Managing juvenile Huntington’s disease

SUMMARY

Huntington’s disease (HD) is a well-recognized progressive neurodegenerative disorder that follows an autosomal dominant pattern of inheritance. Onset is insidious and can occur at almost any age, but most commonly the diagnosis is made between the ages of 35 and 55 years. Onset ≤20 years of age is classified as juvenile HD (JHD). This age-based definition is arbitrary but remains convenient. There is overlap between the clinical pathological and genetic features seen in JHD and more traditional adult-onset HD. Nonetheless, the frequent predominance of bradykinesia and dystonia early in the course of the illness, more frequent occurrence of epilepsy and myoclonus, more widespread pathology, and larger genetic lesion means that the distinction is still relevant. In addition, the relative rarity of JHD means that the clinician managing the patient is often doing so for the first time. Management is, at best, symptomatic and supportive with few or no evidence-based guidelines. In this article, the authors will review what is known of the condition and present some suggestions based on their experience.

Historical note & prevalence

The first descriptions of Huntington’s disease (HD) predate the succinct report by Huntington in 1872 [1]. Similarly, although juvenile HD (JHD) may have been described earlier, the first clear description is attributed to Hoffmann in 1888 [2]. In that article he described a family with HD, one of whom was a female aged 36 years. She had onset of epilepsy at the age of 2–3 years, but its relationship to HD is less clear. She developed abnormal movements before the end of her school years and lost the ability to do ‘handicrafts’ at the age of 22–23 years, at which time the epilepsy became more frequent. Hoffmann clearly described the poverty of movement in this patient. He also gave a briefer description of a female cousin who developed chorea at the age of 10 years and died in her twenties. Interestingly, in both cases the transmitting parent was the mother. An important point from this historical note is that the disease duration may be many years, well into young adulthood. The origin of the term JHD is obscure, but in 1968, Bruyn reviewed the published literature and accepted a definition of JHD as onset before 20 years [3]. A number of publications also include cases with onset at 20 years of age so the definition of ≤20 years will be used in this review; in addition, those with onset at ≤10 years will be described as having ‘childhood-onset’ HD.

The percentage of JHD in studies of HD prevalence varies; however, a recent meta-analysis of studies that used multiple methods of ascertainment from 1980 and were from countries described as high income by the World Bank gave a percentage of 4.81% (95% CI: 3.31–6.58%) [4]. This was contrasted with three studies from Venezuela and South Africa (that are described by the World Bank as high to middle income), which had a percentage of 9.95% (95% CI: 6.37–14.22%). The difference may be due to the different age structures in these populations. If there is a large elderly population then those with later ages of onset will present with the condition and as a consequence the percentage of JHD cases will be lower. Of the JHD cases in this meta-analysis, approximately 20% had childhood-onset HD. Prevalence figures vary between studies and populations, but a convenient figure is ten per 100,000, although in some populations it may be higher [5]; therefore, in a population of 50 million there should be approximately 250 cases of JHD, but it has to be remembered that at any point in time many will be over the age of 20 years.

Clinical features

Any patient with HD will experience a mixture of problems with both voluntary and involuntary movement. Classically, patients with adult HD (AHD) will demonstrate signs of chorea early in the course of the illness but, even at this stage, there can be slowing of rapid alternating movements, which can be demonstrated on clinical examination. As the disease progresses, the chorea becomes more prominent, but eventually plateaus or even declines. Meanwhile, problems with bradykinesia and dystonia become more prominent. In JHD, the pattern tends to be that the bradykinesia, dystonia and parkinsonian features are prominent at an early stage, while chorea, if present, is less prominent [6].

If cases of JHD are divided into predominantly choreic or predominantly dystonic and braykinetic, the proportion will be 40–50 and 50–60%, respectively [7–11]. There is less information available about myoclonus and epilepsy but this is reported in approximately 30–50% of cases [7–9,12].

