This primary neurodegenerative disorder usually begins during adult life, often after the affected individuals have already borne their children. It is inherited in an autosomally dominant pattern, and the disorder has clinical manifestations that often vary among involved family members, and patients may have predominantly behavioral, cognitive, or movement disorder signs.
Pathogenesis and Pathophysiology. Huntington's disease (HD) is caused by a mutation on chromosome 4 consisting of an unstable expansion of CAG repeats. Normal individuals have between 11 and 34 repeats, whereas those with HD have between 37 and 86. Ihe trinucleotide CAG codes for glutamine, and the increase in polyglutamine is thought to cause an overexpression of the gene whose protein is termed huntingtin. This product tightly binds with ubiquitin to form intranuclear inclusions and may subsequently interfere with normal mitochondrial bio-energetic mechanisms. y It is not known why the striatum is preferentially affected because the HD mRNA product has been found in all examined tissues.y Neuronal loss in the caudate and putamen has been correlated with a longer CAG trinucleotide repeat length, and the preproenkephalin medium spiny neuron seems to be particularly vulnerable. y
Pathological changes in the brain of patients with HD include generalized atrophy with neuronal degeneration in the cortex and severe loss of medium spiny projection neurons with preservation of cholinergic aspiny interneurons in the caudate and putamen. Marked caudate atrophy is the pathological hallmark of the disease, and this finding can be detected on MR scans. Mr spectroscopy demonstrates changes that reflect increased levels of lactic acid, suggesting a bioenergetic defect. Additional evidence, particularly in experimental models of HD, suggests that mitochondrial dysfunction may be a possible pathogenetic mechanism of neuronal cell death.y
Several important biochemical abnormalities have been noted in postmortem brain tissue, particularly in the striatum. Ihese include decreases in choline acetyltransferase (CAT) activity and acetylcholine (ACh), a reduction in the total number of cholinergic muscarinic receptors, and depletion of GAD, substance P, angiotensin-converting enzyme, cholecystokinin, enkephalin, and other peptides. In contrast, the concentrations of DA, norepinephrine, serotonin, neurotensin, somatostatin, and thyrotropin-releasing hormone (IRH) are normal or increased. y Ihe result of these changes suggests a functional overactivity of the cerebral glutaminergic and striatal dopaminergic systems and an underactivity of the GABAergic systems.
Epidemiology and Risk Factors. Ihe estimated prevalence of HD is 5 to 10 per 100,000 people in the United States. y Because the CAG repeat length is unstable in sperm, affected fathers often transmit a very high repeat sequence, resulting in an early onset of disease in their offspring.
Clinical Features and Associated Disorders. Gradual onset of chorea, dementia, and behavioral abnormalities in a young or middle-aged adult should suggest the possibility of HD. Slowed saccadic eye movements are usually the first detectable clinical sign, and in 85 percent of patients chorea is the predominant movement disorder. Movements may start as fine, irregular body jerks that have no functional significance, but coordination, gait, and balance difficulties gradually supervene. In the juvenile form of HD, rigidity, bradykinesia, resting tremor, dystonic postures,
ataxia, seizures, myoclonus, and mental retardation are more prominent, and this presentation is termed the Westphal variant of HD. Even in patients with adult-onset and prominent chorea, bradykinesia and postural reflex compromise can occur and may be sources of significant functional disability. In the terminal phases of HD, dysarthria, dysphagia, and respiratory difficulties become the most disabling and life-threatening problems. y
Cognitive impairment is a source of major disability in these patients. Memory difficulties, concentration problems, confusion, and forgetfulness can occur (see Chapter,.?.?. ). In addition, depression and other emotional disturbances may be severe and can lead to erratic, impulsive behavior as well as suicidal ideation. Other psychiatric disturbances include delusional thoughts, paranoia, and hallucinations. y Eventually, patients become demented, and most require assistance and supervision in daily living activities.
