HUNTINGTON DISEASE: OVERVIEW OF A GENETIC NEURODEGENERATIVE DISORDER
Huntington disease (HD) is a rare, progressive and fatal autosomal dominant neurodegenerative disorder, typically of adult onset. In 1872, Dr. George Huntington (1850-1916), a family doctor in the U.S., published the first paper on the disease that he called “Huntington’s chorea” . A chorea is an abnormal, involuntary movement. The name comes from the Greek word chorea, which means dance.
In 1983, HD was the first gene mapped to a chromosomal locus using an anonymous marker technique . After a ten-year struggle, during which fundamental strategies of positional cloning were developed, the causative mutation, a CAG trinucleotide repeat expansion, was identified [3,4]. Since then, HD research and clinical practice have exerted a strong influence on the approach to phenotype-genotype relationships, the practice of genetic (especially presymptomatic) testing, and the understanding of the pathogenesis of neurodegeneration.
The prevalence rate of HD in the US and most parts of Europe is almost 5 cases per 100,000 individuals. The age of onset varies markedly, typically occurring between ages of 35 and 50, but varying from early childhood to 80. The course is insistently progressive, with death occurring 15-20 years after disease onset. Death usually occurs by pneumonia, malnutrition, or heart failure.
HD onset is defined by the beginning of motor symptoms called chorea, which include continuous and irregular twisting and jerking movements. These movements may vary in severity from restlessness, mild intermittent exaggeration of gesture and expression, twitching movements of the hands, and an unstable dance-like gait to a continuous flow of disabling, violent movements. The limbs and trunks are most prominently affected, but respiratory, laryngeal, pharyngeal, oral, and nasal musculature may also be involved [5,6].
The symptoms of Huntington disease are caused by the degeneration of cells, or neurons, located in the striatum, a region deep within the brain that is part of a structure called the basal ganglia (Fig 1). These neurons normally work to shut off excitatory signals from the motor cortex, the part of the brain that dictates movement. When they die, the motor cortex becomes hyperactive, resulting in involuntary movements (chorea). It is less clear how the death of striatal neurons causes the disorder’s psychological symptoms (personality disorders) [6-9].
Genetics of HD
HD is one of nine neurodegenerative disorders caused by CAG repeat expansions, which give rise to protein products with expanded polyglutamine tracts . Each disease in this group is caused by expansion in a different gene, and the genes have little in common with each other except for the presence of the CAG repeat. In the case of HD, the repeat is in exon 1 of the Huntington gene, located on chromosome 4p16.3. The range of repeat length in the unaffected population is 6-35 triplets. Repeats longer than 35 are considered expanded, and no individual with a repeat length less than 36 triplets has been convincingly diagnosed with HD.
Repeats of 27 triplets or less are transmitted stably during meiosis. Repeats in the range of 27-35 triplets will occasionally expand to the disease range. Repeats 36-39 triplets in length are considered variably penetrant, meaning the probability of developing the disease by late life is less than 100% and may be as low as 50% for repeats of 36-37 triplets. The age of HD onset also tends to decrease as the number of repeated triplets increases. As a result, age of onset tends to decrease in successive generations. This is caused by increased expansion of CAG repeats from one generation to the next (likely due to instability of the repeat region during meiosis) .
Treatment & Prevention
There is no cure and there are no treatments that slow the progression of Huntington disease. Symptomatic treatment of patients with HD may improve the quality of life and prevent complications. Huntington disease affects people in different ways. One member of a family may have more trouble with clumsiness while another may have emotional outbursts. Moreover, symptoms of HD in the same individual change over time. Treatments must therefore be tailored to each patient specifically. Symptomatic treatment for HD can include drugs to treat the erratic movement as well as drugs to treat any psychiatric or behavioral problems .
Nothing can be done to prevent the onset of Huntington disease in a person who has already been born. Genetic testing can determine whether someone has the gene that causes Huntington disease. Genetic counseling may be useful for a person with a family history of Huntington disease. The natural desire of patients to avoid the transmission of genetic disease to their children may conflict with the adverse effects of presypmtomatic diagnosis in the parent at risk of carrying the disease. This notion has led to the development of elaborate protocols to ensure that individuals at risk understand and are emotionally prepared to accept all of the implications of presyptomatic diagnosis. Only a minority of adults who are at risk elect to have presypmtomatic testing. As a consequence, the potential of antenatal diagnosis to reduce the burden of genetic disease in the population, and the tragedy of recurrent cases within a family, is seldom realized. There is now a new approach in which antenatal diagnosis can be offered without incurring the adverse effects of the presymptomatic diagnosis . In this approach in vitro fertilization (IVF) is used to produce early embryos, which are then biopsied, often as early as the four cell stage, to permit genetic testing of the embryos by PCR based methods. Therefore, patients who are at high risk of carrying a gene for HD can participate in antenatal genetic testing without incurring the emotional, social, and financial burdens that might result from presymptomatic disclosure of their own carrier status .
1.University of Illinois at Chicago, Department of Neurology & Rehabilitation. Founders of Neurology.
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(Art by Jen Philpot)