Sci. Aging Knowl. Environ., 29 October 2003
Vol. 2003, Issue 43, p. dn3
[DOI: 10.1126/sageke.2003.43.dn3]

NEURODEGENERATIVE DISEASE CASE STUDIES

Huntington's Disease

Mark Groves, Jean-Paul Vonsattel, Pietro Mazzoni, and Karen Marder

Mark Groves is in the Departments of Neurology and Psychiatry, Beth Israel Medical Center, New York, NY 10003, USA. Jean-Paul Vonsattel is at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and in the Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Pietro Mazzoni is in the Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Karen Marder is at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, the Sergievsky Center, and in the Departments of Neurology and Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. E-mail: mgroves{at}chpnet.org (M.G.)

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/43/dn3

Key Words: Huntington's disease • basal ganglia disease • neurodegeneration • chorea

Abstract: In this case study, we describe the symptoms, neurological exam, neuropsychological test results, and brain pathology of a man who died with Huntington's disease (HD). HD is a rare neurodegenerative disease. Like other movement disorders involving the basal ganglia, HD affects motor, cognitive, and psychiatric functioning. The disease follows an autosomal dominant pattern of inheritance, with onset of symptoms most commonly occurring in the late 30s or early 40s, as in this patient. HD is caused by an unstable expansion of the trinucleotide CAG, coding for glutamine, on chromosome 4. Despite knowledge of the gene mutation responsible for HD, no definitive treatment is currently available to slow or halt progression of the disease. However, symptomatic treatment can significantly improve the quality of life for patients with HD.

Introduction

R. M. was in his early to mid-40s when he first noticed feeling less mentally "sharp" than usual. He had developed subtle memory problems and also noticed that he unintentionally dropped objects more often than usual. On a few occasions, he had tripped on sidewalks in his neighborhood despite having walked on them for years before without any problems. His wife and a few friends noticed that his hands and feet occasionally twitched, but R. M. was not aware of such movements. Because these symptoms had developed gradually, R. M. initially was not very concerned; but then he noticed a decline in his functioning at work.

A manager of a small business, R. M. noticed that by age 48 he had great difficulty keeping track of multiple tasks at the same time and was less efficient than in earlier years. In addition, he noticed that he was easily irritated by co-workers and clients. At one meeting, he became so upset that he stormed out of the office and walked home in a rage. Although he had always been demanding and frustrated in situations in which others refused to meet his demands, he previously had not found himself to be so easily upset or unable to regain his composure. At home, R. M.'s approximately 5 years of increased irritability, anxiety, and depression frustrated his wife. She noticed that he was increasingly stubborn and rigid, would not "let go" of ideas, and easily became anxious and upset by unanticipated changes in plans. Work supervisors noticed his unsteady gait and clumsiness; one accused him of coming to work drunk. Eventually, R. M. was fired from his job because of poor performance. Overcome with anxiety and symptoms of depression, R. M. began to seek medical treatment. He consulted many physicians, trying to find an explanation for his various symptoms.

Medical History

Before developing these symptoms, R. M.'s medical history was unremarkable. One year before neurological evaluation, he was in a car accident in which he neither lost consciousness nor sustained significant head injury. When asked about family history of psychiatric or neurological conditions, R. M. described what he knew of his father's side of the family: Estranged from his father after his parents' separation during his early childhood, R. M. knew that his father had been institutionalized at a psychiatric facility for years. Ashamed of the father's institutionalization, family members had rarely spoken about his condition. But they described the father as agitated, restless, and mean. R. M. himself had not seen his father before his death in the institution, when R. M. was a teenager. R. M. also remembered hearing about an aunt who was "crazy" but had never known her.

Examination

On examination, R. M. appeared to be anxious and depressed. He was noticeably irritable during the interview, though not physically aggressive. On questioning, R. M reported problems with sleeping, low energy, feelings of hopelessness and worthlessness, and occasional thoughts of death, though he denied ever thinking of suicide. He also reported obsessions and compulsions involving fear of contamination, leading him to wash his hands many times a day. R. M. did not have other psychiatric symptoms, such as auditory or visual hallucinations.

Cranial nerves showed no motor or sensory deficit. However, although eye movements were conjugate and full in range, saccades were abnormally slow, and ocular pursuit was jerky.

Intermittent, slight chorea was seen in R. M.'s hands, feet, and face. His eyebrows occasionally twitched, and close inspection revealed extraneous movements of his tongue. The involuntary movements of R. M.'s hands were especially noticeable when he walked or was distracted by mental tasks, such as naming state capitals. Interestingly, R. M. appeared to be unaware of these movements. When R. M. walked down a hallway barefoot, his right foot tended to turn in slightly and his left arm swung less than his right, consistent with subtle dystonia.

R. M. had considerable difficulty with voluntary fine motor control of his hands. When asked to rapidly tap his forefinger and thumb together, R. M.'s finger taps were of irregular rhythmicity, and he could not maintain the same amplitude with each finger tap. Motor impersistence was observed in R. M.'s tongue. When asked to protrude his tongue for as long as he could, R.M was unable to keep his tongue out of his mouth for more than 5 s--the tongue appeared as if it wanted to return into his mouth on its own. Similarly, when asked to keep his eyes tightly shut, he was unable to do so for more than 10 s. Muscle strength was normal, and the remainder of R. M.'s physical examination was unremarkable.

Movies of a patient who was subjected to various tests in order to make the diagnosis of HD can be found here.

Neuropsychological Testing and Diagnostic Imaging

Formal neuropsychological testing revealed a deficit in verbal memory that was significant enough to have affected R. M.'s functioning at work. Testing also showed that R. M. had decreased verbal fluency and deficits in executive functions. The combination of his deficits in memory and executive function was sufficient to diagnose mild dementia. Perseveration was observed on a few tests. Results of basic lab tests completed before examination by a neurologist were all within normal limits, and specific tests ruled out thyroid disease, lupus, syphilis, and B12 deficiency. Magnetic resonance imaging (MRI) of the brain also was normal, as was an electroencephalogram.