Differential Diagnosis. Besides HD, other less common heredofamilial choreas include hereditary benign chorea and neuroacanthocytosis (see later discussion in this chapter). If a family history of choreic or psychiatric disorders is lacking, numerous other disorders should be considered, including tardive dyskinesia, CNS vasculitis, Wilson's disease (WD), Sydenham's chorea, and toxin exposure. Drugs causing chorea include oral contraceptives, levodopa, CNS stimulants, neuroleptics, phenytoin, carbamazepine, and ethosuximide. If the diagnosis is approached from the perspective of genetic testing, other hereditary neurodegenerative conditions with expanded trinucleotide repeats of CAG include Kennedy's syndrome (X-linked spinal and bulbar muscular atrophy), myotonic dystrophy, spinocerebellar atrophy type 1, and dentato-rubro-pallidal- luysian atrophy ( ,Xa..bJ§,.3.4-4 ).
Evaluation. In addition to taking a complete family history, blood should be drawn for DNA testing. Careful counseling about the implications of the diagnosis is essential when working with patients who are at risk for the disease. Issues of privacy are particularly important because giving subjects positive diagnostic information reveals information about the parents' genetic makeup. MR scans can detect the presence of caudate and cerebral atrophy. When the family history is in doubt, an assiduous search of autopsy reports on relatives can sometimes unearth the diagnosis in the genealogy.
Management. DA receptor-blocking agents (e.g., haloperidol or fluphenazine) and dopamine-depleting agents (e.g., tetrabenazine, reserpine) reduce the choreic movements but may not improve other symptoms of Huntington's disease. Because of their potentially serious side effects, including tardive dyskinesia (neuroleptics), depression (dopamine-depleting drugs), and parkinsonism (both drug classes), the antidopaminergic drugs should be reserved for patients with disabling chorea or serious psychosis. Xhe tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRI) are often helpful in ameliorating the affective disorders but may precipitate myoclonus. Antiglutaminergic drugs and facilitators of mitochondrial metabolism are currently being tested in clinical trials. Psychological support, genetic counseling, long-term planning, and access to social service agencies are important elements of patient management.
_TABLE 34-4 -- ETIOLOGICAL CLASSIFICATION OF CHOREA_
1. Developmental and aging choreas a. Physiological chorea of infancy b. Cerebral palsy--anoxic, kernicterus c. Minimal cerebral dysfunction d. Buccal-oral-lingual dyskinesia and edentulous orodyskinesia in elderly e. Senile chorea (probably several causes)
2. Hereditary choreas a. Huntington's disease b. Benign hereditary chorea c. Neuroacanthocytosis d. Other CNS "degenerations": Olivopontocerebellar atrophy, Azorean disease, ataxia telangiectasia, tuberous sclerosis, Hallervorden-Spatz, dentato-rubral-pallido-lysian atrophy (DRPLA), familial calcification of basal ganglia, others e. Neurometabolic disorders: Wilson's disease, Lesch-Nyhan disease, Iysosomal storage disorders, amino acid disorders, Leigh's disease, porphyria
3. Drug-induced choreas: neuroleptics (tardive dyskinesia), antiparkinsonian drugs, amphetamines, tricyclics, oral contraceptives, anticonvulsants, anticholinergics, others
4. Toxin-induced choreas: alcohol intoxication and withdrawal, anoxia, carbon monoxide, Mn, Hg, thallium, toluene
5. Metabolic causes a. Hyperthyroidism b. Hypoparathyroidism (various types)
c. Pregnancy (chorea gravidarum)
d. Hyper- and hyponatremia, hypomagnesemia, hypocalcemia e. Hypo- and hyperglycemia (latter may cause hemichorea, hemiballism)
f. Acquired hepatocerebral degeneration g. Nutritional--e.g., beriberi, pellagra, vitamin B 12 deficiency in infants 6. Infectious causes a. Sydenham's chorea b. Encephalitis lethargica c. Various other infections and postinfectious encephalitides, including Creutzfeldt-Jakob disease
Prognosis and Future Perspectives. Despite recent advances in treatment, this disorder results in progressive functional decline and eventual death, usually within 12 to 15 years of onset. Neural transplantation with fetal striatal or other cell sources may become experimental options in the future.
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