Movement Disorders

Winter 1998-1999
Volume 9, Number 2

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Huntington’s Disease (HD) is an important neurodegenerative disease by virtue of its genetic inheritance, clinical manifestations, and devastating impact on families. The biological basis, differential diagnosis, and treatment is reviewed in-depth. Care for patients, specialized genetic testing protocols, and opportunities for enrollment in clinical research trials are offered as part of the CNI Movement Disorders Center.

Introduction. The clinical syndrome known as Huntington’s disease was delineated in 1872 by George Huntington. He reported, “Hereditary chorea... confined to certain, and fortunately, a few families, and has been transmitted to them. An heirloom from generations away back in the dim past. It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror.... There are three marked peculiarities in this disease: (1) Its hereditary nature; (2) A tendency to insanity and suicide, and (3) It’s manifesting itself as a grave disease only in adult life.”12 The degeneration of the striatum was recognized as the essential neuropathologic feature around the turn of the century.1, 2, 18 The gene for Huntington’s disease was the first human gene to be localized by linkage analysis using restriction length polymorphisms,8 and the mutation was discovered to be an expansion of a trinucleotide repeat in a novel gene on chromosome 4.11 The prevalence of affected individuals in the United States is estimated at 5 to 10 per 100 000. Two to 4 times as many individuals have inherited the mutation, but are as yet asymptomatic.

Clinical Manisfestations. Onset of Clinical Disease. Huntington’s disease is an autosomal dominantly inherited, progressive, neurodegenerative disease that causes disorders of motor and emotional control, cognitive ability, and involuntary movements — classically choreic.15 The mean age of onset is approximately 40 years, but there are descriptions of individuals who became symptomatic as early as 2 years old, and as late as 80 years old. By clinical and pathological criteria, juvenile onset cases are often more rapidly progressive and onset cases more slowly progressive.20 The typical duration of Huntington’s Disease is 15 to 20 years from symptom onset until death.

Most studies have not found prominent clinical nor laboratory abnormalities in persons who are many years away from their clinical onset.5 Several signs may portend onset of clinically significant Huntington’s disease. These include increased motor restlessness, slowing of saccadic eye movements, slowing or dysrhythmic production of rapid, repetitive movements of the fingers or tongue.7, 24 A number of individuals have prominent thought, mood, or personality disorders that present in the years prior to onset of motor signs.

Cognitive changes may also precede onset of motor symptoms by many years. In the earliest stages of Huntington’s disease, disturbances of problem-solving abilities, memory deficits, visuospatial skills, and an attention disorder often lead to a decline in performance at work or in the home.30 Decline in cognitive ability most closely relates to the number of years the patient has been affected by Huntington’s disease.13 Because of its serious implications, the diagnosis of Huntington’s disease is usually reserved for gene carriers who have developed motor manifestations.

Juvenile cases make up about 5.4% of all cases of Huntington’s disease.23 Juvenile, and occasionally young adult, cases present with prominent parkinsonism and little or no chorea.

Etiology. Huntington’s disease results from an expanded and unstable trinucleotide repeat in the IT15 gene on the short arm of chromosome 4.11 This gene produces a protein of yet unknown function called huntingtin. Three nucleotide base pairs, CAG, are normally repeated over and over in this gene. Persons without Huntington’s disease may have as many as 35 repetitions of the CAG trinucleotide. Persons with more than 39 repeats will develop Huntington’s disease, and those with 36 to 39 repeats may or may not develop the disease.22 These middle range individuals may have offspring with clinical Huntington’s disease.21 These offspring may represent de novo expansions and new mutations, or expansion of extremely late onset or “never-onset” mutations.16 Patients with juvenile onset have greater expansions, and can have more than 100 CAG repeats. Most juvenile patients have inherited Huntington’s disease from an affected father. It has been determined that marked expansion of the repeat length likely occurs in spermatogenesis, which accounts for this paternal effect on the inheritance of juvenile onset Huntington’s disease.6

Biologic Basis. The pathophysiological cause of the progressive neurodegeneration of Huntington’s disease is not known. The messenger RNA (mRNA) for the Huntington’s disease gene is widely expressed in all tissues so far examined.27 The regional specificity of the neuropathology is therefore not explained by a differential expression of the Huntington’s disease gene in the brain. The function of the Huntington’s disease gene is presently not known. The Huntington’s disease gene normally produces a protein called huntingtin, which may become associated with another protein called huntingtin-associated protein (HAP-1). Huntingtin has a region containing repeated copies of glutamine. Disease-causing mutations increase the number of repetitions of glutamine to 38 or greater, altering its conformation. It thereby increases the tightness of its binding to HAP-1 accumulates in the cell and somehow cause the death of affected nerve cells.

