While most clinicians know about Huntington disease, they may not be aware of its devastating effect in cognition and behavior during onset in childhood and adolescence.
LOOKING OUTSIDE THE BOX
Juvenile Huntington disease (JHD) is a devastating neurodegenerative disease that is characterized by behavioral, cognitive, and motor decline. While most clinicians learn about Huntington disease during professional training, many may not be aware of its onset during childhood and adolescence. JHD accounts for 5% to 10% of Huntington disease cases.1 Manifestation of the disease before age 21 is considered juvenile onset; childhood onset occurs before age 11.
Few studies have attempted to assess the population-based prevalence of JHD. A 2013 study in the UK found that the average annual prevalence of JHD was 6.77 per million (95% confidence interval, 5.60 to 8.12 per million).2 Whether onset occurs during adolescence or adulthood, behavioral and psychiatric manifestations are very common. Initial symptoms of JHD are often insidious and may appear disparate. This can make it difficult to establish the diagnosis, which is often delayed.3,4
Huntington disease is inherited in an autosomal dominant pattern. The disease is caused by a mutation leading to CAG repeat expansion in the first exon of the HTT gene. It appears that the age of onset of JHD is inversely correlated with the number of CAG repeats.5,6 Paternal inheritance is the mode of transmission in the majority of JHD cases.7 It is important, however, to consider the diagnosis even without a positive family history; cases have been reported in which the father had yet to show symptoms at the time of the evaluation of the child.4
More Information on Huntington Disease
Distinctions between the presentations of JHD and adult Huntington disease are outlined in the Table. The Huntington Study Group developed and validated the Unified Huntington Disease Rating Scale, which was published in 1996.8 The scale includes symptom categorization of all disease domains.
The literature describes several cases in which psychiatric and behavioral symptoms precede the typical motor symptoms.4 Symptoms may also appear to plateau before progressing. Symptom categorizations are used to describe disease progression in JHD: initial behavioral and cognitive changes; subsequent gait disturbance, rigidity of the extremities, and involuntary movements; then a phase of worsening cognitive decline, rigidity, speech regression, and seizures; to an ultimate stage of worsening immobility, hypotonia, dysphagia, and aspiration.9
The psychiatric manifestations of JHD fall into several symptom domains. Psychiatric symptoms include depression, anxiety, irritability, agitation, aggression, inattention, obsessiveness, impulsivity, and apathy. Changes in sleep patterns are also common. As the disease progresses, these symptoms become more impairing and increasingly difficult for family and care providers to manage.
Peter, age 14, is brought to the ED after an episode of severe aggression against his brother. ADHD and anxiety disorder were diagnosed when he was in the first grade. He was a bright child but struggled significantly with staying on task at school and with impulsivity and irritability. At age 11, Peter saw a pediatric neurologist because of concerns about changes in his gait and “spacing out” frequently at school. After further workup, JHD was diagnosed. Genetic testing confirmed the diagnosis and documented 82 CAG repeat expansions of the HTT gene. Huntington disease was later diagnosed in his father.
Peter began to struggle more with academic tasks and self-care, and he had increased difficulty with swallowing. Anxiety worsened, and symptoms of depression emerged. The aggressive episodes became very disruptive both at school and at home. Following inpatient psychiatric care, psychiatric symptoms stabilized and he was able to return home with ongoing outpatient management for a period. He was wheelchair bound within the following year and required 24-hour nursing support at home. Deterioration in behavioral and motor control continued, which made management of these symptoms very difficult for his treatment team.
Treatment and management
The psychiatrist is central to the care of individuals with JHD because the behavioral and psychiatric symptoms of the disease are complex and very impairing. There are no disease-modifying agents in the treatment of JHD. Treatments are targeted at associated symptoms. No robust clinical trials for the treatment of psychiatric impairment in JHD exist.
Treatment with psychotropic medications is challenging because of the nature of the brain changes and ongoing disease progression. The adverse effects of drugs such as antipsychotics may worsen parkinsonian symptoms, and there are safety considerations when oral medications are administered to patients with oral motor dysfunction and dysphagia.10 Antidepressants, most commonly SSRIs; both typical and atypical antipsychotic agents; benzodiazepines; and at times medications that target Parkinson-like symptoms may have a role in treatment.2 A skilled clinician can improve day-to-day quality of life with psychopharmacologic and behavioral interventions.
The care of patients with JHD involves many specialties and subspecialties, such as pediatric neurology, physical medicine and rehabilitation, and child and adolescent psychiatry. The diagnostic process is likely to include medical genetics and genetic counseling. Multidisciplinary care should also include occupational, physical, and speech therapies. In the earlier stages of illness, psychotherapy can play a very important role in patient and family coping and in acceptance of the diagnosis as well as in the management of psychiatric comorbidities. Discussion of management should also include the patient’s school to maximize the patient’s quality of life, while recognizing the behavioral and cognitive challenges the disease precipitates.
