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Huntingtons disease

Category: Illness or disabilities

Type

Involuntary

Introduction and description

Mikalojus Konstantinas Čiurlionis Virgo Zodiakas Mergele

Huntington's disease (HD) is a neurodegenerative disorder that affects muscle coordination and leads to mental decline and behavioural symptoms. Symptoms of the disease can vary between individuals, but usually progress predictably. There is no cure for HD. Full-time care is required in the later stages of the disease. Existing non-drug treatments can relieve some symptoms.

Huntington's has been given different names throughout its 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 thorough description of the disease was by George Huntington in 1872.

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.

The worldwide prevalence of HD is 5–10 cases per 100,000 persons, but varies greatly geographically. Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around 7 per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntington's disease in the U.K. between 1990 and 2010, for example, found that the average prevalence for the U.K. was 12.3 per 100,000.

Some localized areas have a much higher prevalence than their regional average. One of the highest incidences is in the isolated populations of the Lake Maracaibo region of Venezuela, where HD affects up to 700 per 100,000 persons. Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden. Iceland, on the contrary, has a rather low prevalence of 1 per 100,000.

In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF), with the aim of curing genetic illnesses by coordinating and supporting research. At roughly the same time as the HDF formed, Marjorie Guthrie helped to found the Committee to Combat Huntington's Disease (now the Huntington's Disease Society of America), after her husband Woody Guthrie died from complications of HD.

Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD.

Symptoms

The earliest symptoms are often subtle problems with mood or cognition. A general lack of coordination and an unsteady gait often follow.

The basal ganglia—the part of the brain most prominently affected in early HD—play a key role in movement and behaviour control. Current theories propose that they are part of the cognitive executive system and the motor circuit. The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to motion or motions to be unintentionally initiated, or a motion to be halted before, or beyond, its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD.

Symptoms show some similarities with those of Parkinson’s disease – also brain damage - which progresses in a similar manner.

As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioural symptoms. Physical abilities gradually worsen until coordinated movement becomes difficult. Mental abilities generally decline into dementia.

Reported rates of behavioral symptoms in Huntington's disease
Irritability	38–73%
Apathy	34–76%
Anxiety	34–61%
Depressed mood	33–69%
Obsessive and compulsive	10–52%
Psychotic	3–11%

Reported neuropsychiatric manifestations are anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, the latter of which can cause or worsen addictions, including alcoholism, gambling, and hypersexuality.

Difficulties in recognizing other people's negative expressions have also been observed.

The prevalence of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%. For many sufferers and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning.

Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy to around twenty years from the point at which symptoms begin.

Physical symptoms can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. The disease may develop earlier in life in each successive generation. About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly. The variant is classified as juvenile, akinetic-rigid, or Westphal variant HD.

HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington's chorea.

Genetics

The generally accepted hypothesis prevalent at the time of writing was that the disease is caused by an autosomal dominant mutation in either of an individual's two copies of a gene called Huntingtin. The Huntingtin gene provides the genetic information for a protein that is also called "huntingtin".

Wikipedia

Expansion of a CAG (cytosine-adenine-guanine) triplet repeat stretch within the Huntingtin gene results in a different form of the protein, which gradually damages cells in the brain, through mechanisms that are not fully understood.

The genetic basis of HD was discovered in 1993 by an international collaborative effort spearheaded by the Hereditary Disease Foundation. Research and support organizations, first founded in the 1960s and increasing in number, work to increase public awareness, to provide support for individuals and their families, and to promote and facilitate research.

Causes

As we have seen, the generally accepted hypothesis prevalent at the time of writing was that the disease is caused by an autosomal dominant mutation in either of an individual's two copies of a gene called Huntingtin.

