overt manifestation is present. It seems that brain volume and brain connections show changes several years before any clinical manifestation is present [23].

Differential Diagnosis

When chorea is the presenting and most prominent sign, taking a history is the first and most valuable step. The frequently occurring differential diagnoses for motor sign chorea are given in Table ​2. In many cases the underlying cause is another general internal disorder or an iatrogenic disorder. Only very few genetically determined disorders are responsible for choreatic syndromes. In about 1% of the cases clinically diagnosed as HD by the clinician, the genetic test does not confirm the diagnosis. These are the so-called phenocopies [24]. Phenocopies are defined by a clinical diagnosis of HD with chorea, psychiatric and or cognitive signs and an autosomal dominant pattern of inheritance or family history. In the last few years, several have been described (Table ​3)

Table 2

Differential Diagnosis for chorea

Table 3

Phenocopy of Huntington's disease (OMIM) [32]

Genetic Counselling

When the gene was localised on chromosome 4 in 1983 [25], premanifest diagnosis became available for the first time using linkage analysis. Linkage analysis provided the applicant with results, initially with a certainty of 93% and later with a certainty of about 98%. When in 1993 the CAG repeat on chromosome 4 was described, real premanifest diagnosis could be given to those at risk of HD. It was the first disease in which this technique became practically available, functioning as an example of how to cope with new questions and problems. A manifest was written by the HD community, a collaboration of scientists, doctors and lay people [26]. The standard procedure was the following: step 1, consultation with a clinical geneticist and preferably in combination with a psychologist and a neurologist. After 4-6 weeks a second consultation (step 2) takes place including blood sampling. After a period of 6-8 weeks a consultation (step 3) with disclosure is planned. Exclusion criteria for the procedure are: age below 18 years, severe psychiatric illness, and external pressure for the applicant. Long discussions took place concerning applicants with a 25% risk at the time of the request. The procedure was extended with the rule that maximal efforts must be taken by the applicant to get a result from the parent with a 50% risk of HD. Finally the 25% at risk applicant can get his test [27].

Prenatal diagnosis

As the test can be performed on any cell with a nucleus containing DNA, antenatal diagnosis is also possible. Between the 10th and 12th weeks of pregnancy, chorionic villus sampling and between the 15th and 17th weeks amniocentesis can be performed and DNA-testing carried out. The procedure is only initiated if the parents already know their own genetic status to prevent unwanted disclosure for two individuals at the same time. The procedure is embarked on with the intention of ending the pregnancy if the HD gene is found in the embryo. The mother cannot be forced to agree with this conclusion.

If the parents have not yet been genotyped, one can opt for an exclusion test by comparing the genetic status of the embryo with that of the grandparents. In this situation the result is either 0% risk for the foetus, and so the parent keeps his or her 50% status, or 50% risk for the foetus. The foetus has received a chromosome from the affected grandparent, but it is not known to which chromosome the HD gen is coupled. In this case the foetus has a 50% risk, comparable to the parent, and the parents can decide to abort a 50% at risk baby.

During the last decade, preimplantation diagnostics has also been offered in several countries. The procedure starts with in vitro fertilisation. When the embryo is in its eight-cell stage, one cell is removed for DNA testing. The embryo without the elongated CAG repeat is placed in the mother's womb to allow a normal pregnancy to develop. Before starting this procedure, the genetic status of the parent must be known, although not all countries follow this line of thinking [28].

Management including treatment

Despite the fact that the pathogenesis of HD has still not been resolved and a cure is not available, many therapeutic options are available for treating symptoms and signs with a view to improving quality of life. Although many signs and symptoms can be treated, it is not always necessary to do so. The patient's limitations in daily life determine whether or not drugs are required. Very little evidence is available about the drug or the dosage to prescribe for any signs and symptoms. Drug treatment is, therefore, individualized and based on expert opinion and daily practice.

Treatment consists of drug prescription and non-medication advice. Surgical treatment does not play an important role in HD and will be addressed only briefly.