Course of Illness

Gradually over the years after his diagnosis, R. M. became increasingly irritable and physically aggressive, at one point requiring psychiatric hospitalization. The dystonia markedly worsened over time, as did his voluntary motor function. With the development of dysphagia, R. M. had severe weight loss and eventually required a feeding tube for adequate nutrition. He gradually developed increasing muscular rigidity and became essentially bed-bound. Approximately 2 years after his placement in a nursing home, R. M. developed aspiration pneumonia and died.

Neuropathology

The weight of the brain was 1305 g. The right half-brain was dissected in the fresh state to obtain many carefully identified samples. The samples were deep-frozen for biochemical, enzymatic, and molecular studies that cannot be conducted on formalin-fixed tissue. The left half-brain was immersed in buffered formalin solution for fixation, and then it was processed for neuropathological evaluation. The macroscopic pathological changes observed during dissection of the fresh right half-brain (Fig. 1) were identical to those seen while evaluating the fixed left half-brain. The following description is of the findings on the fixed left half-brain.



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Fig. 1. Right lateral aspect of the fresh brain. The sulci of the frontal and parietal lobes were wider than normally expected and the overlying leptomeninges were slightly cloudy.

 
Gross examination of the external surface of the fixed left half-brain showed marked widening of the sulci, or grooves, of the frontal lobes and to a lesser extent of the parietal lobes, indicating atrophy. The vessels were within normal limits. The frontal and parietal leptomeninges--the innermost layers of membrane that encase the brain--were mildly cloudy and discolored.

Cerebral hemisphere coronal slices of ~0.3 cm in thickness, transverse slices of the brainstem, and sagittal slices of the cerebellum were obtained. The cerebral hemisphere slices were remarkable for severe atrophy of the striatum, which consists of the caudate nucleus and putamen, and the globus pallidus, all of which are part of the basal ganglia (Fig. 2, A to C). The ventricular outline of the head of the caudate nucleus was almost a straight line, whereas in a normal brain, the ventricular outline of the head of the caudate nucleus is convex and bulges into the frontal horn of the lateral ventricle. The external part of the globus pallidus was more atrophic than the internal region (Fig. 2B). The neocortex and cerebral white matter showed volume loss, especially in the frontal lobe (Fig. 2A). The thalamus was smaller than normal (Fig. 2C). Mild atrophy was seen in the subthalamic nucleus (a part of the basal ganglia), the red nucleus, and other parts of the brainstem, and in the cerebellum, which were otherwise unremarkable (see Fig. 3 and Fig. 4 for topographical details of the striatum shown in Fig. 2, A and B, and for comparison with a normal striatum).



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Fig. 2. Coronal sections of the fixed left cerebral hemisphere passing through the nucleus accumbens (A), globus pallidus (B), and lateral geniculate body (C). The anterior neostriatum was severely atrophic [(A) and (B)]. The body and tail of the caudate nucleus were barely distinguishable (C). Both segments of the globus pallidus were atrophic, the external more so than the internal segment (B). See Fig. 3 for topographical details of the striatum shown in (A) and (B) and for comparison with a normal striatum.

 


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Fig. 3. Comparative coronal sections of the neostriatum, including the head of the caudate nucleus, nucleus accumbens, and putamen. (A) Patient R. M. (B) Normal control. The patient's neostriatum (A) showed severe volume loss as compared to the control (B). The frames indicate the sites of the microscopical photographs shown in Figs. 5 and 7. Luxol fast blue counterstained with hematoxylin and eosin (LHE) was used to stain the sections. Original magnification, x1. ALIC, anterior limb of internal capsule.

 


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Fig. 4. Comparative coronal sections of the neostriatum, including the caudate nucleus, putamen, and globus pallidus. (A) Patient R. M. (B) Normal control. The patient's neostriatum and the globus pallidus (A) were severely atrophic as compared to the normal control (B). LHE stain was used. Original magnification, x1. AWC, anterior white commissure.

 
Blocks from representative regions were processed for examination by microscopy. Thin sections were subjected to treatment with antibodies to assess whether abnormal aggregates were present. Although atrophic, the cerebral cortex showed normal cytoarchitecture. In the neocortex, neuronal loss was mild. Neuritic (or senile) plaques, common in elderly individuals, were rare in the frontal, parietal, and temporal regions. When neuritic plaques are abundant, they are associated with memory impairment.

Most of the pathological changes observed in this brain involved the caudate nucleus, putamen (neostriatum), and, to a lesser extent, the globus pallidus (paleostriatum). The changes consisted of neuronal loss and reactive gliosis (Fig. 5). In addition, the neostriatum contained scattered atrophic neurons referred to as dark neostriatal neurons (Fig. 6). These neurons had a distinct, scalloped cellular membrane, a finely granular dark cytoplasm, and a nucleus with condensed chromatin. The peculiar phenotype of these neurons suggests that they were undergoing apoptosis, or programmed cell death.



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Fig. 5. Reactive fibrillary astrocytes from the dorsal third of the head of the caudate nucleus (see Fig. 3A). In HD, the striatum is the only site where neuronal loss is associated with definite, reactive, fibrillary gliosis. GFAP, glial fibrillary acidic protein. Original magnification, x500.

 


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Fig. 6. Neostriatal shrunken dark neuron undergoing degeneration in the head of the caudate nucleus at the midpoint between the two frames shown in Fig. 3A. Near the upper border is a reactive astrocyte with a process encroaching on the dark neuron. LHE stain was used. Original magnification, x630.

 
The tail of the caudate nucleus was more involved than the head of the caudate nucleus. The dorsal portion of the head of the caudate nucleus (Fig. 7A) and nearby putamen showed more neuronal loss and reactive gliosis than the ventral portion, including the nucleus accumbens (Fig. 7B). The external segment of the globus pallidus was remarkable for the presence of reactive gliosis. This gliosis occurred without an apparent decrease of the neuronal density. Although smaller than normal, the internal segment of the globus pallidus displayed no detectable changes on microscopic examination.