Hunt the pathogen

But, what caused the mutation? The cause appears not to have been systematically investigated. Although the disease is believed to be inherited, there are a number of scenarios that need to be investigated

It may be a pathogen that is causing the mutation and this pathogen is shared by a family, by living together they pass it on. In other words the mutation exists, but is caused by a shared pathogen
The pathogen may be hidden in the genetic material and is passed on at the time of conception. In effect the pathogen has become a part of the person’s genetic material and is passed on this way

One reason a pathogen can be suspected is because new non hereditary cases keep appearing. Not many but enough to make one expect an outside agent

The advent of the direct mutation test for Huntington disease (HD) has made it possible to identify a previously unrecognized symptomatic population of HD, including those with an atypical presentation or patients without a family history of HD. The present study investigated the uptake of this test in the province of British Columbia (BC), Canada and assessed the incidence rate and rate of identification of new mutations for HD. All symptomatic individuals residing in BC who were referred for the genetic test for HD between 1993 and 2000 (n=205) were analyzed for CAG expansion, baseline demographics and clinical data, and a family history of HD.
A total of 141 (or 68.8%) had a CAG expansion > or =36. Of these, almost one-quarter (24.1%) did not have a family history of HD. An extensive chart review revealed that 11 patients (or 7.8%) had reliable information on both parents (who lived well into old age) and therefore possibly could represent new mutations for HD. This indicates a three to four times higher new mutation rate than previously reported. Our findings also show that the yearly incidence rate for HD was 6.9 per million, which is two times higher than previous incidence studies performed prior to the identification of the HD mutation. We also identified five persons with a clinical presentation of HD but without CAG expansion (genocopies) (2.4%). PMID: 11595021

This last finding leads one to wonder whether the damage occurs first from the pathogen and the mutation comes second, not the other way round.

HD is much more common in people of Western European descent than in those of Asian or African ancestry, which means the cause is thus related to western lifestyles.

Links with Sydenham’s chorea

Sydenham's chorea (SC) or chorea minor (historically referred to as Saint Vitus Dance) is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet. Sydenham's chorea results from childhood infection with Group A beta-haemolytic Streptococcus and is reported to occur in 20–30% of patients with acute rheumatic fever (ARF).

Acute rheumatic fever may occur following an infection of the throat by the bacteria Streptococcus pyogenes. If it is untreated ARF occurs in up to three percent of people.

Streptococcus bacteria harbour bacteriophage.

Apparently random appearance of symptoms

There is another reason to suspect pathogen over inheritance. If it is genetic, why then do the symptoms of the disease appear at any age - anything from infancy to old age? If it is genuinely genetic, then symptoms should start to appear from birth. Almost everyone with Huntington's disease eventually exhibits similar physical symptoms, but the onset, progression and extent of cognitive and behavioral symptoms vary significantly between individuals.

In 1993, a paper appeared which appeared to have the answers:

Huntington's disease (HD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene. We have assessed 360 HD individuals from 259 unrelated families and found a highly significant correlation (r = 0.70, p = 10(-7)) between the age of onset and the repeat length, which accounts for approximately 50% of the variation in the age of onset. Significant associations were also found between repeat length and age of death and onset of other clinical features. Sib pair and parent-child analysis revealed that the CAG repeat demonstrates only mild instability. Affected HD siblings had significant correlations for trinucleotide expansion (r = 0.66, p < 0.001) which was not apparent for affected parent-child pairs. PMID: 8401589

But all this actually shows is that the longer the pathogen is active the more damage it does. This leads one to suspect that there is a distinct ‘something’ as yet unidentified that is causing damage and that something works its way round the body until it gets to the brain, at which point symptoms become more noticeable.

This something may well be very very tiny, like a bacteriophage. Something not normally picked up in blood tests – if indeed blood tests are carried out.

When psychomotor functions become impaired, for example, such that any action that requires muscle control is affected, then these are signs that the system in the brain that is responsible for movement has been affected. The consequences will be physical instability, abnormal facial expression, and difficulties chewing, swallowing, and speaking. These are the same symptoms as Parkinson disease which is pathogen related.

