Huntington’s disease

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Abstract

HD is characterized by dysfunction of motor control, emotional control, cognitive ability, as well as by involuntary movements, most prominently chorea. The disease results in a gradual worsening of involuntary movements, and development of gait disturbance, dysarthria, dysphagia, rigidity, and bradykinesia.2 Dystonia is a prominent feature in later stages of the disease and may sometimes replace the chorea, leaving the patient rigid and bed-bound. Difficulties speaking and swallowing are common, and by the late stages may leave the patient mute and unable to take in enough calories orally.

Clinical Presentation of HD

HD is characterized by dysfunction of motor control, emotional control, cognitive ability, as well as by involuntary movements, most prominently chorea.1 The disease results in a gradual worsening of involuntary movements, and development of gait disturbance, dysarthria, dysphagia, rigidity, and bradykinesia.2 Dystonia is a prominent feature in later stages of the disease and may sometimes replace the chorea, leaving the patient rigid and bed-bound.1 Difficulties speaking and swallowing are common, and by the late stages may leave the patient mute and unable to take in enough calories orally.1

In addition to the movement conditions typical of HD, a psychiatric component is also commonly present. Psychiatric disturbances in patients with HD can vary, but include depression, apathy, anxiety, irritable, obsessive or impulsive behavior, paranoia, and/or dementia.2,3

HD can affect children and adolescents. Juvenile onset (before age 20) HD, comprising about 5% of all HD cases, has a clinical appearance distinct from adult HD.1 These individuals typically present with rigidity and may also demonstrate spasticity, bradykinesia, dystonia, rapid cognitive decline, and in some patients, severe behavioral problems.2

Molecular Biology of HD

Huntington’s disease is caused by a trinucleotide repeat (CAG) expansion in the huntingtin gene, IT15, on chromosome 4. The IT15 gene encodes a protein called huntingtin.4 The function of the huntingtin protein throughout the central nervous system is unknown, although recent studies have hypothesized that the expanded polyglutamine residues within the IT15 gene may cause the mutated protein, huntingtin, to have a toxic effect. This toxic effect may contribute to selective neuronal cell death.4

The IT15 HD mutation is inherited in an autosomal dominant pattern – meaning that each child of an affected individual has a 50/50 chance of inheriting the mutation and then one day developing HD. Normal IT15 genes contain 10-26 CAG repeats. IT15 genes with 27-35 repeats are also normal, meaning that they do not cause HD. However, individuals with genes containing 27-35 CAG repeats have occasionally been reported to have affected offspring with higher repeat numbers, suggesting that repeat numbers in this range may be unstable when they are passed on to the next generation.5 IT15 genes with 36-39 repeats are abnormal, but may not lead to symptoms within a normal lifespan.5 A full HD mutation is an IT15 gene with 40 or more CAG repeats; all individuals with this expansion would be expected to develop HD at some point in their lives. Individuals with very large expansion sizes, sometimes as great as 80 CAG repeats, may manifest symptoms of juvenile HD in their first or second decade.1 This dramatic increase in repeat size is typically associated with paternal transmission of the HD gene.1 A DNA test for the expansion in the IT15 gene is greater than 99% accurate and can help confirm or exclude a diagnosis of HD when considered with appropriate clinical workup.

In addition to the autosomal dominant inheritance pattern, Huntington’s disease is one of the trinucleotide repeat disorders that may display anticipation. Anticipation refers to an earlier age of onset of symptoms in succeeding generations. In HD, this can be related to an increased number of trinucleotide repeats when a mutation is passed from one generation to the next. For example, a mother with 40 CAG repeats who developed HD when she was 59-years-old may have a son with 42 CAG repeats who develops HD at 49 years of age.

Predictive Testing for HD

Each patient will have different reasons for avoiding or seeking testing and it is critical in evaluating at-risk individuals to solicit expression of these feelings and to recognize the patient’s right to make an informed and independent decision. A key component in this process is genetic counseling combined with careful evaluation by a psychiatrist or psychologist, and a neurologist. The knowledge that an individual possesses a Huntington disease mutation will not enable the physician to take the preventive steps to avoid or forestall onset of the disorder. However, this knowledge will significantly impact the individual’s psychological health. Studies have shown that predictive testing for Huntington Disease has led to such adverse outcomes as suicide, depression, relationship breakdown, and substance abuse. In one study, the frequency of these outcomes was as high as 16%.6 However, predictive testing may have a positive effect in a patient’s life by removing the burden of uncertainty and allow planning for the future. The HDSA, as well as several other genetic societies, have developed extensive recommendations for predictive testing, which are available online at http://www.hdsa.org or can be ordered by contacting Athena Diagnostics.

Risk Analysis

An individual’s risk of inheriting a mutation can be determined using Bayesian risk analysis. This analysis allows risk assessment to be refined beyond the basic principles of autosomal dominant inheritance by combining the a priori risk with other conditional factors. A priori risk refers to the “Mendelian risk for inheriting a gene”. Conditional factors are elements that modify the likelihood that a person possesses a given mutation. In the case of HD, a conditional factor is age; the older an asymptomatic individual is, the less likely it is that he or she possesses an HD mutation. Thus, the a priori risk of 50% that a son or daughter has inherited an HD mutation from an affected parent is reduced each year the individual remains asymptomatic. (It is important to note that clinical status can only be assessed via neurological exam; asymptomatic status should not be assumed without assessment by a neurologist.) For example, the risk of HD for an at-risk individual who is asymptomatic at 60 years of age is reduced to 18.7% from 50%. Bayesian risk modification is less pronounced with younger, asymptomatic patients.

Harper and Newcombe have calculated the following table of age-specific Bayesian risks for asymptomatic (as confirmed by neurological exam) individuals at a 50% prior risk of HD:7

Age (Years) Probability of anHD mutation(%)
20.0 49.6
22.5 49.3
25.0 49.0
27.5 48.4
30.0 47.6
32.5 46.6
35.0 45.5
37.5 44.2
40.0 42.5
42.5 40.3
45.0 37.8
47.5 34.8
50.0 31.5
52.5 27.8
55.0 24.8
57.5 22.1
60.0 18.7
62.5 15.2
65.0 12.8
67.5 10.8
70.0 6.2
72.5 4.6

 

Interactive Pedigree

This family pedigree illustrates the inheritance of the IT15 HD mutation and how various individuals are affected by a positive diagnosis in the family. Two aspects of the disease are examined in selected family members: the individual’s risk of possessing a mutation and psychosocial considerations, including genetic counseling. Click on a circle or square, representing a family member in the pedigree below, to learn of that person’s unique circumstances involving HD.

Instructions:Click on individuals in the pedigree to learn more. A new browser window will open with details on that individual.

Patient Management

Management of patients with HD is multifaceted and is designed to treat the various symptoms of the disease including: psychiatric symptoms, movement problems, and even nutritional problems. The following are examples of some standard patient management alternatives:9

Anti-depressant medications
Neuroleptic medications, benzodiazepines, or dopamine depleting agents to control chorea
Supportive counseling for patients and caregivers
Genetic counseling for patients and family members
Cognitive assessment and training
Speech-language therapy
Physical therapy
Wheelchair use to prevent falls
Botulinum toxin injections to lessen rigidity in small muscles
Assistive devices such as ankle and wrist weights to decrease chorea
Avoidance of food that might present a choking hazard, such as meat
Alternative feeding methods such as nasogastric tube or gastrostomy tube
Dietary consultation for increased calorie intake and nutrient rich supplement shakes or foods to prevent weight loss
Social service consultation for financial concerns, in-home or community programs and services, and nursing home placement

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