Huntington’s Disease (HD)

Definition

Autosomal dominant progressive neurodegenerative disorder characterized by movement disorders, psychiatric symptoms and cognitive decline including dementia.

Etiology

Genetic disorder inherited in an autosomal dominant (AD) manner due to expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene (or HD or IT15 gene) and is located on chromosome 4.

Age of onset of the disease correlates with number of expanded repeats in the HTT i.e. at earlier age occurs with greater number of repeats.

• Children of an affected parent with Huntington’s disease have ~50% risk of developing the condition
• Abnormal expansion of the CAG triplet repeat within the HTT gene results in abnormal processing of the corresponding Huntingtin protein, which gradually leads to neuronal damage within the basal ganglia
• Large CAG expansions produce more widespread injury in the neurons

Epidemiology

• Most often between 40 and 50 years (mean age 45 years)
• 25% present after the age of 50 years
• 10% after the age of 60 years

Pathophysiology

• Under normal conditions, Huntingtin protein is present throughout the brain, and within a large number of tissues throughout the body
• Mutant Huntingtin gene with CAG expansion leads to transcription and expression of abnormal Huntingtin protein
• Selective neuronal loss within the caudate and putamen underlies the development of Huntington’s symptoms
• Thus despite widespread presence of abnormal huntingtin protein, selective neuronal vulnerability results in a specific pattern of cell loss and the clinical features of the disease
• The abnormal huntingtin protein is cleaved into smaller, toxic fragments that bind together and accumulate within neurons, disrupting the normal functions of these cells, including impaired axonal transport and synaptic transmission. Other potential mechanisms of neuronal cells death include:
  • Increased oxidative stress
  • Mitochondrial dysfunction
  • Activation of proteases → leading to proteolysis
  • Apoptosis

Clinical Presentation

The clinical features can be divided into motor, cognitive and psychiatric deficits. Among these chorea (abnormal involuntary movements), intellectual decline and emotional disturbances are most prominent.

• Clinical features of HD

The presentation is divided into early, middle and late stage.

• Clinical stages of HD

Differential Diagnosis

Hereditary:

• Neuroacanthocytosis:
  • Onset typically in 4th-5th decades
  • Childhood and elderly cases can occur
  • Chorea often milder than HD
  • Other differentiating clinical features include: Personality changes, tics, obsessive-compulsive disorder (OCD), neuropathy, seizures. Test – blood smear for acanthocytes; elevated creatine kinase(CK), liver enzymes

• Benign hereditary chorea (BHC): Autosomal dominant, non-progressive movement disorder, with onset in infancy or early childhood. No cognitive or psychiatric changes

• Wilson’s disease: Autosomal recessive disorder with abnormal copper metabolism leading to accumulation of copper in liver and other organs including brain, kidneys, and eyes. Manifests with movement disorders and psychiatric/behavioral abnormalities. Dystonia and tremor are more common in Wilson’s disease compared to HD. Investigations include 24h urinary copper collection, serum ceruloplasmin and ophthalmological evaluation for the presence of Kayser-Fleischer rings

• Dentatorubropallidoluysian atrophy (DRPLA)
  • Autosomal dominant (AD), Japanese ancestry
  • Clinically mixed chorea, myoclonus, dystonia, cognitive decline, ataxia, tremor

• Spinocerebellar ataxias (SCA)1,2,3, and 17
  • Cerebellar ataxia plus psychiatric symptoms, and chorea

• Neuroferritinopathy
  • AD inheritance; mutation of light chain ferritin, low serum ferritin
  • MRI – shows iron deposition

• Huntington’s disease-like 2 (HDL-2)
  • African ancestry
  • Autosomal dominant inheritance caused by a CTG/ repeat expansion in the junctophilin gene
  • Chorea and dementia 3-4th decade

Autoimmune:

• Sydenham’s chorea: Autoimmune etiology secondary to exposure to group A beta-hemolytic streptococcus
• Systemic lupus erythematosus (SLE): Associated with presence of prothrombotic antiphospholipid antibodies (lupus anticoagulant)

Infectious:

• Viral encephalitis, HIV, TB, syphilis, Lyme disease may all cause chorea

Drugs:

• Antiemetics e.g. metoclopramide can also cause orofacial and limb dyskinesia
• Stimulant drugs of abuse e.g. cocaine, amphetamines may induce personality change and chorea
• Antipsychotics
  • Tardive dyskinesia: Classically orofacial stereotypic movements, as well as limb chorea. Differentiating from chorea in HD
  • Tardive dyskinesia (TD) is usually suppressible e.g. when patient eats in TD movements are less compared to HD where food may fall out of the mouth

Metabolic/endocrine disorders:

• Chorea gravidarum
• Hyperthyroidism
• Hyperosmolar hyperglycemic non-ketotic syndrome may have chorea-ballism as an accompanying feature, likely due to hypoperfusion of the striatum
• Acquired hepatolenticular degeneration; orofacial dyskinesia can occur in chronic liver disease due to manganese deposition in the striatum
• Idiopathic calcification in the basal ganglia (Fahr’s disease); get a CT brain scan