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Fig. 7. (A) Head of the caudate nucleus obtained at the site of the upper frame shown in Fig. 3. (B) Nucleus accumbens obtained at the site of the lower frame. In (A), neuronal loss and reactive gliosis are severe. The subependymal zone of the lateral ventricle is on the right border of the picture. Conversely, the ALIC (not shown) is beyond the left border of the picture. Note that the parenchyma is loose-textured near the ventricle and becomes gradually denser toward the ALIC. In contrast, the nucleus accumbens (B) shows minimal neuronal loss and scant reactive astrocytes. The neuropil is apparently normal. Comparison between (A) and (B) illustrates that striatal degeneration has an ordered and topographic distribution in HD. The dorsal portion of the head of the caudate nucleus (A) is more involved than the nucleus accumbens (B). Furthermore, the involvement of the head of the caudate nucleus is more severe medially [(A), right] than laterally [(A), left]. LHE stain was used. Original magnification, x200.

 
Sections subjected to antibodies directed against ubiquitinated proteins revealed scattered cortical neurons containing a discrete nuclear round inclusion (Fig. 8). These nuclear inclusions were about the same size as the nucleolus (1.0 µm or less in diameter). Rare medium-sized neostriatal neurons displayed similar nuclear inclusions. These inclusions were made up of aggregates of mutated huntingtin protein, the product of the mutated gene in HD. In addition, scattered ubiquitinated aggregates of huntingtin were present in the cortical neuropil and in the white matter. Microscopic evaluation did not reveal other significant abnormalities.



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Fig. 8. Ubiquitinated nuclear inclusions in two neurons of the ventral part of the head of the caudate nucleus. The neuron near the lower border is atrophic. Ubiquitin antibody stain was used. Original magnification, x630.

 
The speed of degeneration of the neostriatal neurons depends to some extent on the type of neuron. Medium spiny projection neurons, which send axons outside the neostriatum, bear the brunt of the degenerative process. The rate of degeneration varies among different types of spiny neurons. For example, enkephalin-containing spiny neurons projecting to the external segment of the globus pallidus are more affected than substance P-containing neurons projecting to the internal segment of the globus pallidus. Aspiny interneurons, which send axons within the neostriatum, are relatively resistant to degeneration in HD.

The changes in this patient's brain are those characteristically observed in patients with HD. First, as in 80% of brains from patients with HD, on gross external examination, atrophy was seen to involve mainly the frontal lobes. Second, as in 95% of HD brains, the striatum was atrophic. Third, in the striatum, the extent of neuronal loss and reactive gliosis was region-dependent (for example, the dorsal part of the head of the caudate nucleus was more involved than the ventral part). Fourth, scattered cortical and neostriatal neurons contained ubiquitinated nuclear inclusions, indicating the presence of aggregates of mutated huntingtin. Finally, no changes other than those characteristic of HD were found that could have accounted for R. M.'s symptoms.

The pathological hallmark of HD is gradual atrophy of the striatum. The length of the abnormal CAG expansion on chromosome 4 governs, at least in part, both the course and extent of striatal atrophy. Depending on the extent of detectable changes in the striatum of HD brains, a postmortem grade of neuropathological severity is assigned. The assignment of a grade of neuropathological severity is based on gross and microscopic findings of the striatum obtained from three standardized coronal slices that include the striatum (Fig. 2). This system has five grades (0 to 4) of severity of striatal involvement. Grade 1 is assigned when the striatum is apparently normal on gross examination, but neuronal loss and gliosis are detected microscopically at the sites of early involvement, such as the tail of the caudate nucleus and the dorsal part of the rostral neostriatum. Grade 4 is assigned when striatal atrophy is very severe. In grade 4, up to 90% of the neostriatal neurons are lost. Because of the extent of atrophy of the neostriatum and the extent of the neostriatal areas still containing neurons, the grade of HD neuropathological severity assigned to R. M.'s brain is 3 to 4.

Discussion

When first examined by a neurologist, R. M. was in his late 40s and had a several-year history of increasing clumsiness, subtle chorea, memory problems, and an array of psychiatric symptoms, including depression, anxiety, irritability, obsessions, and compulsions. Neurological examination showed the presence of involuntary movement: chorea of the extremities and face, subtle dystonia observed during walking, and abnormalities of voluntary movement, such as decreased fine motor control, slow saccadic eye movements, and gait impairment. Cognitive testing and history were consistent with deficits in memory and executive function sufficient to diagnose mild dementia. In previous medical evaluations, imaging and laboratory testing had ruled out structural brain lesions, reversible causes of dementia such as thyroid disease, vitamin B12 deficiency, syphilis, and other medical problems, such as systemic lupus erythematosus, which can be associated with chorea.

The insidious progressive course of R. M.'s illness, his age at the onset of symptoms, and this particular constellation of motor, cognitive, and psychiatric signs and symptoms are commonly seen in and consistent with a diagnosis of HD. As HD progresses, the frequency and magnitude of choreiform movements increase. However, the disability caused by this disease is more closely associated with the decline in voluntary motor function than with the degree of involuntary movements. As deficits in voluntary motor function worsen, dysarthria and dysphagia often develop. Swallowing problems increase the risk of choking and the need for nutritional support. Cognitive function also worsens. In late stages of the illness, chorea may be less prominent or disappear, dystonia typically worsens, and rigidity and bradykinesia may predominate. Fifteen to 25 years after the onset of motor symptoms, choking, falling, or other accidents often cause death.

Many hereditary and nonhereditary conditions must be considered in the differential diagnosis of a patient presenting with chorea. These conditions are distinguished from HD by associated clinical features, course of illness, and specific laboratory tests. Among genetic causes of chorea, Wilson's disease is especially important to rule out, because it is treatable. Wilson's disease is an autosomal recessive disorder of copper metabolism that can present with neurological and psychiatric symptoms. It is excluded through slit-lamp examination of the cornea for Kayser-Fleischer rings or laboratory measurement of serum ceruloplasmin.