In most cases of HD, the motor symptoms are less of a problem for the family than the cognitive and behavioral problems. In fact, not only are behavioral and cognitive problems more difficult for the family, they are the most common presenting symptoms [10,12]. It is well recognized that declining school performance can be a significant feature of JHD [13]. Speech and language problems may occur early in the course of the illness and can be a pointer toward the diagnosis [14]. The evidence basis for the behavioral effects of JHD in relation to changes in puberty and sexual activity is limited. It is not possible to give specific advice; each case should to be managed by the multidisciplinary team described below.

HD is considered to be a disease of the nervous system, but there are some wider manifestations such as weight loss and cachexia [15] and, as may be expected, these also occur in JHD.

Pathology

There is similarity between the pathology seen in HD and JHD. Although the pathological process affects several areas of the brain, the initial brunt of the pathology occurs in the corpus striatum, with significant atrophy of the caudate and putamen nuclei, and globus pallidus, which is divided into internal and external nuclei. The pathology in JHD is likely to be more extensive and severe than in a more classical AHD case, provided the patient has not died prematurely [16,17]. In 20% of AHD cases the frontal lobe can appear normal, whereas in JHD the brains are small with prominent frontal and parietal atrophy. In contrast to AHD, the internal globus pallidus is grossly atrophic in JHD and this may account for some of the symptoms related to poverty of movement [16,17]. There have been reports that cerebellar atrophy occurs in JHD [18–24], but not in every case with very early onset [25,26]. It has been suggested that this could be related to hypoxic–ischemic changes secondary to epilepsy [15,16]; however, this is less likely as, more recently, cerebellar changes in AHD have been recognized as occurring early in the course of the disease, which were not correlated with the extent of the striatal atrophy, but may explain some of the features seen in HD [27].

HD results from an unstable expansion of a CAG repeat sequence in the first exon of the huntingtin gene such that the resulting protein (HTT), contains an expanded glutamine sequence [28]. The abnormal protein is widely expressed, but the neurodegenerative process is selective; therefore, within the caudate and putamen nuclei, the medium spiny neurons are especially sensitive to the neuropathological process. There has been a large number of studies trying to explain how the normal protein affects cellular processes and in turn explain how the abnormal protein subsequently results in the pathological changes seen in HD. HTT has a number of functions within the cell and, to date, there is not a coherent explanation of how the multifaceted functions of normal and abnormal HTT in cells results in the well-recognized clinical and pathological features.

Genetic issues

There is a consensus about the reporting of genetic testing results: under 27 CAG repeats is unequivocally normal; 27–35 CAG repeats has the potential to expand into the abnormal range in future generations; 36–39 CAG repeats is abnormal, but there may be reduced penetrance; and over 40 CAG repeats is considered unequivocally abnormal [29]. Soon after the gene was cloned it became clear that there was a negative correlation between the mean CAG repeat length and the age of onset [30–37]. Although this relationship has proved to be robust, there is such a large range around the mean that the specific CAG result does not provide reliable information regarding a predicted age of disease onset for an individual [38].

It is often stated that individuals with CAG repeat lengths >60 have JHD. However, it is not appropriate to define JHD based on >60 CAG repeats because approximately half of the cases have a CAG repeat length <60 and in some rare cases repeat length can be in the 40s [11–13,31]. In addition, there may be a few patients with repeat lengths >60 and an onset just over 20 years [39]. The extent of the overlap of the CAG repeat lengths between AHD and JHD is often not fully appreciated [40].

Apart from man, no known natural animal develops HD. The cloning of the HTT gene led to the development of a number of mouse and other animal models of the condition. In order to drive the pathological process, most animal models of HD contain grossly abnormal CAG repeat lengths so, in a broad sense, they are more likely to model JHD rather than AHD. The mouse models have recapitulated a number of features of HD, including the presence of intra-neuronal inclusions, transcriptional and energetic deficits, as well as the development of progressive motor and cognitive defects, predictably leading to death [41].

