2011 Group Project 4

From Embryology
Note - This page is an undergraduate science embryology student group project 2011.
2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip




Huntington's Disease

Introduction

Huntington’s disease (HD) is an autosomal dominant disease that is established by the mutated huntingtin protein gene. HD is characterized by neuronal degeneration and dysfunction of the cerebral cortex and striatum which may be the cause of its clinical manifestations in jerky, involuntary movements such as chorea [1] [2].

History

Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”[3]. Huntington’s disease was initially known as chorea, derived from the Greek word “khoreia” which means dancing in unison.

George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that HD was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

"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.".[4]

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

Epidemiology

There seem to be an increased prevalence of Huntington's disease among white people as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.[5]

Two of the most well-known populations in which high prevalence of HD was notably in the state of Zulia, Venezuela [6] and Northern Ireland with a prevalence of 6.4 individuals per 100,000.[7] A fairly recent study in Slovenia showed that the prevalence of HD in the country was estimated to be 5.16 individuals per 100,000.[8] The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.[9] An epidemiologic study in Taiwan showed that the prevalence was 0.42 individuals per 100,000 in 2007.[10] Hong Kong had a reported prevalence of 0.37 per 100,000[11] while Japan had a prevalence of 0.37 per 100,000 individuals.[12] This indicates the lower prevalence of HD in Asia as compared to that in European populations.


The difference in prevalence of HD between European and East Asian populations is due to HTT haplotypes. It was hypothesised that different HD haplotypes have different mutation rates. This is supported by the findings that higher risk A1 and A2 HD halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.[13]

For those areas where there are intermarriages with white people, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in white individuals and the fact the disease is autosomal dominant. [14]


The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.[15] This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.[16] Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

Pathogenesis and Genetics

HD is an autosomal dominant disease. It is localised to the 4th chromosome where one gene of its gene pair is not functioning correclty. In unaffected individuals the CAG segemnt is repeated up to 26 times. Howver in HD patients this segment can be repeated from 40-100 times.[17]


Diagnostic Tests

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically in the middle ages. The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics [18]. These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis [19]. In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations [20]. Huntington’s disease can also be diagnosed when a patient is asymptomatic, by genetic testing. This also enables detection of the disease in embryos.

Neuropathology

Anton (1896) and Lannois (1897) were the first to observe neuropathological changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease [21]. Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, amygdala, cerebellum, superior olive as well as the claustrum [22]. Other brain areas greatly affected include the substantia nigra [23] and the centromedial-parafascicular complex of the thalamus. The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the atrophy of the caudate of nucleus, putamen and external segment of the globus pallidus [24].

Clinical Manifestations

Treatment

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms can be treated to slow down the progression of the disease.

Medications

  • Movement disorders
  • Psychiatric disorders

Therapies

  • Psychotherapy
  • Speech Therapy
  • Physical Therapy
  • Occupational Therapy

Breakthroughs

Quite recently, there are a couple of breakthroughs for the treatment of Huntington's.

  • Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients. [25]
  • Using adult neurotrophic factor-secreting stem cells. [26]

Current/Future Research

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s [27] to demonstrate the degenerative progression of the disease. They also provide biological, histopathological and cell-to-cell evidence which allow for the basis of finding treatment options as well as allowing us to see the effects of gene modification.

External Links

Glossary

Asymptomatic: Showing no evidence of disease

Atrophy: A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

Chorea: a disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word khoreia which means dance.

Neuropathological: The pathology of the nervous system

References

  1. <pubmed>21841917</pubmed>
  2. <pubmed>21847326</pubmed>
  3. Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [1]
  4. <pubmed>11232352</pubmed>
  5. <pubmed>1535611</pubmed>
  6. <pubmed>2139171</pubmed>
  7. <pubmed>7562964</pubmed>
  8. Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.Epidemiology of Huntington’s disease in Slovenia. Acta Neurol Scand.: 2009 PMID:18976322 [2]
  9. <pubmed>19672992</pubmed>
  10. <pubmed>20881427</pubmed>
  11. <pubmed>7586664</pubmed>
  12. <pubmed>8700304</pubmed>
  13. <pubmed>21248742</pubmed>
  14. DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.
  15. <pubmed>20881427</pubmed>
  16. <pubmed>7562964</pubmed>
  17. C, Landles., & G, P. Bates. (2004). Huntingtin and the molecular pathogenesis of Huntington's disease. EMBO reports, 5, 958-963. doi:10.1038/sj.embor.7400250
  18. <pubmed>17240289</pubmed>
  19. <pubmed>16003113</pubmed>
  20. <pubmed>11807185</pubmed>
  21. <pubmed>2147116</pubmed>
  22. <pubmed>2932539</pubmed>
  23. <pubmed>8505640</pubmed>
  24. <pubmed>21496571</pubmed>
  25. <pubmed>19361997</pubmed>
  26. <pubmed>19603590</pubmed>
  27. <pubmed>8731</pubmed>

2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip