Huntington Disease Case File

Huntington Disease Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 2

A 40-year-old man presents to the psychiatry emergency room for an increase in inappropriate, impulsive behavior. He works as a janitor and has had reasonably good work attendance. His coworkers say that he has appeared “fidgety” for several years. They specifically mention jerky movements that seem to affect his entire body more recently. His mother is alive and well, but his father died at age 58 in an auto accident and reportedly experienced similar symptoms. On examination, he is alert but easily distracted. His speech is fluent without paraphasias but is noted to be tangential. He has trouble with spelling the word “world” backward and serial sevens but recalls three objects at 3 minutes. When he walks, there is excessive distal hand movement and his balance is precarious, although he can stand with both feet together without falling. His reflexes are increased bilaterally, throughout. A urine drug screen is negative.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the molecular or genetic basis of this disorder?

ANSWERS TO CASE 2:

Huntington Disease                                        

Summary: A 40-year-old man is seen in the emergency room for inappropriate and impulsive behavior. He has appeared “fidgety” for several years and, more recently, has had generalized choreiform movements. He is alert but easily distracted and tangential. With ambulation, distal chorea is present, and his balance is altered. He also has evidence of pyramidal tract involvement with symmetrically increased reflexes. His deceased father reportedly experienced similar symptoms.

• Most likely diagnosis: Huntington disease (HD).
• Next diagnostic step: Genetic counseling and genetic testing for HD.
• Molecular or genetic basis: Expanded CAG repeats on a gene called huntingtin located on chromosome 4p16.3. Repeat lengths greater than 40 are associated with clinical HD. CAG repeats greater than 36 but less than 40 correspond to incomplete penetrance.

ANALYSIS

Objectives

1. Recognize the differential diagnosis of chorea.
2. Describe the basis for genetic confirmation of HD testing.
3. Be aware of the available symptomatic pharmacotherapy for patients with HD.

Considerations

HD is a progressive neurodegenerative disorder inherited in an autosomal dominant fashion affecting both men and women equally. The most common motor symptom is chorea, defined as a dance-like hyperkinetic movement. Early in the disease course, affected individuals may experience personality changes or mild cognitive decline. As the disease progresses, chorea becomes more prominent along with postural instability and continued cognitive decline. Significant psychiatric features are often present, such as apathy, depression, and anxiety. This is a 40-year-old man with a history of fidgeting for several years, who now presents with increased impulsivity and, difficulty with calculations but intact short-term memory. He has more recently developed “jerky movements affecting his entire body.” He has difficulty with balance and has brisk reflexes. The distal hand movements and long history of fidgeting are typical for the chorea associated with HD. He also likely has a positive family history. The insidious onset is typical. Medications or illicit drug effects should be ruled out. Laboratory testing should be performed to evaluate for other diagnostic possibilities. These studies should include antinuclear antibody (ANA), electrolytes, glucose level, renal and liver function tests, rapid plasma reagin (RPR), thyroid-stimulating hormone level, human immunodeficiency virus (HIV) antibody, anticardiolipin antibodies, and vitamin B12 level. Imaging is also often recommended to evaluate for secondary or structural causes of chorea. Lumbar puncture may also be considered for infectious, inflammatory, or paraneoplastic etiologies. Genetic testing is the best diagnostic test for HD.

APPROACH TO:

Huntington Disease                                                                            

DEFINITIONS

CHOREA: Sudden, jerky, irregular movements with muscle contractions that are not repetitive or rhythmic but appear to flow from one muscle to the next.

ATHETOSIS: Twisting and writhing movements often associated with chorea.

DYSTONIA: Sustained muscle contractions causing twisting and repetitive movements or abnormal postures.

TARDIVE DYSKINESIA: A hyperkinetic disorder caused by the long-term and/or high-dose use of dopamine antagonists, most often the typical neuroleptics. The most common movements are repetitive involuntary movements of the tongue, lips, and face.

CLINICAL APPROACH

HD is inherited in an autosomal dominant fashion. The disease is associated with increases in the length of a CAG triplet repeat present in a gene called huntingtin located on chromosome 4p16.3. Repeat lengths greater than 40 are associated with full penetrance and definite phenoconversion to HD. CAG repeats 36 to 39 are associated with incomplete penetrance and uncertain phenoconversion. There is an inverse correlation between the number of CAG repeats and age of onset of clinical symptoms. The average age of onset is 40. The repeat length can increase from generation to generation, particularly with paternal transmission, often resulting in a phenomenon known as anticipation. If one parent has 39 repeats and the child has 42, the parent may show symptoms late in life or never, while the child can have onset at age 40, which can contribute to confusing inheritance patterns in the family history.