It has been widely recognized that in the majority of JHD cases the transmitting parent is the father: this occurs in approximately 70–80% of those cases with an onset between 11 and 20 years of age and may be over 90% in those with childhood-onset HD [3,8–12,31,42–47]. This observation was originally made before the gene was cloned, but we now have an explanation in that there is instability in the CAG repeat length during spermatogenesis, which increases if the father has a longer CAG repeat length [31–33,48–50]. Care has to be taken with remarks about paternal transmission in JHD because families may have increased worry about their children. While it is true that in the majority of cases the transmitting parent is the father, it does not follow that fathers affected by HD will necessarily have offspring with JHD. In some families, specific reassurance on this point may be required, as in some notable cases the transmitting parent was the mother [2,25,26,51].

Disease duration & progression

Patients with AHD have a slowly progressive condition that lasts for many years. It is often said to last 15–20 years, but there is wide variation around this figure, with some patients having longer disease duration. Gusella and MacDonald reviewed the data presented in Persichetti et al. [52] and demonstrated that, while there was a correlation between CAG repeat length and age of onset, there was no correlation with disease duration [53]. The implication of this observation is that once the disease process starts it continues and factors other than the CAG repeat length determine progression of the pathological process. Unfortunately, there were only two to four cases with onset at ≤20 years of age in that dataset and no cases of childhood-onset HD.

There is a perception that JHD patients have shorter disease duration, but there is conflicting evidence on this topic within the published literature [8,54–56]. There have been case reports of individuals with very high repeat lengths (95–240) of whom three have died: they had onsets at ages 2.5, 3.5 and 3 years, and their duration of illness was 13.5, 4 and 8 years, respectively. [23,25,26]. It is often difficult to draw conclusions from single case reports. It may be the case that disease duration is shorter in childhood-onset cases; however, they are much less common than those with onset in the second decade so a large international study is required to settle the question.

The view that the illness in JHD progresses at a faster rate is widely held [6]. The problem with a review of the literature is that some studies are cross-sectional whereas others are longitudinal; in addition, progression has been assessed with a variety of different clinical assessments or different imaging measurements [6]. Taken as a whole, there is probably a greater rate of disease progression in those with JHD, but given the relative rarity of JHD, the assessment of disease progression may require the collection of data as part of a multinational collaboration such as the European Huntington’s Disease Network (EHDN) project REGISTRY [101]. The EHDN has established a working group on JHD and a specific substudy for JHD [102]. This work will be developed further as part of a new study called ENROLL-HD [103].

The issue of disease progression is not wholly academic because parents will ask about how long the illness lasts and may themselves have come across comments that JHD is associated with shorter disease duration. As in any medical discussion, the clinical features of the young individual need to be considered but, in general, it may be wise to avoid categorical statements and still speak in terms of a duration measured in years, up to as much as a decade or two.

Issues with diagnosis

The diagnosis of HD, whether AHD or JHD, is based on a clinical judgment that unequivocal neurological signs are present. If a young individual comes from a family with HD and unequivocal neurological signs are present, then undertaking a genetic test to confirm the diagnosis is noncontroversial. Nance and the US Huntington Disease Genetic Testing Group have proposed that a clinical diagnosis of JHD can be made in those with onset aged under 10 years if the criteria in Box 1 are met [12]; identifying a similar set of diagnostic criteria for those with onset between 11 and 20 years of age proved more challenging.

Box 1. Diagnostic criteria for childhood-onset Huntington’s disease (≤10 years).

A family history of Huntington’s disease (usually in the father) and two or more of: Declining school performance Seizures Oral motor dysfunction Rigidity Gait disturbance

Reproduced with permission from [13].

