Huntington's Disease - History

History

Although Huntington's has been recognized as a disorder since at least the Middle Ages, the cause has been unknown until fairly recently. Huntington's was given different names throughout this history as understanding of the disease changed. Originally called simply 'chorea' for the jerky dancelike movements associated with the disease, HD has also been called "hereditary chorea" and "chronic progressive chorea". The first definite mention of HD was in a letter by Charles Oscar Waters, published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease. In 1846 Charles Gorman observed how higher prevalence seemed to occur in localized regions. Independently of Gorman and Waters, both students of Dunglison at Jefferson Medical College in Philadelphia, Johan Christian Lund also produced an early description in 1860. He specifically noted that in Setesdalen, a secluded mountain valley in Norway, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that ran in families.

The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.".

Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating that "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described." Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community. Great interest was shown by scientists in Europe, including Louis Théophile Joseph Landouzy, Désiré-Magloire Bourneville, Camillo Golgi, and Joseph Jules Dejerine, and until the end of the century, much of the research into HD was European in origin. By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.

During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance. The English biologist William Bateson used the pedigrees of affected families to establish that HD had an autosomal dominant inheritance pattern. The strong inheritance pattern prompted several researchers, including Smith Ely Jelliffe, to attempt to trace and connect family members of previous studies. Jelliffe collected information from across New York State and published several articles regarding the genealogy of HD in New England. Jelliffe's research roused the interest of his college friend, Charles Davenport, who commissioned Elizabeth Muncey to produce the first field study on the East Coast of the United States of families with HD and to construct their pedigrees. Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the USA could be traced back to a handful of individuals. This research was further embellished in 1932 by P. R. Vessie, who popularized the idea that three brothers who left England in 1630 bound for Boston were the progenitors of HD in the USA. The claim that the earliest progenators had been established and eugenic bias of Muncey's, Davenport, and Vessie's work contributed to misunderstandings and prejudice about HD. Muncey and Davenport also popularized the idea that in the past some HD sufferers may have been thought to be possessed by spirits or victims of witchcraft, and were sometimes shunned or exiled by society. This idea has not been proven. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.

The search for the cause of this condition was enhanced considerably in 1968 when the Hereditary Disease Foundation (HDF) was created by Milton Wexler, a psychoanalyst based in Los Angeles, California whose wife Leonore Sabin had been diagnosed earlier that year with Huntingdon's disease. The three brothers of Wexler's wife also suffered from this disease. The foundation was involved in the recruitment of over 100 scientists in the Huntington's Disease Collaborative Research Project who over a 10 year period worked to locate the responsible gene.

Thanks to the HDF, the ongoing US-Venezuela Huntington's Disease Collaborative Research Project was started in 1979, and reported a major breakthrough in 1983 with the discovery of the approximate location of a causal gene. This was the result of an extensive study focusing on the populations of two isolated Venezuelan villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of the disease. It involved over 18,000 people - mostly from a single extended family.

Among other innovations, the project developed DNA-marking methods which were an important step in making the Human Genome Project possible. In 1993, the research group isolated the precise causal gene at 4p16.3, making this the first autosomal disease locus found using genetic linkage analysis.

In the same time frame, key discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita Harding's research group on the effects of the gene's length.

Modelling the disease in various types of animals, such as the transgenic mouse developed in 1996, enabled larger scale experiments. As these animals have faster metabolisms and much shorter lifespans than humans, results from experiments are received sooner, speeding research. The 1997 discovery that mHtt fragments misfold led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.

The condition was formerly called 'Huntington's chorea', but this term has been replaced by 'Huntington's disease', because not all patients develop chorea, and because of the importance of cognitive and behavioral problems.