Motor signs

Hyperkinesia, or chorea, is treated with dopamine receptor blocking or depleting agents. Most commonly used drugs for chorea (Table ​4) are typical or atypical neuroleptics (dopamine receptor blocking) and tetrabenazine (dopamine depleting). The drugs prescribed differ per country. An extensive review of all medication is given by Bonelli [29,30]. The most commonly used drugs for depression and aggression are listed in Table ​5. Clozapine and olanzapine are atypical neuroleptics. Both have an antichoreatic effect. Clozapine requires white cell control in the blood and is, therefore, less practical, making olanzapine the preferred drug. The most frequently reported side effects are weight increase and anti-depressive effects. From small case studies some support can be found for prescribing quetiapine, zotepine, ziprasidone, and risperidon. However, only tetrabenazine, a dopamine depleting drug, has been shown in a controlled trial to significantly reduce chorea [31]. The most common side-effects are depression and sedation. There is a long list of drugs without or with only a very limited result, mostly in open case studies: α-tocopherol amantadine, baclofen, cannabidiol, chlordiazepoxide, choline, clonazepam, creatine, deanol, dextromethorphan, fluoxetine, idebenone, ketamine, lamotrigine, levatiracetam, milacemide, minocycline, muscimol, OPC 14117, PUFA, remacemide, riluzole.

Table 5

Drug Treatment for depression (A) and aggression (B)

Drug treatment for hypokinesia has been tried using antiparkinsonian drugs, but almost always with very disappointing results. In practice, therefore, dopaminergic drug are not prescribed.

To date, despite several claims, no drug is available with any neuroprotective or disease-delaying effect. Disease modifying drugs are developed, but not available. Also embryonic cell implants, still under study, are not proven treatment options at the moment.

Surgical intervention to treat chorea has been described in a few cases. Deep brain stimulation has a place in other movement disorders such as Parkinson disease.

In Alzheimer's disease, anticholinesterase drugs are in use. In Huntington's disease no clinical trials with Rivastigmine or Donepezil are available. In short-term, open studies, no effect was found.

Psychiatric signs

As depression and aggressive behaviour are the most devastating to family life, the majority of drugs are prescribed for these signs. All advice is based on open studies and expert opinion. (Table ​5)

Besides medication, many other care measures are available. It is important to find the right therapy for the right person at the right time. Non-medical interventions available are: physiotherapy, occupational therapy, speech therapy, dietician, psychologist, social worker, and nurse.

During the course of the disease, the patient requires more care, which can also help his/her partner, for example by having a nurse at home to help with showering. The burden for the caregiver can become too heavy and so help must be found in day-care institutions, usually connected to nursing home facilities. In the period that follows the patient moves into a transition phase and eventually a 24-hour care situation. Throughout the whole process of increasing dependency, psychological help is often needed for the caregiver, who has to deal with increasing responsibilities while losing contact with his or her former partner. Partner groups can be very useful. In general, lay organizations play an enormous role in educating caregivers, patients and families.

Medical and non-medical treatment must be individually tailored, as the symptoms and signs differ by person and over time tremendously. Ideally treatment of patients and their families should be organised by a multidisciplinary team. Treatment is intended to improve quality of life. To date, no cure is available unfortunately.

Future perspectives

Huntington's disease is a physically, psychologically and socially devastating disorder. Knowledge about the disease and care for patients has increased enormously over the last two decades. As the mean duration of illness is more than 17 years, one tends to forget the many years prior to the onset of symptoms during the at-risk and the preclinical periods, or the premanifest period. Huntington's disease is a lifelong disease for both the individual and the family. From the moment the gene was localised in 1983, and particularly after 1993, attention has focussed on the pathophysiological pathway with the aim of developing a therapy. It was the first autosomal dominant disease where premanifest diagnosis became possible and it was the first trinucleotide disease to be described. Consequently, since 1993 many researchers have developed an interest in this disorder. The number of publications has increased enormously.

What is the current perspective? The basic studies mainly focus on the pathophysiology and the search for biomarkers. A better understanding of the pathophysiology will surely lead to drug development to interfere in the pathological process. Drugs that can slow down, delay, or stop the onset of the disease are being sought. The second issue is the search for reliable, early to detect and clinically relevant markers for onset of the end course of the disease. In the search for biomarkers, a very well organised study is underway: TRACK-HD, a multinational study with 366 participants. This will end in 2011 [22]. The Registry study, the main project of the European Huntington Disease Network, also aims to prepare the field for larger studies when drugs become available for human testing.

In parallel with the rational pathway to find solutions to treat this disorder, attention is being paid to finding the best care for all patients and at-risk persons at this point in time. The developments are promising, but one thing is certain: the road to a solution is a long one.

Competing interests

The author declares that he has no competing interests.

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Articles from Orphanet Journal of Rare Diseases are provided here courtesy of BioMed Central

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