Although symptomatic and supportive treatment is available for HD, there is no treatment that is disease modifying. For this reason, the genetic test is used cautiously and guidelines have been developed for undertaking predictive testing. The updated guidelines specify that predictive testing is not recommended for those aged under 18 years [37]. This poses a difficulty if a young individual presents with behavioral problems as it can lead to delays in diagnosis [11,57]. Quite reasonably, there is reluctance to undertake genetic testing in this scenario. If the CAG repeat length is >60 then JHD onset is very likely. If the result is in the normal range then it is clear that the problems are unrelated to HD. However, if the result is in the more usual abnormal range then it will have been established that the young individual has inherited the mutation, but whether the current symptoms are related to JHD will remain unclear. Moreover, it is possible that the current problems are unrelated to HD and the individual is due to start to have symptoms at a more distant time in the future. The delay in diagnosis may lead to frustration for the parents and care must be taken not to imply that the behavioral difficulties result from bad parenting [58].

In the circumstances of a child with exclusively behavioral symptoms, a baseline cognitive assessment and MRI scan may be considered, not because they are diagnostic in themselves, but because they can be repeated at a future time to assess whether there has been decline. This, in turn, can help with the management of the young individual and their family.

It is possible for a young individual to present with HD before one parent, usually the father, is diagnosed; this has happened in cases with very long CAG repeats [22,25,49,59,60], but the extent to which it happens with teenage onset is less clear, although the authors have personal experience of this in at least one case. In this circumstance, managing the family requires additional care because the possibility of nonpaternity may arise or, if a history of HD is described in other relatives, the relevant parent may be reluctant to undergo genetic testing.

A further problem may arise if behavioral issues occur in a teenager and the parents do not want HD discussed in front of the young individual. This has to be handled sensitively and progress can only be made at a pace allowed by the family.

Management

Once a diagnosis of JHD has been established it is essential to consider a multiprofessional approach as outlined in Table 1. There is no disease-modifying treatment available and no specific evidence basis for interventions so the team needs to consider the symptoms and work together to provide effective symptomatic and supportive care. Given the progressive neurodegeneration, the role and relative importance of each team member will vary according to the stage of the illness. In the majority of cases, the individual professional may come across JHD for the first time so it is important to recognize this and not pretend to have knowledge. Families may prefer a response along the lines of: ‘I do not know the answer to your question but will find out’ [58]. Schooling is especially important and teachers may value an annual assessment of the cognitive decline so as to plan a relevant curriculum. Given that there is, as yet, no disease-modifying therapy, considerable emphasis needs to be placed on nonpharmacological interventions.

Table 1.

Professionals involved in the care of patients with juvenile Huntington’s disease.

Professional	Potential role
General pediatrician/community pediatrician	Address general health needs and act as a focal point for specialist input
Pediatric neurologist possibly supplemented by a clinician (neurologist, psychiatrist or geneticist) with a specific interest in HD	Advice on pharmacological management and assessment of the disease stage
Child psychiatrist	Advise on management of the family and pharmacotherapy for behavioral disorders
Child psychologist or neuropsychologist	Assess cognition, provide strengths and weaknesses, assist with educational curriculum and recommend compensatory strategies for cognitive losses
Dietician	Manage the weight loss that is associated with HD
Nonclinical case manager able to coordinate non-medical services for the family (could be a social worker or nurse)	Relate to school teachers, arrange respite care, provide support for the family and arrange for adaptations to the house if necessary
Dentist	Dental hygiene may become a challenge given the problems with movement and behavior
Speech therapist	Advise on aspects of communication and swallowing difficulties
Physiotherapist and occupational therapist	Important for maintaining independence for as long as possible
Palliative care specialist	Important for the end stage of illness, which may last for many years

HD: Huntington’s disease.