The neurodegeneration in a Huntington’s disease brain primarily affects caudate and putamen, but brain weight is decreased, and neuronal loss in the cortex and other nuclei has been documented. In the striatum, there is predominant loss of spiny projection neurons with perseveration of the aspiny interneurons and large aspiny acetylcholinesterase positive neurons.17 This pattern has been produced in animals by excitotoxic lesions and by the systemic or local injection of mitochondrial toxins.4 Magnetic resonance spectroscopy has documented an increase in brain lactate in patients with Huntington’s disease, as might be expected in the case of mitochondrial dysfunction or increased excitatory stress.9, 14 Recently reported data indicates that using magnetic resonance imaging (MRI) to assess basal ganglia volume may be useful to follow progression of the disease.3

Diagnostic Evaluation. The diagnosis of Huntington’s disease can be made on the basis of the clinical presentation described above in the context of a confirmed family history of Huntington’s disease. Magnetic resonance imaging or computed tomography scans show prominent caudate atrophy in young patients with moderate disability, but may be within normal range in patients with very early signs of Huntington’s disease. In elderly patients with Huntington’s disease, caudate atrophy may not stand out as conspicuous in comparison to the degree of cortical atrophy. DNA testing can now confirm if a patient with a suspicious clinical syndrome has Huntington’s disease. Initial genetic testing to rule out Huntington’s disease is probably the most cost-effective way to evaluate adult onset chorea given the large differential diagnosis. Appropriate genetic counseling should be available. Neuropsychological testing can be very helpful in delineating the patient’s degree of cognitive disability.

DNA testing for the Huntington’s disease mutation is a complex procedure with a variety of medical, psychological, ethical, and financial implications for the person being tested and, in some cases, for multiple relatives.10 Some individuals who initially seek testing later withdraw after personal reflection and counseling. Testing of asymptomatic at-risk individuals should therefore only be performed after appropriate counseling over a time period during which the person can consider the personal implications of an imminent diagnosis of Huntington’s disease. Such testing is available through the CNI Movement Disorder Center and other specialty centers throughout the world.

Genetic testing of children and juveniles at risk for Huntington’s disease should be avoided except under very special circumstances. Children who present under 10 years of age should be considered for confirmatory testing only if they have a positive family history (primarily the father), and at least 2 of the following; declining school performance, seizures, oral motor dysfunction, rigidity, or a gait disorder.23

Motor Disorders. Chorea, from the Greek meaning “to dance,” is an involuntary movement around multiple joints. There may be an attempt to incorporate some involuntary movements in seemingly purposeful activity and to suppress other movements. The mouth, trunk, and proximal, as well as distal muscles, are prominently affected. It can consist of jerks, such as the “cigarette flicking” movements commonly seen in the fingers or fast contractions of facial muscles. More flowing and somewhat slower choreoathetotic movements often occur with more advanced disease, as do fast, large amplitude, flinging movements resembling ballism. Dystonia, akinesia, and parkinsonism is prominent in the later stages of the illness when patients can develop fixed dystonic contraction of limb and axial muscles leading to contractures and immobility.

A disorder of voluntary motor control contributes prominently to the physical disability in patients with Huntington’s disease.27 Bradykinesia generally coexists with chorea.28 A parkinsonian state with prominent slowing of saccadic velocity is seen in the juvenile onset cases that may also have seizure disorders and myoclonus (Westphal variant). There appears to be a serious impairment in the patient’s ability to produce sequences of movements, or to rhythmically produce rapid repetitions of a single movement.29 Patients are also unable to learn complicated motor skills. Loss of voluntary motor control progresses throughout the course of the illness until it causes complete inability to perform any purposeful motor act. Speech and swallowing dysfunction are common in the mid-stages of the illness and lead to inability to communicate and swallow. Deep tendon reflexes are hyperactive.