Neuroacanthocytosis is a rare hereditary cause of chorea. In some families, it has autosomal dominant inheritance like HD. Clinically, neuroacanthocytosis differs from HD by the presence of lip or tongue biting, tics, or signs of neuropathy and muscle wasting. It is diagnosed by detecting acanthocytes on a peripheral blood smear. Another laboratory abnormality often seen in neuroacanthocytosis is a high concentration of creatine phosphokinase in serum. Dentatorubro-pallidoluysian atrophy (DRPLA) is another neurodegenerative disease that can mimic HD. The symptoms vary and can include chorea, myoclonus, dystonia, parkinsonism, epilepsy, ataxia, and dementia. DRPLA is an autosomal dominant condition caused by an unstable CAG repeat on chromosome 12. It has been described primarily in Japan but is also found in other populations.

Recently, investigators have described rare hereditary neurodegenerative disorders with clinical features similar to those of HD and distinct from conditions such as DRPLA. These HD-like disorders are caused by mutations on chromosomes other than chromosome 4, the location of the HD gene. They have been named HD-like 1, 2, and 3 (HDL-1, HDL-2, and HDL-3). HDL-1 and HDL-2 exhibit autosomal dominant inheritance, whereas HDL-3 has autosomal recessive inheritance. It is estimated that approximately 1% of all individuals believed to have HD actually do not, but instead have other rare genetic mutations, such as these HD-like mutations, which produce a similar clinical phenotype. Hereditary spinocerebellar ataxias are distinguished from HD by their cerebellar signs. Benign hereditary chorea, an autosomal dominant disorder, is distinguished from HD by its lack of progression and absence of dementia.

Nonhereditary causes of chorea include encephalitis, tertiary syphilis, HIV infection, and Sydenham's chorea, a self-limited childhood chorea that is associated with prior group A Streptococcus infection. Central nervous system systemic lupus erythematosus also should be considered in patients without a clear family history of HD. It is associated with antinuclear antibodies and antiphospholipid antibodies circulating in serum. Thyrotoxicosis can cause chorea; therefore, thyroid function tests should be included in the laboratory workup of a patient with chorea. Cerebrovascular disease and structural lesions also can cause chorea. They are readily diagnosed by MRI of the brain. Lesions in the subthalamic nucleus can cause hemichorea and hemiballismus, both easily distinguished from HD by their sudden onset and unilateral signs.

Drug-induced dyskinesia must always be considered in the differential diagnosis of a patient with chorea. Years of levodopa treatment of Parkinson's disease can cause dyskinesias that appear very similar to the chorea seen in HD (see Constantino Case Study and Andersen Review). Tardive dyskinesia must also be considered. Therefore, patients should be asked about prior exposure to dopamine receptor-blocking agents, such as antipsychotic medications and antiemetics (drugs that inhibit nausea and vomiting, such as metoclopramide and prochlorperazine). Tardive dyskinesia usually spares the upper face. The choreiform eyebrow elevations that are sometimes seen in HD are not typically seen in tardive dyskinesia. Stereotyped repetitive movements of the mouth or tongue, or both, such as lip smacking, lip pursing, and tongue protrusion, are seen most commonly in tardive dyskinesia. Unlike in HD, motor impersistence is not seen in tardive dyskinesia; patients usually can protrude their tongue for more than 10 s. Other medications that can cause chorea include some anti-epileptic medications and oral contraceptives.

Although HD is sometimes still referred to as "Huntington's chorea," as R. M. illustrates, the more appropriate name for this clinically variable condition is Huntington's disease: Chorea is only one aspect of HD. In fact, some juvenile-onset cases (first symptoms at less than 20 years of age) are characterized mainly by rigidity and bradykinesia, rather than chorea. Myoclonus, tics, tremor, and seizures are much rarer symptoms that are more commonly seen in juvenile-onset disease. The juvenile form of HD occurs in 6 to 10% of all HD patients.

Although choreiform movements can be dramatic, the patient may be unaware of or minimally bothered by them. If a patient requires or requests treatment of involuntary movements, dopamine-depleting agents, such as tetrabenazine and reserpine, are preferred because they do not cause tardive dyskinesia. These agents can precipitate or worsen depression, however, so careful monitoring is essential. Tetrabenazine has a shorter half-life and is less likely to cause orthostatic hypotension. It currently is approved only outside the United States. Chorea also can respond readily to treatment with dopamine receptor-blocking agents such as haloperidol, a high-potency antipsychotic medication. However, the use of dopamine receptor-blocking agents is generally discouraged for a number of reasons: High-potency antipsychotic medications can cause rigidity or worsen dystonia, which may increase the risk of falls. They also may worsen cognitive function and are known to worsen apathy. Finally, long-term use can lead to the development of tardive dyskinesia, which would be superimposed on the motor symptoms of HD. Nonpharmacological interventions such as wrist weights to decrease the amplitude of choreiform movements during eating can be very helpful. Physical therapy helps maintain strength and range of motion, thereby reducing the risk of falls.

Cognitive deficits observed in HD have cortical and subcortical components. HD patients with early dementia have deficits in short-term memory on neuropsychological tests but often recognize correct test words when given choices, indicating that they retain the ability to store new information. Such deficits in recall with relative preservation of recognition are consistent with a subcortical dementia. Executive functions, planning, sequencing, and organizing, also are impaired in HD. These functions involve the frontal lobes of the brain, which are extensively connected to the basal ganglia through multiple parallel frontal-subcortical circuits. Although the primary pathological changes of HD are located in the caudate nucleus and adjacent areas of the basal ganglia, these changes disrupt the function of the frontal-subcortical circuits, leading to cognitive deficits in HD similar to those observed in patients with direct damage to the frontal lobes.

Cognitive dysfunction generally does not respond to pharmacological treatment. However, education of the patient and family about these symptoms is important, because changes in the patient's environment can improve functioning and decrease stress. Reducing the complexity of the patient's environment, decreasing some of the patient's responsibilities, and providing a predictable routine can be helpful. Medications known to worsen cognitive function, such as anticholinergic agents and highly sedating medications, should be avoided. R. M.'s psychiatric symptoms (irritability, depression, and anxiety) appear to have preceded his development of motor symptoms, which is not uncommon. However, some patients do not exhibit psychiatric symptoms. Of psychiatric symptoms in HD, irritability and depression are most common. R. M.'s inflexibility and obsessiveness (not being able to "let go" of an idea and getting upset when a need is not met) are seen much more often than true obsessions and compulsions that would fulfill the criteria for obsessive-compulsive disorder, such as his fear of contamination and frequent compulsive hand washing. Psychotic symptoms, such as auditory or visual hallucinations, which R. M. did not report, are uncommon in HD.

