History and Metabolic Context

History of Huntington’s Disease (HD)

Huntington’s Disease received its name from the physician Dr. George Huntington, who wrote of a form of hereditary chorea in his 1972  paper “On Chorea”. His observations on this form of hereditary chorea came from treatment of families on Long Island that displayed adult onset symptoms of chorea, that persisted through generations. Using notes from his father and grandfather (both of whom were also doctors), Dr. George Huntington, also observed a pattern of the age of onset and “other peculiarities” that existed within the afflicted families on Long Island. Hereditary Chorea had been observed and written about by other physicians, but Dr. Huntington’s paper, “On Chorea”, brought hereditary chorea to the public eye as it gained the most traction within the medical community for its vivid descriptions of hereditary and disease progression. (Lanska 2000)  Decades before the rediscovery of Mendel’s work on Inheritance, Dr. Huntington observed that this disease had a great likelihood of affecting a least one child of a parent with the disease and that individuals that never inherited the disease would not pass the disease on to their children or grandchildren, as Dr. George Huntington described it “the thread had been cut”. In the following decades the condition would become known as  Huntington’s Chorea and then Huntington’s Disease (HD). (Lanska 2000)


Figure 1: The polar zipper of polyglutamines, that Dr. Max Perutz hypothesized was the cause of protein aggregation.
Figure 1: The polar zipper of polyglutamines, that Dr. Max Perutz hypothesized was the cause of mutant huntingtin aggregation.

For the next century the treatment and understanding of Huntington’s disease made very slow progress. Until 1993, the Huntington’s Disease Collaborative Research Group isolated the the Huntington’s Disease gene. The identification of the gene, subsequently led to further research into the gene’s sequence and identification of the mutation causing HD, the increase in the number of CAG repeats in the gene, Htt. (Bates, Tabrizi, and Jones 2014) In 1994, Dr. Max Perutz hypothesized that the increase in CAG repeats, translated into an elongated polyglutamine tail, in the protein Huntingtin (Htt), which creates a “polar zipper” that causes aggregation of the mutant protein. Experimental Data and mice models showed that Dr. Max Perutz was correct. (Bates, Tabrizi, and Jones 2014)

Diagnosis and Symptoms

The contributions made by George Huntington, Huntington’s Disease Collaborative Research Group, and Dr. Perutz were crucial for forming today’s definition of Huntington’s Disease. Huntington’s Disease is a neurodegenerative disorder that follows an autosomal pattern of inheritance with complete penetrance. It is caused by a mutation that encodes an increase in CAG repeats, which encode glutamine, in the N-terminus of the gene encoding huntingtin (Htt) on chromosome 4.(Bates, Tabrizi, and Jones 2014; Walker 2007) Individuals without Huntington’s, typically have 9-36 CAG repeats. Huntington’s disease, and therefore, mutant huntingtin, is characterized by the presence of more than 36 CAG repeats. (Trottier et al. 1995) The symptoms of Huntington’s disease typically appear at 40- 50 years of age, but can appear anytime from ages 1 to 80, and usually causes death within 10 to 20 years. (Walker 2007; Cattaneo, Zuccato, and Tartari 2005) The number of CAG repeats is inversely correlated with the age of onset of Huntington’s Disease, so the more CAG repeats present, the earlier symptoms of Huntington’s Disease appear. Therefore, individuals with more than 60 CAG repeats can potentially show symptoms during adolescence, in what is known as Juvenile Huntington’s Disease (Pascu et al. 2015; Sturrock and Leavitt 2010)

Figure 2: Estimated Global Incidence of Huntington’s Disease. Obtained from: http://www.cmmt.ubc.ca/research/diseases/huntingtons/HD_Prevalence