Psychiatric Disorder. George Huntington described the “tendency to insanity, and sometimes that form of insanity that leads to suicide, is marked.” Psychiatric manifestation is prevalent in patients with Huntington’s disease and a variety of disturbances have been observed. These include psychosis with visual hallucinations which rarely occur, a delusional thought disorder, mania, obsessive behavior, or rigidity of thought. Depression and emotional lability with outbursts of disruptive behavior are common. Cognitive decline occurs in all patients and may be more or less as disabling as the motor disorder.30 There is usually a more rapid decline in visuospatial as compared to verbal skills.

Differential Diagnosis. The major errors in diagnosis occur in the following groups: 

1. Patients with Huntington’s disease chorea or the rigid form of Huntington’s disease without a definitive family history; 
2. Patients at risk for Huntington’s disease with non-choreic neurologic or psychiatric symptoms, not due to Huntington’s disease; 
3. Patients with old onset chorea due to Huntington’s disease who may have little dementia; and 
4. Patients with chorea due to other illnesses.

A variety of illnesses may cause chorea and dystonia. These illnesses may be associated with dementia. Neurocanthocytosis is the most likely disorder to be confused with Huntington’s disease, as it causes dementia, involuntary movements, and caudate atrophy. However, distinguishing features of neurocanthocytosis include abnormal red cell morphology, neuropathy, myopathy, epilepsy, elevated creatine phosphokinase, self-mutilation behavior, and a peculiar eating disorder (food is pushed out of the mouth by a dystonic tongue movement).

Pregnancy. Persons at risk for the disease should be counseled to consider questions regarding presymptomatic testing prior to, rather than during, pregnancy. Those who carry the gene should also have genetic counseling prior to conception. Prenatal diagnostic testing is available at some centers.

Management. Treatment of patients with Huntington’s disease requires a coordinated effort on the part of medical, social services, physical, and occupational teams.25 Treatment is tailored to the treatable symptoms and cannot be generalized to all patients or to an individual patient over all stages of the illness. Depression often responds partially to treatment with standard antidepressants, in particular, the serotonin reuptake inhibiters. These agents are less likely to exacerbate chorea or pain compared with TCA’s. Carbamazepine or valproate may improve patients with a manic disorder. Delusions and paranoia often respond to antipsychotics. Neuroleptics also decrease chorea, but care is needed not to use doses that impair the individual’s functional level. Low doses of neuroleptics are often well tolerated, while high doses are rarely helpful and may impair motor functioning, swallowing or cognitive function. Irritability and emotional dyscontrol are common in patients with Huntington’s disease and can cause great disturbances in their families or living situation. Behavioral modification on the part of the patient and care giver can alleviate such stressful situations. Carbamazepine, fluoxetine, clonazepam, propranolol, valproate, or clomipramine may be helpful. The newer atypical antipsychotics, such as olanzapine (Zyprexa) or quetiapine (Seroqrel) show promise. Frequent awakening during sleep may become problematic and sleep cycles may reverse. Avoidance of daytime sleeping and clonazepam or amitriptyline at bedtime can help modify this problem.

Nutrition is important in Huntington’s disease patients as their caloric requirements may be tremendously increased, up to 5000 calories per day. Eventually, dysphagia and aspiration become problematic. The patient’s wishes regarding gastric tube feeding should be ascertained in preparation for this stage of illness. Patients will usually require nursing care or other specialized long-term care at home or in a facility with staff knowledge about the disease.

Conclusion. Remarkable progress has been made in the past 15 years. From the initial discovery of the genetic linkage to chromosome 4 through identification of the CAG repeat mutation and the accumulation of abnormal protein in striatal neurons, we are poised on the verge of a cure for Huntington’s disease. While the pace of research has increased, the diagnosis, treatment and care of patients and families still requires a team approach of dedicated clinicians with access to state-of-the-art treatment protocols, genetic testing and community resources. It is our hope that the next CNI Review on Movement Disorders will report on breakthroughs in research that will put an end to this devastating condition.

Address comments and questions to:

Lauren C Seeberger, MD
701 East Hampden Avenue, Suite 530
Englewood, CO 80113

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