Huntington Disease Dementia

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Huntington disease (HD) is a genetic, autosomal dominant, neurodegenerative disorder characterized clinically by disorders of movement, progressive dementia, and psychiatric and/or behavioral disturbance. In 1872, George Huntington, MD, presented a disease featuring “hereditary nature, adult onset, chorea, mind impairment,” and “with a tendency to insanity and suicide.” Although Huntington was not the first to describe this “dancing mania,” his account was so comprehensive that he received international recognition. In the following 128 years, HD has inspired thousands of research papers in which elucidation of this unrelenting neurodegenerative disorder has been attempted.

The progressive nature of the disorder, the variation in symptoms, and the complexity of diagnosis and treatment is well portrayed in a case study published by Lipe and Bird. They reviewed clinical and genetic features in 34 cases of late-onset Huntington disease.^[1]

Among the cases reviewed was a 74-year-old male who presented with mild chorea, memory problems, and anxiety at the age of 61 years. Though his family had no known history of HD, a number of family members were believed to have been afflicted by dementia, a staggering gait, emphysema, and Parkinson disease. Genetic testing revealed 43 CAG repeats in the HD gene. His motor and cognitive function deteriorated over several years following diagnosis. Mild depression progressed to severe depression and suicidal thoughts, followed by psychosis including delusions and hallucinations, requiring multiple psychiatric hospitalizations.

Huntington disease (HD) is associated with an excessive sequence of CAG repeats in the 5′ end of HTT (alias IT15- interesting transcript number 15), a 350-kD gene located on the short arm of chromosome 4.^[2]Healthy individuals may have between 9 and 35 CAG repeats, while patients diagnosed with HD, as well as carriers, have an abnormal expansion accommodating 36 or more CAG repeats.^[3]The HTT gene, or HD gene, codes for a protein called huntingtin. This protein is found in neurons throughout the brain; its normal function is unknown. In affected patients, neuronal degeneration initiates in the striatum and progresses to the cerebral cortex, following a pattern that correlates to clinical progression of HD.^[2]

Possibly, the abnormal huntingtin protein undergoes proteolysis and is then transported to the nucleus, where it undergoes aggregation. Transport to the nucleus may involve specific protein-to-protein interactions that occur in certain cell types only, possibly explaining the selective neuronal vulnerability present in patients with HD. The genetic mutation is theorized to cause an imbalance between free radical production and removal, resulting in the subsequent neuronal degeneration and neurotransmitter decline.

Great insight has been shed on the HD gene on a molecular level; however, if and how this leads to the clinical symptoms of HD still are not clear. Evidence also indicates the presence of inappropriate neuronal apoptosis in persons with HD. Symptoms result from the selective loss of neurons, mostly in the caudate nucleus and putamen. Vonsattel et al devised a neural pathologic grading system that scaled the microscopic and gross striatum changes. The grades of this scale range from 0 (normal) to 4 (severe neuronal loss; astrocytosis; and atrophy of the globus, pallidus, and caudate putamen).

The role of mitochondrial dysfunction in HD has been under investigation. Quintanilla et al published the results of a study that focused on the contribution of mitochondrial dysfunction and transcriptional dysregulation to the pathogenesis of HD and the possibility of therapeutic intervention. The authors note that impaired energy generally precedes clinical diagnosis of HD, suggesting that the disruption of energy homeostasis is linked to the pathogenesis of HD. Based on their findings, Quintanilla et al suggest the possibility that the effects of mutant HD can be reduced by increasing the availability and activity of PGC-1 α, a co-activator involved in mitochondrial function and glucose, lipid, and energy homeostasis, the function of which seems to be disrupted by mutant HD interactions that interfere with signaling pathways.^[2]

Neurochemically, levels of transmitter substances (eg, GABA and its synthetic enzyme glutamic acid decarboxylase) are markedly decreased throughout the basal ganglia. Levels of acetylcholine, substance P, and enkephalins are also reduced. Nuclear magnetic resonance spectroscopy in living persons with HD has shown elevated levels of lactate in the basal ganglia.

HD supposedly can cause psychiatric disorders in 2 ways: (1) by the direct action of the gene on striatal neurons, and (2) by the indirect effect of the disordered family environment on the children, regardless of whether they inherited the HD gene.

United States

Several epidemiologic studies in the United States, conducted from 1945–1980, show consistent statistics stating that approximately 30,000 people have HD.

Recent estimates of the prevalence of HD in the United States are between 5 and 10 people per 100,000.^[4]

International

HD occurs in various geographic and cultural ethnicities worldwide. The worldwide prevalence of this disorder is 5–10 cases per 100,000 persons. In North America and Europe, HD has a prevalence of 0.5-9.95 cases per 100,000 individuals. The prevalence of HD in the United Kingdom is currently estimated at 8 cases per 100,000 individuals. In a study by Walker et al in South Wales, a prevalence of 7.61 cases per 100,000 persons was reported. This study was reanalyzed in 1988 and showed the prevalence to be higher (8.85 cases per 100,000 persons), indicating a slight rise over the years. The prevalence in Japan is estimated at 1 case per 100,000 people.^[4]

HD is a progressive disorder, typically lasting approximately 15–20 years from onset of symptoms until death.

Early onset affecting patients younger than 20 years (juvenile HD) is associated with rigidity, ataxia, cognitive decline, and more rapid progression. The typical duration is approximately 8 years. Seizures are more common with juvenile-onset disease than other forms.

Individuals who inherit the disease from their fathers tend to become symptomatic much earlier in life than those who inherit it from their mothers.

Death is usually secondary to pneumonia, cardiopulmonary failure, trauma, or suicide.

No significant differences exist among national and ethnic groups in the number of CAG repeats; however, the higher frequency of HD among white persons and its lower prevalence in other populations, including black persons and Japanese persons, has led to the hypothesis that the mutation responsible for the disease was carried to different parts of the world by immigrant European settlers.

This theory is further supported by the suggestion that the mutation rate in the HD gene is exceedingly low, perhaps the lowest such rate for any human genetic disease. The fact that the mutation rate for HD is higher than previously estimated and that new mutations may account for as many as 3% of the cases is now apparent; therefore, new mutations, in addition to European migration, may account for the disease’s presence in many different and sometimes isolated communities.

HD affects males and females in relatively equal numbers.

The onset of disease usually occurs in the fourth or fifth decade of life, with a wide range in age from childhood to later years in life. Juvenile onset has a large repeat expansion and occurs most often when the father is the affected parent (a form of genetic anticipation).

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Idan Sharon, MD Consulting Staff, Departments of Neurology and Psychiatry, Cornell New York Methodist Hospital; Private Practice

Idan Sharon, MD is a member of the following medical societies: American Academy of Neurology, Medical Society of the State of New York