HD is manifested by motor, cognitive, and behavioral symptoms. The most common motor feature is chorea (from the Greek word for dance) and consists of involuntary, random movements involving the limbs, trunk, and face. Difficulty with coordination, dexterity, and balance can also occur. As the disease progresses, difficulty with swallowing (dysphagia) occurs, with aspiration pneumonia being the most common cause of death. Slowing of saccades (fast eye movements) is an early sign, and increased reflexes with disinhibition of primitive reflexes may be seen. Executive dysfunction is common, and patients often develop a subcortical pattern of dementia. Behavioral disinhibition, depression, impulsivity, and anxiety are often seen. Suicide is another common cause of death in patients with HD. While the most common symptoms and signs are listed previously, there is significant phenotypic variability between patients.

Juvenile-onset HD is rare (~ 5% of patients) and is termed the Westphal variant. Unlike adults with HD who have hyperkinetic motor manifestations, patients with juvenile HD have hypokinetic motor features and are often described as parkinsonian. The primary symptoms include bradykinesia and rigidity. Dystonia, myoclonus, and seizures can also occur. Diagnosis has been greatly aided by the ability to test for the number of repeats in the huntingtin gene. Anatomically, the predominant involvement is of the striatum; bilateral atrophy of the head of caudate nucleus and putamen (Figure 2–1) can be seen via neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]).

There is a fairly extensive differential diagnosis for chorea, including other conditions that are inherited, autoimmune, metabolic, and drug- or toxin-induced (Table 2–1). In the context of an adult with an insidious onset and slow progression over several years, the likelihood of a neurodegenerative disease increases. The most common cause of a hereditary neurodegenerative cause of chorea is HD. An example of an autoimmune form of chorea is Sydenham chorea; it is an acute, usually self-limited disorder of younger individuals, usually between ages 5 and 15, more common in females than males. Sydenham chorea is closely linked with group A beta-hemolytic streptococcal infection, with approximately 30% of patients with preceding rheumatic fever. Antistreptolysin-O (ASO) and anti-DNase B titers may be elevated and can assist in supporting the diagnosis. Symptomatic treatment to attenuate the chorea is often necessary.

Figure 2–1. CT of the brain in Huntington dementia. Image A is a patient with HD, and image B shows a normal brain as comparison. (Reproduced, with permission, from Ropper AH, Brown RH. Adams and Victor’s Principles of Neurology. 8th ed. New York, NY: McGraw-Hill; 2005:912.)

Table 2–1 • DIFFERENTIAL DIAGNOSIS OF CHOREA IN ADULTS

Hereditary     Huntington disease (HD)a     HD–like syndrome type 2     Spinocerebellar ataxia 1, 2, 3, 17a     Pseudohypoparathyroidism/pseudopseudohypoparathyroidism     Dentatorubropallidoluysian atrophy     Fahr disease     Neuroferritinopathy Autoimmune     Systemic lupus erythematosusa     Polyarteritis nodosaa     Behçet diseasea     Sjögren syndromea     Sydenham chorea     Antiphospholipid syndromea     Multiple sclerosisa     Celiac disease Neoplasia     Directly involving striatum     Paraneoplastic syndromea Vascular     Infarct     Arteriovenous malformation     Subdural hematoma Infectious Metabolic     Hyponatremia/hypernatremia     Hypocalcemia     Hypoglycemia/hyperglycemia     Hyperthyroidisma     Hepatocerebral degeneration     Renal failure     Thiamine deficiency     Niacin deficiency     Hypoparathyroidism     Polycythemia     Chorea gravidarum Toxins     Alcohol (intoxication and withdrawal)     Carbon monoxide     Mercury     Manganese     Postanoxia Drugs     Neuroleptics (tardive)a     Antiparkinsonian medications     Anticonvulsantsa     Amphetaminesa     Steroids     Opiates

aEntities that merit consideration in this case.

Management

Currently, there is no Food and Drug Administration (FDA)-approved agent to slow or halt disease progression in patients with HD. As this is a relentless disease affecting motor, cognitive, and psychiatric function, it is important to discuss end-of-life issues with the patient and family before impairment becomes severe and communication ability is lost. Although experiments on transgenic mice with the huntingtin gene have suggested that certain compounds may exert a disease-modifying effect, this remains to be confirmed in humans with HD.

The motor and psychiatric symptoms are usually treated symptomatically.