Pharmacological treatment has a place in the management of JHD but as no current evidence exists. Box 2 summarizes the symptoms that may need to be managed over the course of the illness. A recent report of medications that are prescribed in JHD showed evidence of polypharmacy [61]; therefore, it may be wise to have periodic reassessment of the pharmacological treatments as the needs of patients vary over the course of the illness. Table 2 summarizes the drugs that were prescribed to 45 European patients [61]. The current authors emphasize that, to date, there is no evidence for the use of these medications in JHD so the fact that they have been mentioned in this review should not imply that we endorse any particular drug. In that study, the most commonly prescribed drugs were dopa blockers, antidepressants and dopa agonists [61]. Dopa blockers and dopa agonists (if parkinsonian features are present), muscle relaxants and benzodiazepines have been used to manage motor symptoms. Behavioral symptoms can be managed with the use of dopa blockers (antipsychotics are often used to quell aggression), antidepressants and mood-stabilizing agents. Antiepileptic medications may be used either as mood stabilizers or for the management of epilepsy. Treatment of cognitive problems, such as inattention, with stimulants can be useful; however, these should be used cautiously in the context of monitoring adverse effects on motor symptoms; therefore, nonstimulant treatments, such as atomoxetine, may be an important alternative. Parents or care providers may have contact with another family with JHD and may not understand why the medications that have been prescribed differ and may wonder if another clinician could suggest something more helpful. This requires a willingness to consider the suggestion proposed by the family while, at the same time, explaining that each patient’s symptoms vary and in certain circumstances why a particular medication is inappropriate for their child.

Box 2. Summary of Huntington’s disease symptoms that require treatment.

• Movement disorder:

  • Involuntary movements

  • Incoordination of voluntary movements

  • Rigidity/dystonia

  • Oral–motor dysfunction

• Cognitive disorder:

  • Progressive cognitive dysfunction (treated by repeated testing, and creation of appropriate school or vocational programs and goals)

• Psychological/behavioral disorder:

  • Depression

  • Anxiety

  • Obsessiveness

  • Inattention/ADHD

  • Apathy

  • Impulsiveness

  • Irritability

• Family issues:

  • Caregiver stress

  • School placement

  • Work placement

• Other:

  • Weight loss

  • Poor oral hygiene

  • Aspiration pneumonia (late)

Table 2.

Examples of pharmacological management data for Huntington’s disease.

Class of drug	Examples
Dopa blockers or dopa-depleting agents	Tiapride Haloperidol Tetrabenazine
Antidepressant	Mirtazapine Citalopram Fluoxetine Sertraline
Dopa agonist	L-dopa Amantadine
Antiepileptic	Valproic acid Clonazepam
Vitamin preparations	Tocopherol Ascorbic acid Coenzyme Q10
Anxiolytic	Lorazepam Diazepam Hydroxyzine Alprazolam
Antidementia	Memantine hydrochloride
Muscle relaxant	Baclofen Tizanidine

Data taken from [61].

The progressive dystonia may be difficult to treat and, depending on the individual concerned, there can be difficulty in managing the behavioral problems. This underscores the need for a multiprofessional approach and the importance of reinforcing the point that the disruptive behavior results from the underlying neurodegenerative process.

The progressive nature of the illness means that at some stage there has to be a discussion of end-of-life care, which, in the case of JHD, can be over a prolonged period of time. Weight loss and dysphagia with its attendant risk of aspiration pneumonia means that use of a percutaneous endoscopic gastrostomy feeding tube needs consideration; ideally, this should have been discussed earlier in the course of the illness so that its mention later does not come as a surprise. There is a limited literature of end-of-life care in JHD [62]. Nonetheless, palliative care clinicians can advise on symptomatic medication and management of pain, which may be associated with dystonic spasms.

Views of families

So far, this review has focused on JHD from the perspective of the clinician. There has been one account of JHD given by an individual with JHD in which he describes his losses and the progressive isolation from his friends, but he also describes those aspects of his life that are important to him [63]. Qualitative methods are valuable when attempting to understand the participant’s perspective, especially when the phenomenon is rare. A British study employed such an approach to examine the experience of parents/primary carers of children with JHD [64].

When questioned about their experience, parents/care providers reported that they slowly became aware that something was wrong: at times, this could be based on nonspecific observations with small gradual changes often not noticed by others. Carers spoke about the physical symptoms and were distressed by falls, epilepsy and pain. Similarly, problems with communication and progressive isolation from friends caused distress for the parents. The behavioral problems were difficult for carers, especially when these occurred in public and resulted in perceived criticism from others. Carers also spoke of the slow and relentless nature of the condition. Aspects of helpful and unhelpful support and of feeling isolated were described in separate reports [58,65]. A study employing the same methodology to examine the experiences of parents in different European countries has recently been completed and reports similar findings [66].