Psychiatric symptoms are the most treatable of all of the symptoms of HD, and their treatment can greatly improve a patient's quality of life. Anxiety generally worsens movement disorder symptoms; therefore, psychiatric treatment can sometimes indirectly lead to improvement in the motor symptoms. The suicide rate in HD has been reported to be four to six times greater than that of the general population (Schoenfeld et al. 1984). Anxiety, depression, and irritability can respond rapidly to selective serotonin-reuptake inhibitors. When irritability is severe or a patient is aggressive or violent, other agents may be indicated or preferred. Psychotherapy can be a useful adjunctive treatment but is generally not helpful when memory deficits are significant.

It is interesting, and not that unusual, that R. M. was not aware of his family history of HD. We assume from oral history that his father had HD, but the father's psychiatric institutionalization prevented R. M. from witnessing the full spectrum of symptoms likely experienced by his father. Apparently no family member of R. M. has ever been formally diagnosed or tested for HD. Because HD exhibits autosomal dominant inheritance, one would expect to find at least one affected individual in each ancestral generation. Within families, successive generations of individuals with HD can develop earlier onset of symptoms than individuals from previous generations. Such genetic anticipation primarily occurs when the gene is passed through a father, because sperm have greater meiotic instability than eggs.

The gene for HD is located on chromsome 4 and codes for a protein called huntingtin, the function of which is unknown. Disease results when the trinucleotide CAG is repeated too many times in a row in the gene. Individuals with between 27 and 35 trinucleotide repeats are considered to have a mutable normal allele; they will not develop HD. However, because of meiotic instability, there is a chance that their children could inherit a number of repeats sufficient to cause HD. Expansion of trinucleotide repeats in the mutable normal range to form HD-causing alleles can account for the rare "sporadic" cases that have been reported in the literature. Incomplete penetrance is seen with 36 to 39 repeats, and complete penetrance occurs when there are more than 40 repeats. With higher repeat lengths, the number of repeats is inversely correlated with age at onset of symptoms; that is, greater repeat lengths are associated with earlier age at onset of clinical symptoms. However, among patients with identical numbers of trinucleotide repeats, significant variation in age at onset and clinical presentation can occur.

The availability of genetic testing has helped to increase the accuracy of diagnosis of HD and has facilitated research on the disease; however, diagnosis of disease must still rely on the presence of clinical symptoms. Many individuals who test positive for the HD mutation may not develop symptoms of the disease for years, or even decades. Therefore, detection of the HD mutation is not indicative of onset of HD symptoms. Just because genetic testing is now readily available, that does not mean that it is indicated or is the appropriate choice for every individual. It is important to confirm an HD diagnosis of one affected family member through genetic testing or autopsy; other affected family members can then be diagnosed clinically.

Genetic testing has complex implications and ideally should be coordinated by a genetic counselor with expertise in HD at specialized centers, so that appropriate pretest and posttest counseling can be given. Symptomatic patients who are undergoing confirmatory genetic testing can also benefit from participation in a genetic counseling program. Current guidelines strongly advise against the testing of asymptomatic children who are at risk for the HD gene. Such knowledge could have tremendous impact on a child's psychosocial development and, given the current lack of neuroprotective therapies that can clearly delay or slow the progression of disease, may not benefit the child. The scope of this discussion cannot fully address the complexities of the issue of pregnancy for at-risk or affected individuals who wish to have children. New options are available, such as fetal genetic testing and preimplantation genetic testing, for individuals who may not want to know their own genetic status but want to have children free of the HD mutation. One good resource for more information on these complicated and controversial issues is the Web site http://www.genetests.org.