A number of ethical challenges arise in the treatment of patients with JHD and their families. One of the most obvious is genetic testing. Discussion and education must take place with the family regarding the testing of other family members, particularly siblings. This decision can be extremely difficult, and the inclusion of genetic counselors is very important. A family may also struggle with how to disclose the diagnosis and prognosis to the child or adolescent.
Parents may wish to protect their child from the knowledge of the morbidity and mortality associated with this disease. At the same time, providers may feel the desire to advocate for the autonomy and rights of the patient. Institutional ethics committees and professional organizations’ ethics advisory committees can be helpful to providers and their families when questions and possible conflicts arise.
Evidence from the management of other progressive childhood diseases, such as cancer, demonstrates the benefits to both the pediatric patient and their families of the honest disclosure of information regarding a child’s prognosis.11 This should be done within the context of the developmental stage of the child and, in the case of JHD, with the child’s current cognitive capacity in mind.
Inclusion of palliative care in treatment planning and management can help the patient and family anticipate future needs-whether related to nutritional support or end-of-life planning. Many families find it difficult to care for these patients adequately at home once the disease progresses to its more terminal stages. Early investigation into local facilities that can provide appropriate care is recommended. Because of the relative rarity of this disease in younger age groups, long-term care facilities may be less familiar with meeting these patients’ needs.
Future targets of assessment and treatment
Research is ongoing to understand the molecular mechanisms of this disease to target and develop potential therapies. Mesenchymal stem cell transplant in animal models of both adult Huntington disease and JHD is showing some promise.12 Development of animal models to aid in understanding the disease and its progression is ongoing.13
Neuroimaging offers important insights into the impact and progression of the disease. Degeneration of the caudate and putamen is a hallmark finding in Huntington disease; white matter changes have also been documented.14 Future neuroimaging studies may elucidate further neuroanatomical findings that will aid in the development of targeted interventions.
Dr Quigley is Clinical Assistant Professor of Psychiatry in the department of psychiatry at the University of Michigan in Ann Arbor, MI. She reports no conflicts concerning the subject matter of this article.
1. Quarrell O, O’Donovan KL, Bandmann O, Strong M. The prevalence of juvenile Huntington disease: a review of the literature and meta-analysis. PLoS Curr. 2012;4:e4f8606b742ef3.
2. Douglas I, Evans S, Rawlins MD, et al. Juvenile Huntington disease: a population-based study using the General Practice Research Database. BMJ Open. 2013;3:e002085.
3. Chuo YP, Hou PH, Chan CH, et al. Juvenile Huntington disease presenting as difficult to treat seizure and the first episode of psychosis. Gen Hosp Psychiatry. 2012;34:436.e9-11.
4. Ribai P, Nguyen K, Hahn-Barma V, et al. Psychiatric and cognitive difficulties as indicators of juvenile Huntington disease onset in 29 patients. Arch Neurol. 2007;64:813-819.
5. Telenius H, Kremer HPH, Theilmann J, et al. Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum Mol Genet. 1993;2:1535-1540.
6. Cloud LJ, Rosenblatt A, Margolis RL, et al. Seizures in juvenile Huntington disease: frequency and characterization in a multicenter cohort. Mov Disord. 2012;27:1797-1800.
7. Nicolas G, Devys D, Goldenberg A, et al. Juvenile Huntington disease in an 18-month-old boy revealed by global developmental delay and reduced cerebellar volume. Am J Med Genet A. 2011;155:815-818.
8. Huntington Study Group. Unified Huntington Disease Rating Scale: reliability and consistency. Mov Disord. 1996;11:136-142.
9. Gonzalez-Alegre P, Afifi AK. Clinical characteristics of childhood-onset (juvenile) Huntington disease: report of 12 patients and review of the literature. J Child Neurol. 2006;21:223-229.
10. Robertson L, Santini H, O’Donovan KL, et al. Current pharmacological management in juvenile Huntington disease. PLOS Curr. 2012;4:RRN1304.
11. Beale EA, Baile WF, Aaron J. Silence is not golden: communicating with children dying from cancer. J Clin Oncol. 2005;23:3629-3631.
12. Fink KD, Deng P, Torrest A, et al. Developing stem cell therapies for juvenile and adult-onset Huntington’s disease. Regen Med. 2015;10:623-646.
13. Chan AW, Jiang J, Chen Y, et al. Progressive cognitive deficit, motor impairment and striatal pathology in a transgenic Huntington disease monkey model from infancy to adulthood. PLoS One. 2015;10: e0122335.
14. Beglinger LJ, Nopoulos PC, Jorge RE, et al. White matter volume and cognitive dysfunction in early Huntington disease. Cog Behav Neurol. 2005;18:102-107.
15. Patra P, Shirolkar MS. Childhood onset (juvenile) Huntington disease: a rare case report. J Pediatr Neurosci. 2015;10:276-279.