Huntington’s Disease is most typically diagnosed by looking at the family history of the patient and confirmed through DNA testing for the number of CAG repeats in the Htt gene. Diagnosis can also occur at onset of symptoms. The symptoms of Huntington’s disease include movement disorders such as chorea, hypokinesia, and dystonia. Huntington’s is also characterized by slower thinking, development of dementia, and increasing levels of anxiety, irritability and apathy. (Bates, Tabrizi, and Jones 2014) Incidence of Personality change, aggression, and depression have also been reported. Depression may be a result, of the fact that there are very limited treatment options, which also attributes to that fact that suicide rate among people with Huntington’s Disease increase just before onset of symptoms and during progression of disease, as shown in figure 3. (Walker 2007)

time
Figure 3: Timeline of Huntington’s Disease, including the stages of disease, suicide rate, diagnosis of disease, and how progression of disease affects family members. Figure from: Walker, Francis O. 2007. “Huntington’s Disease.” The Lancet 369 (9557): 218–28. doi:10.1016/S0140-6736(07)60111-1

Normal Function of Huntingtin

The protein Huntingtin (HTT) is ubiquitously expressed in the human body and functions as control of transcription through epigenetic regulation, vascular trafficking ciliogenesis, and mitosis. (Pascu et al. 2015) There is also evidence that Htt is important for the transcription of brain derived neurotrophin factor, a protein crucial to striatal cell growth and survival and interacts with vacuole proteins that impotant for endocystosis and exocytosis at synaptic terminals. (Cattaneo, Zuccato, and Tartari 2005)  Htt is crucial for early embryonic patterning and development, and is necessary for neural tube formation. The wildtype function of the polyQ of Htt (the glutamine repeats) is that it interacts with the targets of Htt which can vary depending on cellular localization. Thus the expansion of the PolyQ region changes Htt interactions with proteins, and subsequently leads to alterations to the epigenetics of the cell, that are associated with Huntington’s Disease. (Bates, Tabrizi, and Jones 2014)

4 Replies to “History and Metabolic Context”

  1. Zach,

    Interesting to learn a little more about this devastating disease. You mentioned that htt is required for embryonic development and neural tube formation. Is there an increased incidence in embryonic neural tube defects in the children of patients with huntingtons or in patients with huntingtons themselves? Are there impacts on fertility in huntingtons disease patients due to this crucial role? Has it been shown how htt functions within the embryonic system and if it undergoes the same aggregate formation as occurs in adults?

    1. Great Questions. No, there no increased incidence in embryonic neural tube defects. Huntingtin’s role in neural tube formation, was shown by reducing Htt expression to less than 50% of wildtype expression. The CAG repeat expansion of Huntington’s does not reduce it expression was not shown to cause embryonic defects in mice models; even patients that are homozygous for the CAG expansion undego normal developmet.(White 1997; Cattaneo 2005) In the embyronic system , it is hypothesized that Htt is important for the survival of mammalian neurons, in which it controls many cell functions, such as neuronal gene transcription, and axonal and vesicular transport. (Cattaneo 2005) I could find any sources that explicitly stated whether aggregate formation is undergone in embryos, but the CAG expansion would still be more vulnerable to fragmentation so aggregate formation is likely.

  2. Hey Zach. It was really neat to gain a biochemical perspective on such a well-known disease and you did a great job of explaining it. When I saw Figure 2 on this page, I was extremely intrigued because clearly Huntington’s Disease, and therefore the CAG repeats that cause the polyQ in Htt, are more prominent in North America and Australia than the rest of the world. Have there been any studies to explain this on an evolutionary scale? Do researchers in the field think there might be an environmental factor on this inherited epigenetic disruption?

  3. Thanks, and interesting question. I could not find any sources that pertain to the dispersal of Huntington’s disease on an evolutionary scale or environmental factors linked to the epigenetic dysfunction of Huntington’s disease. From looking at the map, countries with high population of European descent have increased incidence of Huntington’s, which could indicate that Huntington’s disease has it origins in Europe, but that is just speculation. This map also contains many countries with unknown HD prevalence, so incidence in Africa and Latin America remains unclear.

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