October 29, 2003

Abbreviations: Acanthocytes. Abnormally shaped red blood cells characterized by irregularly spaced protrusions of varying shapes and sizes along their surface. • Anticholinergic agents. Substances that block a subset of acetylcholine receptors (muscarinic receptors) in the central nervous system and other parts of the body. Blockage may be a primary action of the drug or a secondary effect. Side effects of these agents include dry mouth, confusion, constipation, hallucinations, dry skin, and urinary retention. Patients who are elderly or have brain disease are more vulnerable to side effects from these agents. • Antinuclear antibodies (ANAs). Nonspecific serum autoantibodies (antibodies directed against self) that are present in some autoimmune diseases, such as systemic lupus erythematosus. • Antiphospholipid antibodies. Antibodies directed against phospholipid membranes. They are associated with some autoimmune conditions. Their presence can raise the risk of stroke. • Apathy. Lack of interest in the environment. This symptom is seen in dementias and other brain diseases that affect the function of the brain's frontal lobe. • Autosomal dominant. Autosomal inheritance is the transmission, from parent to offspring, of a gene that is located on any chromosome other than the X or Y chromosomes. Dominant inheritance indicates that only one abnormal gene in a pair of genes is necessary to produce the condition. If complete penetrance exists (if the dominant mutation always produces manifest disease, as is the case for HD), a child of an affected parent has a 50% chance of inheriting the condition. • Autosomal recessive. Inheritance through a gene that is located on any chromosome other than the X and Y chromosomes. Recessive inheritance indicates that both genes in a pair must be abnormal for an individual to show symptoms of the condition. Individuals who have only one abnormal gene are carriers and generally do not show signs of the disease. • Basal ganglia. Several large clusters of neurons located within the cerebral hemispheres and upper brainstem, composed of the putamen, caudate nucleus, globus pallidus, subthalamic nucleus, and substantia nigra. The cells of these regions are crucial to initiating and coordinating movement. Disorders associated with diseases of the basal ganglia include chorea, athetosis, hemiballismus, and Parkinson's disease. • Benign hereditary chorea. A disorder of variable inheritance that is characterized by the development of choreiform movements in early childhood. These movements do not progress and dementia is absent, distinguishing this condition from HD and other causes of chorea. • Bradykinesia. Slowness of voluntary motor activity and reduction of autonomic movement. Bradykinesia can be a symptom of neurological disorders of the basal ganglia, such as Parkinson's disease, and can be a side effect of medication. • Brainstem. The portion of the brain immediately superior to the spinal cord, consisting of the pons, medulla, and midbrain. Collected here are neuronal circuits that control respiration, cardiovascular function, eye movement, equilibrium, and many stereotyped movements of the body. Many of the cranial nerves arise in the brainstem, and all of the nerve fibers running between the spinal cord and higher brain centers pass through this region. • Caudate nucleus. A cluster of neurons in the basal ganglia. The cells of this region are crucial to initiating and coordinating movement. Disorders associated with diseases of the basal ganglia include chorea, athetosis, hemiballism, and Parkinson's disease. • Cerebellum. Portion of the brain that lies just below the posterior part of the cerebrum and behind the brainstem. The cerebellum plays an essential role in coordinating voluntary movement, controlling muscle tone, and maintaining balance by integrating information from the cerebrum and peripheral parts of the body. Symptoms of cerebellar lesions include motor incoordination, tremors, disturbances of gait and balance, slurred speech, and nystagmus. • Cerebral cortex. The thin layer of gray matter on the surface of the cerebral hemisphere. • Ceruloplasmin. A protein that transports copper through the bloodstream. Ceruloplasmin facilitates the excretion of excess copper from the body by the liver into the gallbladder. Laboratory measurement of ceruloplasmin level in the blood is used to diagnose Wilson's disease. More than 90% of patients with Wilson's disease have lower than normal levels of ceruloplasmin. • Chorea. Abrupt, involuntary, irregular movement, randomly distributed throughout the body. • Choreiform. Resembling chorea. • Complete penetrance. In inheritance, the situation in which all individuals with the abnormal genotype (one copy of an abnormal gene that is autosomal dominant or two copies of an abnormal gene that is autosomal recessive) will have the disease phenotype. In other words, in an autosomal dominant disease with complete penetrance, 100% of individuals who have one copy of the abnormal gene will develop the disease. • Compulsions. Repetitive behaviors or mental acts (such as counting) that an individual feels driven to perform, often in response to an obsession. These behaviors are motivated by a desire to ward off a dreaded event or situation or to decrease anxiety or distress. • Creatine phosphokinase (CPK). An enzyme that catalyzes the transfer of phosphate from phosphocreatine to adenosine diphosphate to form creatine and adenosine triphosphate. CPK is important for muscle contraction. Increased levels of CPK in the blood are associated with a number of medical conditions. • Dementia. Loss of cognitive abilities sufficient to impair functioning. Dementia is characterized by deficits in memory, attention, orientation, language, judgment and motor and spatial skills and by altered emotional behavior and personality. Dementia is most commonly caused by conditions that injure the brain at tissue or cellular levels, such as Alzheimer's disease or HD. • Dopamine. A catecholamine neurotransmitter synthesized by cells of the substantia nigra and essential to normal movement and balance. Parkinson's disease is linked to neurodegeneration in the substantia nigra, with an associated decrease in dopamine. • Dopamine-depleting agents. Medications, such as reserpine and tetrabenazine, that prevent normal storage of dopamine and other monoamine neurotransmitters, such as norepinephrine, in vesicles of neurons. Lack of storage leads to low availability of these neurotransmitters for neurotransmission. Dopamine-depleting agents generally are used to treat chorea and tardive dyskinesia. In these disorders, depletion of dopamine in neurons is thought to contribute a beneficial effect; however, depletion of other monoamine neurotransmitters can cause depression. The advantage of dopamine depletors over dopamine-receptor blocking agents for treatment of conditions such as chorea is that they are not associated with a risk for tardive dyskinesia. • Dopamine-receptor blocking agents. Drugs that block dopamine receptors in the brain. Examples of dopamine-receptor blocking agents are antipsychotic medications, such as haloperidol, and antinausea medications, such as prochlorperazine and metoclopramide. • Dysarthria. Disturbance of the mechanical production of speech. • Dysphagia. Disturbance of the mechanical process of swallowing. • Dyskinesia. A general term for brief, rapid, involuntary movements, such as seen in chorea, athetosis, and ballismus. An alternative term is hyperkinesia. • Dystonia. Change in muscle tone causing sustained abnormal postures and disruption of voluntary movement. Dystonia can be a separate disease entity or a symptom in a broader condition, such as HD. Dystonia appears to be associated with changes in activity in several brain areas, including the basal ganglia, thalamus, and cerebral cortex. • Electroencephalogram. A recording, made on the scalp, of electrical impulses that originate