Juvenile HD differs from adult HD in that it generally progresses faster and chorea is exhibited briefly, if at all, with rigidity being the dominant symptom. Seizures are also a common symptom of this form of HD.

Seizures are a symptom of pathogen attack not gene mutation.

Toxic effects

Mutant Huntingtin is eventually expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy. In effect whatever is causing this is creeping round the body at times of either low immunity or when immunosuppressants or antibiotics are prescribed by doctors.

Wikipedia
The behavior of this mutated protein is not completely understood, but it is toxic to certain cell types, particularly in the brain…..

Htt is expressed in all mammalian cells. The highest concentrations are found in the brain and testes, with moderate amounts in the liver, heart, and lungs. The function of Htt in humans is unclear. It interacts with proteins which are involved in transcription, cell signaling and intracellular transporting. In animals genetically modified to exhibit HD, several functions of Htt have been found…..It is thought that the disease is not caused by inadequate production of Htt, but by a gain of toxic function of mHtt.

Links with other diseases

The mutation in the gene seems to bear similarity with the mutation that occurs in some other diseases:

Thus, the HD mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype. PMID: 8458085

If we take myotonic dystrophy, we find that….

Small interfering RNA (siRNA) duplexes induce the specific cleavage of target RNAs in mammalian cells. Their involvement in down-regulation of gene expression is termed RNA interference (RNAi). It is widely believed that RNAi predominates in the cytoplasm. We report here the co-existence of cytoplasmic and nuclear RNAi phenomena in primary human myotonic dystrophy type 1 (DM1) cells. PMID: 15722335

Diagnosis

Another reason why we should be cautious about the statement that this is ‘simply’ an inherited genetic disease without any pathogenic input is that diagnosis and testing appears to be totally haphazard. It appears that once you have been blighted by the label ‘an HD family’, no tests are carried out to look for any other cause if symptoms appear. Genetic testing appears only to be used to confirm a physical diagnosis if there is no family history of HD. A physical examination, sometimes combined with a psychological examination, is used to determine whether the onset of the disease has begun. There are no blood tests, no tests of the lymph system or similar to search for pathogens and no biopsy tests.

What is in a sense worse is that once you have been blighted with the label, the whole family is subjected to ‘Genetic counseling’, which provides ‘advice and guidance’ on the implications of a confirmed diagnosis. These implications include the impact on an “individual's psychology, career, family planning decisions, relatives and relationships”.

And blight this diagnosis becomes – to the whole family. In one study, genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurred at higher rates within personal relationships than health insurance or employment relations.

All this without any real diagnosis having been given and with no real proof that the disease is not – like all others related to brain damage – pathogen related.

So final is the blight attached to the victim’s families, that despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so. As Wikipedia says “Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because there is no treatment”. The genetic test for HD consists of a blood test which counts the numbers of CAG repeats in each of the HTT alleles, it tests for nothing else – the cause. “the risk of suicide is increased after a positive test result.”

It also appears to be not in the person’s interests to be genetically tested. Financial institutions and businesses may use genetic test results when assessing an individual, such as for life insurance or employment. Although the United Kingdom's insurance companies have agreed that until 2014 they will not use genetic information when writing most insurance policies, Huntington's is explicitly excluded from this agreement.

There is yet more cause for dismay. If a person goes to his doctor with “excessive unintentional movements of any part of the body”. Without any test at all he may be labelled tentatively as an HD possible. The doctors then use Medical imaging, such as computerized tomography (CT) and magnetic resonance imaging (MRI) to see what has happened. However wonderful we believe these technologies to be, there is growing evidence that the use of the heavy metal gadolinium causes brain damage. Gadolinium is classed as an MRI contrast agent. These are used to improve the visibility of internal body structures in magnetic resonance imaging (MRI). The most commonly used compounds for contrast enhancement are gadolinium-based.

It is a real possibility that many cases of HD, diagnosed only by mean of a scan are not HD at all. They may even be gadolinium poisoning.