1. Chorea is typically improved with drugs that interfere with dopaminergic function. Tetrabenazine (TBZ) is the only FDA-approved medication to treat HD chorea. TBZ reversibly depletes monamines from nerve terminals, ultimately decreasing the release of dopamine. Atypical neuroleptics such as olanzapine or risperidone may also be used to attenuate chorea if TBZ is not appropriate for the patient or poorly tolerated. High-potency neuroleptics such as haloperidol may be used for chorea attenuation. With the exception of TBZ, these medications carry the risk of causing tardive dyskinesia, though this has rarely been reported in this condition. As HD progresses, bradykinesia and rigidity may become more apparent but can also be caused by neuroleptics, so close follow-up is important and medication adjustment may be necessary. It is not uncommon for these agents to be discontinued as the disease progresses.
2. Depression is very common, as is irritability and anxiety, and is usually treated with selective serotonin reuptake inhibitors (SSRIs). There is a high risk of suicide in patients with HD due to the high incidence of depression and impulsivity.
3. Problems with swallowing and aspiration are apparent later in the course. Discussion in consideration of percutaneous endoscopic gastrostomy (PEG) tube is advised, especially early in the course of the disease to provide adequate nutrition and decrease aspiration.
4. Genetic counseling of the patient’s relatives is extremely important.
5. Support services such as physical, occupational, and speech therapy should be initiated early to decrease the risk of falling, injury, and aspiration.

COMPREHENSION QUESTIONS

2.1 A 33-year-old man is noted to have dancing-like movements of his arms and trunk. He is apathetic and depressed. His dad and grandfather had similar symptoms. Which of the following is the best test to confirm the suspected diagnosis of Huntington disease?

A. Cerebral positron emission tomography (PET) scanning

B. Genetic testing

C. MRI of the brain

D. Rectal biopsy

2.2 The same patient noted in Question 2.1 is noted to have disabling chorea. Which of the following is most likely to be helpful for the choreiform movements?

A. Haloperidol 1 mg one to three times per day

B. Carbidopa/levodopa three times per day

C. Deep brain stimulation of the subthalamus

D. Fluoxetine 10 mg daily

2.3 Which of the following clinical features is associated with juvenile or childhood HD?

A. Seizures

B. Myoclonus

C. Rigidity

D. Dystonia

E. All of the above

ANSWERS

2.1 B. A result showing greater than 40 CAG repeats in the huntingtin gene confirms the diagnosis of HD.

2.2 A. Judicious use of dopamine-blocking agents is effective in many patients with chorea. Patients need to be monitored for side effects, particularly parkinsonism and tardive dyskinesia. Levodopa can worsen chorea, although in HD patients with significant bradykinesia, it can be helpful.

2.3 E. Onset of HD in childhood (~ 5% of patients) is more severe and is called the Westphal variant. It causes parkinsonism with prominent bradykinesia and rigidity. Dystonia, myoclonus, and seizures are additional clinical features that may occur.

    CLINICAL PEARLS    

▶ Huntington disease (HD) is a progressive neurodegenerative disease that encompasses motor, cognitive, and psychiatric symptoms. ▶ HD is inherited in an autosomal dominant fashion and is the most common inherited cause of chorea. ▶ HD is a triplet repeat disease. Individuals with greater than 40 CAG repeats will manifest symptoms associated with HD. ▶ While there is no approved disease-modifying agent for HD, effective symptomatic treatments are available and should be used when appropriate. ▶ Paternal inheritance is associated with earlier symptom onset (anticipation) and increased disease severity.

REFERENCES

Anderson KE, Marshall FJ. Behavioral symptoms associated with Huntington’s disease. Adv Neurol. 2005;96:197-208. 

Bates GP. History of genetic disease: the molecular genetics of Huntington disease—a history. Nat Rev Genet. 2005;6:766-773. 

Handley OJ, Naji JJ, Dunnett SB, et al. Pharmaceutical, cellular and genetic therapies for Huntington’s disease. Clin Sci (Lond). 2006;110:73-88. 

Mestre T. Chorea. Continuum (Minneap Minn). 2016;22(4):1186-1207. 

Nance M, Paulsen JS, Rosenblatt A, Wheelock V. A Physician’s Guide to the Management of Huntington’s Disease. 3rd ed. New York, NY: Huntington’s Disease Society of America; 2011. 

Paulsen JS, Nehl C, Hoth KF, et al. Depression and stages of Huntington’s disease. J Neuropsychiatry Clin Neurosci. 2005;17(4):496-502. 

Semaka A, Creighton S, Warby S, et al. Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Clin Genet. 2006;70:283-294.

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