in neurons within the brain and reach electrodes on the scalp. Electroencephalography can be used in the diagnosis of epilepsy, herpes simplex encephalitis, toxic and metabolic encephalopathies, and dementia. • Enkephalin. A neurotransmitter of the endorphin group, made up of five amino acids. • Executive functions. Higher-level cognitive functions, such as planning, organizing, and executing complex goal-directed behavior. These cognitive functions are generally associated with the frontal lobes, and deficits in these functions can be observed in diseases that affect frontal lobe function, such as HD, Pick's disease, traumatic brain injury, and human immunodeficiency virus (HIV) dementia. • Frontal lobes. Region of the anterior cerebral hemispheres where the motor cortex, speech centers, and some association cortices are located. Damage to the frontal lobes may be marked by deficits in motor function, language use, memory, abstract and creative thinking, problem solving, concentration, judgment, and impulse control, as well as by changes in behavior and personality. • Genetic anticipation. A pattern of inheritance in which symptoms manifest at earlier ages, with increasing severity, or both, as the gene is passed through generations. The genetic mutation responsible for HD (an increased number of a trinucleotide repeat base sequence in DNA) is unstable in sperm cells, leading to a higher chance of further expansion of this sequence at the time of meiosis (meiotic instability). Thus, genetic anticipation sometimes occurs when an HD gene is inherited through a father. The consequence can be severe juvenile-onset HD. • Gliosis. A proliferation of glial cells in response to injury or disease in the central nervous system, which leaves a glial scar composed primarily of astrocytes. Gliosis coupled with neuronal loss in certain brain regions is associated with various neurodegenerative diseases. • Globus pallidus. One of the basal ganglia, with connections to the striatum, thalamus, and mesencephalon. The globus pallidus acts as an antagonist of the striatum and facilitates motor information. Dysfunction in this area results in hypokinesia, poor timing of movements, and motor clumsiness. • Hallucinations. Sensations or perceptions experienced as real in the absence of external stimuli. Occurring in any sensory modality, hallucinations may be provoked by drugs, epilepsy, psychiatric illness, neurodegenerative disease, or sensory deprivation. Fragmentary visual hallucinations may be present in people with degenerative brain changes, whereas auditory hallucinations of voices are a primary symptom of schizophrenia. • Hemiballismus. Abnormal involuntary movement characterized by uncontrollable large-amplitude movement of the proximal portion of limbs on one side of the body. Such movements are classically associated with lesions of the subthalamic nucleus contralateral to the side of the body that shows the movement disorder. • Hemichorea. Chorea restricted to one side of the body. Hemichorea generally is caused by a lesion in the caudate nucleus contralateral to the affected side of the body. Hereditary causes of chorea usually are bilateral. • Huntingtin. The protein of unknown function that is mutated in HD. Research has shown that this protein is essential for normal development. Although the protein is expressed throughout many tissues in the body, in HD neuronal cell death appears to be primarily restricted to the brain and is greatest in the basal ganglia. • Incomplete penetrance. In inheritance, the situation in which not all individuals with the abnormal genotype will develop signs or symptoms of the disease during their lifetimes. Incomplete penetrance can explain the apparent skipping of generations by some autosomal dominant genetic diseases. • Irritability. An emotional state characterized by decreased control of the temper: "a short fuse." Although it can be observed in individuals without disease, irritability is particularly common in individuals with neurological disorders that affect the frontal lobes. Irritability can lead to verbal outbursts and physical aggression. • Kayser-Fleischer rings. Classic ophthalmologic signs in patients with Wilson's disease. The ring is formed by deposition of excess copper along a specific membrane of the cornea of the eye. Not all patients with Wilson's disease have this eye finding; however, virtually all patients with neurologic or psychiatric symptoms of Wilson's disease have Kayser-Fleischer rings that are visible by slit-lamp examination. In patients with unexplained neurological signs, such as dystonia, a slit-lamp examination can rule out Wilson's disease as the etiology. • Magnetic resonance imaging (MRI). A diagnostic technique in which the body to be imaged is placed in a magnetic field, causing the magnetic spin of hydrogen nuclei to align with the external magnetic field. Radio signals are used to transiently perturb this alignment. As the nuclei snap back into alignment, weak magnetic signals are produced by the body's tissues. Multiple signals are integrated by computer to construct an image of the tissue. MRI provides excellent resolution for detecting and localizing brain pathologies. MRI is also referred to as nuclear magnetic resonance imaging. • Meiotic instability. In polyglutamine-repeat diseases, the ability of an allele to increase or decrease the number of trinucleotide repeats during meiosis. As a result, the most common number of repeats in the individual's gametes differs from that of his or her somatic cells. By increasing the number of trinucleotide repeats, meiotic instability in sperm accounts for the phenomenon of genetic anticipation in HD when the gene is inherited through a father. • Motor impersistence. Inability to sustain muscle contraction. This finding is sometimes observed in patients with diseases affecting the basal ganglia, including HD. Patients with motor impersistence may report frequent dropping of objects, because they cannot keep their hands closed for more than a few seconds at a time. • Myoclonus. A movement disorder characterized by rapid, brief, involuntary twitching or jerking contractions of a muscle or muscle group. Although myoclonus can occur alone, it often appears with other neurologic abnormalities in nervous system disorders such as Creutzfeld-Jakob disease, Alzheimer's disease, and epilepsy. • Neocortex. Six-layered portion of the cerebral cortex that formed most recently during evolution and consists of the cortex, excluding the olfactory, hippocampal, and piriform regions. The wrinkled surface of the neocortex has distinct territories concerned with sensory, motor, and association functions. • Neostriatum. Consists of the caudate nucleus and putamen. This brain structure is a subcortical mass of gray and white matter located frontolateral to the thalamus in the cerebral hemisphere. This part of the basal ganglia plays an important inhibitory role in processing cortical motor signals. Damage to the striatum results in symptoms of chorea and athetosis. • Neuroacanthocytosis. A genetic disorder characterized by involuntary movements and acanthocytes in the peripheral blood. This disorder has variable inheritance, sometimes appearing as autosomal dominant, like HD. Neuroacanthocytosis should be considered on the differential diagnosis of patients with chorea, dystonia, parkinsonism, or tics. Distinguishing features may include tongue biting and mutilation; noisy tics, such as hissing and lip smacking; and signs of neuropathy or muscle wasting. An abnormal laboratory finding sometimes observed in neuroacanthocytosis is an elevated concentration of serum creatine phosphokinase. • Neuropil. A dense area in the gray matter of the central nervous system, made up of interwoven dendrites and axons--the cytoplasmic processes of nerve cells--and neuroglial cells. • Obsessions. Recurrent and intrusive thoughts, images, or impulses that an individual usually attempts to