Tests and testing

It is possible to obtain a prenatal diagnosis for an embryo or fetus in the womb, using fetal genetic material acquired through chorionic villus sampling. An amniocentesis can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation.

This might be a good time to look for pathogens. At the moment no one is, and much research money appears to be being poured into areas that are not at all promising, one of which is stem cells:

The field of embryonic stem cell research has been plagued by exaggeration and misrepresentation, as three major journals have had to retract significant claims about progress in this field. This problem is exacerbated by the politicized climate in which the research is conducted and defended; it may also lie deeper, in a utilitarian ethic that in principle could justify unethical actions for admittedly worthwhile long-term goals. Such an ethic risks undermining the credibility of science, which must show a commitment to the facts that is independent of social and political goals. PMID: 18181947

References and further reading

Walker FO (2007). "Huntington's disease". Lancet 369 (9557): 218–28. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289.
Subramaniam S, Sixt KM, Barrow R, Snyder SH (2009). "Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity". Science 324 (5932): 1327–30. doi:10.1126/science.1172871. PMC 2745286. PMID 19498170.
Purves D, Augustine GA, Fitzpatrick D, Hall W, LaMantia A-S, McNamara JO, Williams SM (2001). "Modulation of Movement by the Basal Ganglia – Circuits within the Basal Ganglia System". In Purves D. Neuroscience (2nd ed.). Sunderland, MA: Sinauer Associates. ISBN 0-87893-742-0. Retrieved 1 April 2009.
Erwin C, Williams JK, Juhl AR, Mengeling M, Mills JA, Bombard Y, Hayden MR, Quaid K, Shoulson I, Taylor S, Paulsen JS (2010). "Perception, experience, and response to genetic discrimination in Huntington disease: the international RESPOND-HD study". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics 153B (5): 1081–93. doi:10.1002/ajmg.b.31079. PMC 3593716. PMID 20468061.
Burson CM, Markey KR (2001). "Genetic counseling issues in predictive genetic testing for familial adult-onset neurologic diseases". Semin Pediatr Neurol 8 (3): 177–86. doi:10.1053/spen.2001.26451. PMID 11575847.
Schulman JD, Black SH, Handyside A, Nance WE (1996). "Preimplantation genetic testing for Huntington disease and certain other dominantly inherited disorders". Clinical Genetics 49 (2): 57–58. doi:10.1111/j.1399-0004.1996.tb04327.x. PMID 8740912.
Schneider SA, Walker RH, Bhatia KP (2007). "The Huntington's disease-like syndromes: what to consider in patients with a negative Huntington's disease gene test". Nat Clin Pract Neurol 3 (9): 517–25. doi:10.1038/ncpneuro0606. PMID 17805246.
Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA (1993). "The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease". Nat. Genet. 4 (4): 398–403. doi:10.1038/ng0893-398. PMID 8401589.
Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM (1993). "Suicide risk in Huntington's disease". J. Med. Genet. 30 (4): 293–5. doi:10.1136/jmg.30.4.293. PMC 1016335. PMID 8487273.
Harper P (2002). "The epidemiology of Huntington's disease". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 159–189. ISBN 0-19-851060-8.
Evans SJ, Douglas I, Rawlins MD, Wexler NS, Tabrizi SJ, Smeeth L (2013). "Prevalence of adult Huntington's disease in the UK based on diagnoses recorded in general practice records". Journal of Neurology, Neurosurgery, and Psychiatry 84 (10): 1156–60. doi:10.1136/jnnp-2012-304636. PMC 3786631. PMID 23482661.
Almqvist EW, Elterman DS, MacLeod PM, Hayden MR (2001). "High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia". Clin. Genet. 60 (3): 198–205. doi:10.1034/j.1399-0004.2001.600305.x. PMID 11595021.
Macdonald M (1993). "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group". Cell 72 (6): 971–83. doi:10.1016/0092-8674(93)90585-E. PMID 8458085.
ProPublica. Left in the Brain: Potentially Toxic Residue from MRI Drugs

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