I was recently invited to talk about my column on Help 4 HD Live! The host, Lauren Holder, asked me how the revelation that I am a gene carrier has affected my relationships. My friends were sad to learn my news, but remain incredibly supportive. I also have been fortunate with my romantic relationships. Right after I received the results confirming that I was a gene carrier, I started to see someone new. I mentioned in a previous column how caring he was when I told him about my status on a particularly rough day.
The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington disease. This condition is inherited in an autosomal dominant patternwhich means one copy of the altered gene in each cell is sufficient to cause the disorder.
An affected person usually inherits the altered gene from one affected parent. In rare cases, an individual with Huntington disease does not have a parent with the disorder. As the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size.
A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation.
People with the adult-onset form of Huntington disease typically have 40 to 50 CAG repeats in the HTT gene, while people with the juvenile form of the disorder tend to have more than 60 CAG repeats. Individuals who have 27 to 35 CAG repeats in the HTT gene do not develop Huntington diseasebut they are at risk of having children who will develop the disorder.
As the gene is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into the range associated with Huntington disease 36 repeats or more. Bates GP. History of genetic disease: the molecular genetics of Huntington disease - a history. Nat Rev Genet.
Clinical characteristics of childhood-onset juvenile Huntington disease: report of 12 patients and review of the literature. J Child Neurol. Huntington's disease: from pathology and genetics to potential therapies. Biochem J. The key conclusion was that predictive testing has few negative effects on couple relationships. As the authors noted, this conclusion matches the findings of several other studies Tibben et al.
An additional finding from the study is interesting.
The couples that underwent predictive testing were categorized into couples in which the at-risk partner was a carrier and couples in which the at-risk partner was a non-carrier.
Unexpectedly, the carrier couples had higher couple scores stronger couple relationships of statistical significance than the non-carrier couples. This suggests that, for some couples, the knowledge that their at-risk partner did not have HD had a greater negative effect on their marital relationship than the knowledge that their partner did have HD.
Once this threat is removed, partners may no longer feel a duty or need to remain in the marriage to care or to be cared for.
Oct 25, Alexus Jones ponders the topic of dating and concludes that Huntington's merely adds another element of uncertainty to an uteknoderas.comedictable life. I was recently invited to talk about my column on Help 4 HD Live!, a weekly podcast for the Huntington's disease community. Huntington disease is a brain disorder in which brain cells, or neurons, in certain areas of your brain start to break down. As the neurons degenerate, the disease can lead to emotional disturbances, loss of intellectual abilities, and uncontrolled movements. Huntington disease has 2 subtypes: Adult-onset Huntington teknoderas.comg: dating. Analysis of triplet repeats in the huntingtin gene in Huntingtons families affected with Huntington's disease. Huntington's disease-neuropathology. Handb Clin Neurol. Onjisaponin SOMEONE derived from radix polygalae enhances autophagy and accelerates the degradation of mutant a-synuclein and huntingtin in PC cells.
Another possible explanation is provided by examining family patterns via family systems theory rather than individual behavior. When the results prove to be different from expectations, conflict can arise contributing to relationship deterioration and lower couple scores.
Studies by Huggins et al. Similar to the work of Richards and Williams reviewed above, a study by Decruyenaere in also used the Dyadic Adjustment Scale to measure changes in the couple relationship for 5 years following predictive testing. But the study also collected qualitative data from separate interviews with the at-risk persons and their partners. Qualitative data are useful because they can provide more thorough explanations for trends observed in couple relationship over time.
The specific couple relationship examined in the Decruyenaere study was marriage. In this study, all at-risk persons were undergoing predictive testingwith 26 carriers and 14 of their partners, and 33 of non-carriers and 17 of their partners participating in the study.
As for the quality of the marital relationship, half of the couples reported no change in that interval compared to the quality before the predictive testing.
Out of those that did report change, non-carrier couples cited less distress and more communication. Carrier couples that experienced increased relationship quality over the five years cited more mutual support. A conclusion that can be drawn from this study is that the test result does not by itself predict outcomes in the couple relationship; even couples with negative test results for HD may experience post-test psychosocial distress and couple relationship breakdown.
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The important factor for couples undergoing predictive testing is whether the test result causes role shifts that upset the balance of the pre-test couple relationship. For example, two couples that received positive test results reported frustration as the partners shifted toward caretaking roles even before the people with HD showed any symptoms. In another couple tested, a woman believed to be at risk for HD gained self-esteem from a negative result.
With low self-esteem before the test, she had married someone who did not match her ideals in a spouse.
After the testing showed she did not have HD, she regretted her decision to marry her husband, clearly leading to relationship deterioration. Since undesired shifts in roles may contribute to couple relationship breakdown whether the test result is positive or negative, the researchers of this study strongly support post-test counseling. Key differences between HD dementia and a classic cortical dementia is that, in memory tasks, patients with HD can recall items better if cued, suggesting that it involves an inefficient search of memory rather than a deficient memory per se.