resist, suppress, or neutralize. Obsessions are recognized by the individual as a product of his or her mind, distinguishing them from psychotic symptoms, such as hallucinations. • Paleostriatum. The globus pallidus. The paleostriatum and the neostriatum together make up the corpus striatum. • Parkinson's disease. A degenerative disorder of the central nervous system distinguished by bradykinesia, rigidity, postural instability, and resting tremor. Additional symptoms include changes in gait, stooped posture, "mask-like" facial expression, and vocal weakness. A progressive loss of neurons in the substantia nigra and the resultant depletion of dopamine underlie this condition. • Perseveration. Continuation or repetition of a behavior without an appropriate stimulus. For example, during examination a patient may repeat answers to previous questions or repeat previous behaviors despite a change in the question or task. Perseveration frequently is observed in patients with impaired frontal lobe function. The Wisconsin Card Sorting test is a neuropsychological test that detects perseveration. • Putamen. One of the basal ganglia, with an inhibitory role in motor movement programs and diverse connections with the globus pallidus, substantia nigra, and motor cortex. Lesions of the putamen can result in dystonia. • Rigidity. Stiffness due to an increase in muscle tone at rest and characterized by increased resistance to passive movement of a limb. In Parkinson's disease, cell degeneration in the substantia nigra results in rigidity. • Saccades. Fast, conjugate, voluntary eye movements that shift the gaze from one point in the visual field to another. • Selective serotonin-reuptake inhibitors. Antidepressant drugs that act by blocking the reuptake of the neurotransmitter serotonin, so that more serotonin is available in the synapse. • Spinocerebellar ataxias. Genetic neurodegenerative disorders in which large numbers of neurons in the cerebellum and brainstem die, interfering with muscle coordination and leading to clumsiness, immobility, and sometimes death. Some of the hereditary spinocerebellar ataxias are caused by expansions of CAG trinucleotide repeats, coding for glutamine. • Striatum. A commonly used name for the neostriatum. • Subcortical dementia. Dementia characterized by impaired function of the basal ganglia. The term is used to distinguish this dementia (for example, that of HD, HIV, and Parkinson's disease) from "cortical" dementia, such as that found in Alzheimer's disease. Typical features of subcortical dementia include slowed thought processes (bradyphrenia), impaired verbal recall with relative preservation of verbal recognition, and impaired executive functioning. Typically, language comprehension and naming are preserved, unlike in Alzheimer's disease. The term is a misnomer, because many deficits observed in subcortical dementias are due to dysfunction of the frontal cortex. Dysfunction may be direct, in the form of damage of the frontal lobes, or indirect, through dysfunction of frontal-subcortical circuits connecting areas of the frontal lobes to the basal ganglia. • Substance P. A neurotransmitter made up of 11 amino acids. • Subthalamic nucleus. A component of the basal ganglia. Lesions in the subthalamic nucleus classically cause hemiballismus or ballismus. The neurons of the subthalamic nucleus are hyperactive in diseases such as Parkinson's disease and hypoactive in diseases such as HD. • Systemic lupus erythematosis. A chronic inflammatory autoimmune disorder that may affect many organ systems, causing signs such as skin eruptions, arthritis, anemia, visceral lesions, neurologic manifestations, fever, and other constitutional symptoms. • Tardive dyskinesia. A movement disorder resulting from exposure to dopamine receptor-blocking agents. It is characterized by rapid, brief, involuntary movements of the mouth, lips, or tongue, such as repetitive involuntary tongue protrusion, lip smacking, and chewing movements. Severity varies, but can be debilitating. Although most tardive dyskinesia occurs in patients who have been exposed to dopamine receptor-blocking agents for long periods of time, there have been cases in which onset occurred after only a single exposure to this class of medication. Tardive dyskinesia can persist despite discontinuation of dopamine receptor-blocking agents. • Thalamus. Ovoid mass of gray matter that forms part of the lateral wall of the third ventricle. It is the principal relay site for sensory signals traveling to the cerebral cortex and is involved in emotional associations of sensations and in arousal and alerting mechanisms. Thalamic lesions can cause decreased or increased sensitivity to sensory stimuli. • Thyrotoxicosis. The clinical state of thyroid hormone excess. Symptoms and signs vary and may include hyperactivity, irritability, mania, excessive sweating, weight loss, palpitations, weakness, diarrhea, tremor, and chorea. Causes include Graves' disease and some thyroid adenomas. • Tics. Repetitive, stereotyped, brief vocalizations or movements, usually of sudden onset. They are commonly associated with premonitory urges or feelings, and performance of the movements may lead to a sense of relief. The individual is generally able to temporarily suppress these movements, distinguishing tics from other hyperkinetic movements, such as myoclonus and chorea. • Tremor. A rhythmic oscillation of part of the body that is caused by alternating or synchronous contractions of opposing muscles. Tremors can be present at particular times: when a limb is at rest, when undertaking a particular action, when undertaking a particular task (task-specific), or when in a particular position (position-specific). Tremor can be caused by a wide variety of neurologic and medical conditions, including Parkinson's disease. Normal physiological tremor is seen in many healthy people when they hold out their hands. • Trinucleotide repeats. Repeated DNA sequence of three nucleotides (usually CAG) implicated in some genetic diseases, such as HD and a number of spinocerebellar ataxias. CAG codes for glutamine, and so these disorders are also known as polyglutamine repeat diseases. The number of repeats can vary among mutant alleles and can change between generations in a pedigree because of meiotic instability. • Verbal fluency. The ability to produce spontaneous continuous speech. Fluency can be tested by asking a patient to name a number of words, for example, in a specific category, such as animals, or beginning with a specific letter, such as S. Conditions affecting frontal lobe function can impair fluency. • White matter. The portion of the brain and spinal cord that appears white in unstained specimens and occurs in the more central (nonsurface) regions of the central nervous system. It is composed of myelinated nerve fibers and myelin-producing oligodendrocytes. • Wilson's disease. An autosomal recessive defect in copper transport that leads to the accumulation of toxic unbound copper in various tissues of the body. Multiple organs are affected, most commonly the liver, brain, and eye, resulting in wide variation in clinical presentation. Depending on the organ affected, patients may experience a combination of fatigue, jaundice, liver failure, dystonia, anxiety, psychosis, changes in behavior, and cognitive deterioration. Diagnosis is based on a low concentration of serum ceruloplasmin, the presence of Kayser-Fleischer rings in the cornea, and increased copper detected on liver biopsy. Wilson's disease should be considered in the differential diagnosis of patients with a combination of unexplained neurological symptoms, psychiatric symptoms, and evidence of liver dysfunction.

Suggested ReadingBack to Top

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Citation: M. Groves, J.-P. Vonsattel, P. Mazzoni, K. Marder, Huntington's Disease. Sci. Aging Knowl. Environ. 2003 (43), dn3 (2003).








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