Conclusion & future perspective

HD research has benefited from multicenter and international observational studies, such as REGISTRY [67,101], COHORT [68], PREDICT [69] and TRACK-HD [70]. The REGISTRY and COHORT studies are going to be merged into a global observational study called ENROLL-HD [103]. These studies will allow information on cases of JHD to be shared. This exposes a problem that the rating scale most often used to monitor disease progression in HD, the Unified Huntington’s Disease Rating Scale (UHDRS), is not suitable for assessing younger patients [71]. New rating scales are being developed so that some specific questions related to JHD can be addressed [72].

The development of specific rating scales will allow a more rigorous assessment of the treatments currently used for JHD. At the same time, it is important to develop biomarkers to assess disease progression. Imaging studies provide the prospect of objectively measuring the rate of atrophy in the caudate and putamen nuclei, which can be used as an assessment of treatment in both AHD and JHD patients in future clinical trials.

Hopefully disease-modifying treatments will become available. Clinical trials of proposed therapies are likely to be undertaken on patients with AHD in the first instance. These could include treatments to prevent the abnormal protein from being produced (using RNA suppression or gene repair strategies) or the use of compounds to promote increased clearance of mutant HTT using the cell’s own mechanisms. Experiments are being undertaken with stem cells, including induced pluripotent stem cell technology. There is an active research pipeline involving the identification of new treatment targets and testing these in cell cultures and model organisms, through to supporting the development of new outcome measures that can be used in clinical trials.

An effective treatment could be identified serendipitously but, short of that, an understanding of the multifaceted nature of HD, of which JHD is a part, is an essential prerequisite for developing effective disease-modifying treatments. There is now a greater prospect for therapies that alter the natural history of HD than ever before.

New emerging drugs might represent future resources for JHD patients. One example is pridopidine, a dopamine stabilizer, recently tested in AHD; it did not achieve significance in its primary outcome measure but improved motor scores, particularly in those with dystonia [73]. Another potential pharmacological resource might be creatine, a food supplement expected to improve energy metabolism in HD. This is the subject of a current clinical trial and, for the first time, patients with an age as low as 18 years are currently under experimental treatment in a trial named the CREST-E study [104].

A question arises as to whether abnormal HTT has an effect on development. A recent study evaluated 20 asymptomatic children at risk of HD with basic morphometric measures of height, BMI, weight and head circumference, as well as a research laboratory assessment of CAG repeats in HTT (no genetic results were provided to subjects) [74]. The gene-expanded (CAG repeats >39) subset of asymptomatic children were compared with 138 healthy control children who did not have a family history of HD. The gene-expanded children had a significantly smaller mean head circumference and lower BMI compared with controls. Head circumference, a noninvasive proxy for brain size, was abnormally low even after correcting for height, suggesting a specific deficit in brain growth, rather than a global growth abnormality. These findings suggest that abnormal HTT may have a direct effect on brain development and led to the speculation that this phenomenon is more pronounced in JHD.

Practice Points.

• Juvenile Huntington’s disease (JHD) is defined as Huntington’s disease (HD) with an age of onset ≤20 years and accounts for approximately 5% of all HD cases.

• Individuals with a CAG repeat length of >60 usually have JHD, but a significant proportion of JHD cases (~50%) have <60 CAG repeats.

• The transmitting parent is frequently the father (~70–80% of cases), but this is not an absolute even in those cases with very large CAG repeat lengths.

• Issues of disease duration and disease progression are contested, and it is wise to avoid categorical statements when talking to families.

• If a young individual from a HD family has behavioral problems, it is important for clinicians to avoid implying that these result from ‘poor parenting skills’.

• The disease duration is prolonged; therefore, a multiprofessional approach is required for management.

• Pharmacological treatment is aimed at symptomatic and supportive care.

• End-of-life issues have to be considered on an individual basis.