Vascular:

• Ischemic or hemorrhagic lesion of the subthalamic nucleus may result in contralateral hemi-ballisms and hemi-chorea. Onset is often abrupt, may persist but often diminishes over time
• Cerebral hypoperfusion that might occur with prolonged cardiac bypass (on-pump time) or circulatory arrest may result in a post-pump syndrome that includes choreoathetosis

Senile Chorea:

• Late-onset, non-familial chorea, often involving the face, tongue, and mouth. Various metabolic conditions have been implicated including hypocalcemia and antiphospholipid antibody syndrome

Investigation and Workup

Diagnosis is assisted by:

➣ Clinical presentation

➣ Positive family history

➣ Genetic testing for CAG expansion in the huntingtin gene

Imaging:

• CT/ MRI brain

Genetic testing:

• Targeted mutation analysis:
  • PCR-based methods detect alleles up to about 115 CAG repeats
• Southern blot analysis:
  • Identification of large expansions which may fail to amplify well by PCR analysis associated with juvenile-onset HD
  • Confirmation of apparent homozygous genotypes obtained by PCR analysis

Genetic counselling:

All patients or family members should be offered genetic counselling, but not all patients may want or need genetic testing.

Issues to be addressed are as follows:

Inheritance pattern:

• Each child of an affected individual has a 50% chance of inheriting the abnormal huntingtin gene
• Inheriting a normal huntingtin gene from the unaffected parent does not prevent or counteract the disease-causing effects of the abnormal gene
• Greater expansion with paternal inheritance

Absent family history of HD:

• ~2-5% of all cases develop HD without knowing that they were at risk
• Parent carrying a gene did not live long enough to manifest the symptoms)
• Non-paternity

Usefulness of genetic testing:

• Diagnostic or confirmatory testing – (if the clinical suspicion is strong then it is the only diagnostic test needed)
• Predictive or presymptomatic testing** (recommended in individuals with no symptoms, but wishes to know if he carries the expanded gene). Current implications are that no cure or treatment to slow down disease progression currently exists
• ** May pose potential psychosocial risks and hence often requires different clinical approach with appropriate counselling.
• Prenatal testing: Prenatal testing for HD is possible, and should be performed in conjunction with detailed genetic counselling

Treatment

Clinical Trials

• The effect of video game-based exercise on dynamic balance and mobility in individuals with Huntington’s disease

Pipeline Agents

• Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial

Physician Resources

1. Tips for Patient Care

General:

• Educate patients, caregivers, and family about HD including anticipated clinical course and treatment
• If dysarthria is present, caregivers should allow enough time for the patient to communicate
• If dysphagia is present patients are encouraged to concentrate on chewing and swallowing; avoid talking while eating
• Ensure the patient has adequate nutrition
• Patients should be encouraged to openly express their concerns and feelings as this might help reveal cognitive/psychiatric concerns such as suicidal ideation

Activities:

• Encourage patient to participate fully in various physical activities, including activities of daily living, as long as possible and if safe enough to do so, but avoid overwork and fatigue.
• Encourage patient to participate in activities of daily living, if it is safe enough to do so. Advise to avoid fatigue and overwork
• Patients should get involved in learning relaxation techniques
• If the patient is obese weight loss may decrease stress on weight-bearing joints, and help with mobility

Counseling:

• Genetic counseling/testing may be considered if there is a family history of Huntington’s disease; this however remain a personal decision and varies from patient to patient. A skilled genetic counsellor would be helpful
• Other areas that may require counselling includes:
  • Requirement for assistive devices and mobility aids
  • Feeding tubes for patients unable to swallow
  • Placement/nursing home
  • Power of attorney for handling legal affairs

Monitoring:

Patients should be monitored for:

• Fall risk
• Behavioural changes
• Response to therapy, and side effects of any treatments
• Suicidal thoughts

Medications:

• Treatment requires integrated, multidisciplinary approach
• Treatment should be individually tailored
• Medications should begin with low doses, whenever possible
• Currently, no treatment can alter, slow, or reverse the progression of HD
• Treatment is to palliate the symptoms; causing distress
• Consider concurrent risk factors and disease states with the prescribed therapy
• Monitor all patients for notable behaviour changes, such as suicidal thoughts
• Discuss potential adverse events/side effects of medications
• Evaluate cost, affordability and insurance coverage for patients

Social and stress factors:

• Chorea is exacerbated by stress, anxiety, or depression
• Patient and family members are often confronted with the social challenges surrounding the physical disability as well as the psychiatric aspects of impulse control, disinhibition, and outbursts

Tips:

• Symptoms may vary from individual to individual, even within a family
• Chorea is the most evident feature of HD and may diminish over time
• Chorea does not always need to be treated as side-effects of currently available drugs may out way benefit
• The most common specific psychiatric disorder in HD is depression
• As dysphagia develops, a soft diet with liquid supplements may be needed. However, complications surrounding dysphagia is the most common cause of death in people with late-stage Huntington’s disease
• Suicide is the second commonest cause of death in HD
• Apathy is also common in HD and can be hard to distinguish from depression

Expected outcome:

• There is no cure for Huntington’s disease
• Progressive impairment
• Life expectancy is ~15 to 20 years from diagnosis

2. Scales and Table

• Clinical features of Huntington’s disease
• Clinical stages of Huntington’s disease
• Interpretation of genetic testing for CAG repeats

References

Core Resources:

• Compendium of Pharmaceuticals and Specialties (CPS). Canadian Pharmacist Association. Toronto: Webcom Inc. 2012
• Day RA, Paul P, Williams B, et al (eds). Brunner & Suddarth’s Textbook of Canadian Medical-Surgical Nursing. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2010
• Foster C, Mistry NF, Peddi PF, Sharma S, eds. The Washington Manual of Medical Therapeutics. 33rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010
• Gray J, ed. Therapeutic Choices. Canadian Pharmacists Association. 6th ed. Toronto: Webcom Inc. 2011
• Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology. 11th ed. New York: McGraw-Hill; 2009
• Longo D, Fauci A, Kasper D, et al (eds). Harrison’s Principles of Internal Medicine. 18thed. New York: McGraw-Hill; 2011
• McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49th ed. New York: McGraw-Hill; 2010
• Pagana KD, Pagana TJ eds. Mosby’s Diagnostic and Laboratory Test Reference. 9th ed. St. Louis: Elsevier-Mosby; 2009
• Skidmore-Roth L. ed. Mosby’s drug guide for nurses. 9th ed. St. Louis: Elsevier-Mosby; 2011
• Skidmore-Roth L, ed. Mosby’s nursing drug reference. 24th ed. St. Louis: Elsevier-Mosby; 2011

• Online Resources:
  • http://bjp.rcpsych.org/content/149/6/682
  • http://www.ncbi.nlm.nih.gov/books/NBK1305/
  • http://www.hdfoundation.org/html/testwfn.php
  • http://www.hdac.org/features/article.php?p_articleNumber=519
  • http://www.huntingtonsociety.ca/english/content/?page=91
  • http://www.hdac.org/features/article.php?p_articleNumber=519
  • http://ghr.nlm.nih.gov/gene/HTT
  • www.wemove.org

Online Pharmacological Resources:

• e-Therapeutics
• Lexicomp
• RxList
• Epocrates

Journals/Clinical Trials:

• Bonelli RM, Wenning GK. Pharmacological management of Huntington’s disease: an evidence-based review. Curr Pharm Des 2006; 12:2701
• de Yebenes JG, Landwehrmeyer B, Squitieri F, Reilmann R, Rosser A, Barker RA, Saft C, Magnet MK, Sword A, Rembratt A, Tedroff J; MermaiHD study investigators.Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2011 Dec; 10(12):1049-1057
• Duff K, Paulsen J, Mills J, et al. Mild cognitive impairment in prediagnosed Huntington disease. Neurology 2010; 75:500
• Gil JM, Rego AC. Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci 2008; 27:2803
• Huntington Study Group (HSG) A Phase III, Randomized, Double-Blind, Placebo-Controlled, Safety and Efficacy Study of Dimebon in Patients with Mild-To-Moderate Huntington Disease (http://www.hdsa.org/research/clinical-trials/ongoing-clinical-trials/dimebontrial.html)
• Kegelmeyer D, Fritz N, Kostyk S, Kloos A, et al. The effect of video game-based exercise on dynamic balance and mobility in individuals with Huntington’s disease. J Neurol Neurosurg Psychiatry 2010;81:A40 doi:10.1136/jnnp.2010.222661.4
• Leigh RJ, Newman SA, Folstein SE, et al. Abnormal ocular motor control in Huntington’s disease. Neurology 1983; 33:1268
• Mestre T, Ferreira J, Coelho MM, et al. Therapeutic interventions for symptomatic treatment in Huntington’s disease. Cochrane Database Syst Rev 2009;CD006456
• Ondo WG, Tintner R, Thomas M, Jankovic J. Tetrabenazine treatment for Huntington’s disease-associated chorea. Clin Neuropharmacol 2002; 25:300
• Potter NT, Spector EB, Prior TW. Technical standards and guidelines for Huntington disease testing. Genet Med 2004:6:61-65
• Pringsheim T, Wiltshire K, Day L, et al. The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 2012; 27:1083
• Seneca S, Fagnart D, Keymolen K, et al. Early onset Huntington disease: a neuronal degeneration syndrome. Eur J Pediatr 2004; 163:717
• Walker FO. Huntington’s disease. Lancet 2007; 369:218
• Warby SC, Graham RK, and Hayden MR. Huntington Disease. NCBI Bookshelf. Initial Posting: October 23, 1998; Last Update: April 22, 2010