In general, memory loss occurs later in HD, and problems that are typical of cortical dementias, such as aphasia and apraxia, are not as common in HD. Importantly, the cognitive deficits in HD may precede the motor symptoms by many years.
It is not uncommon in a clinical setting to have a formal clinical diagnosis of HD made for the first time based on motor abnormality though the cognitive deficits have already reached the level of dementia. Psychiatric symptoms associated with HD can span a variety of domains; however, the most common symptoms are consistent with frontal lobe dysfunction, in line with the known pathophysiology of the disease. Early in the disease course, family members often conceptualize such symptoms as a personality change.
This is accompanied by pervasive emotional blandness.
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Family members often interpret these symptoms as depression, and objectively, the patient certainly appears more withdrawn, uninterested, and noninteractive. However, subjectively, patients will deny any feelings of sadness or hopelessness and typically describe their mood as fine or good.
These frontal lobe symptoms disinhibition and abulia of HD are a likely manifestation of the frontostriatal pathology of degeneration. Apathy is, in general, the most common feature of the disease, occurring at the highest prevalence and is progressive, 11 tracking along with other progressive features such as motor symptoms and cognitive decline. Depression is a feature that is commonly reported to be associated with HD.
Importantly, the course of depressive symptoms is opposite what one would expect if these symptoms were core features that were directly linked to the pathophysiology of the degenerative process. That is, depression is most common at early points in the illness-the first period is right around the time of diagnosis, and the second is during stage 2 when some impairment begins to hamper function.
Parallel with this time course is risk of suicide, which is highest near the time of diagnosis and which then drops off and diminishes after that. It may well be that the increase in depressive symptoms occurring early in the course of disease may be due to an appropriate psychological reaction to the stressors of dealing with either the knowledge or the emergence of a fatal brain disease. Despite the etiology of depressive symptoms in HD, the treatment of these symptoms and the need for careful screening of suicide risk remains a vital part of the care of this patient population.
A prominent feature of HD is lack of awareness or lack of insight into the nature or severity of symptoms that the patient is experiencing. This can include lack of awareness of any feature of the disease, including all three domains of motor, cognitive, or behavioral symptoms.
The gene HTT is but one in a class of genes in which a CAG repeat triplet coding for glutamine, represented as Q is present, which when expanded causes brain disease.
These can be classified as the polyQ meaning repeating glutamine diseases and include spinocerebellar ataxia of which there are several typesdentatorubropallidoluysian atrophy DRPLA and spinal and bulbar muscular atrophy SBMA.
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All polyQ diseases share the features of being autosomal dominant and causing disease when the number of CAG repeats crosses a certain threshold. Although a lot of work has been done on the study of the expanded or mutant form of HTT mHTTthere has been relatively little work on understanding the normal gene and its function.
The actual function is not clear and may vary, but reports support functions in transcriptional regulation, nucleocytoplasmic shuttling, synaptic function, and antiapoptic activity. It is also known that HTT is a highly conserved gene. However, the CAG repeats in the gene are not conserved. Work by Tatari et al 20 demonstrated that phylogenetic comparison of HTT homologs reveal the appearance of repeats first in deuteros tomes, and the repeats then increase - the more evolved the species, the greater the number of repeats, with humans having the highest number.
For this and a number of reasons, it has been postulated thaXHTT, and possibly other genes like it, may have an important role in the evolution of the brain from primate to human. In terms of mHTT and the disease process, the conundrum is that, despite ubiquitous expression throughout the entire body and from conception through adulthood, the primary site of pathology is specific to the striatum.
Even more specific is the type of neuron that is most vulnerable. It is the iSPNs that are affected first and are consistent with the manifestation of chorea as the presenting motor abnormality. Later in the disease, dSPNs are affected, leading to the hypokinetic motor symptoms of later-stage disease.
Most recent evidence points to the pathophysiology of mHTT being the impairment of cortical pyramidal neurons to provide the striatum with needed brain derived neurotrophic factor BDNF.
Although eventually all regions and tissues of the brain are affected, the disease process is clearly selective and specific to the striatum. Another major theme in the research on etiology of HD is the disturbance of cell metabolism.
Biochemical studies have shown disrupted metabolic processes of post-mortem HD brains 24 and lymphoblast cell lines of HD patients. This disturbance in metabolism has been linked clinically to the symptoms of lower weight and body mass index BMI in patients with HD. This has been shown to be independent of the amount of chorea that is present, and in later stages of the disease, it can lead to cachexia. More importantly, low BMI is present in preHD subjects and points to an energy imbalance that may be primary to the disease process.
In general, HD is classically conceptualized as a neurodegenerative disease of the striatum.
Oct 08, Huntington's Disease Support Group. Huntington's disease (HD), formerly known as Huntington's chorea, is a rare inherited genetic disorder characterized by abnormal body movements called chorea, and a reduction of various mental abilities. The symptoms of Huntington's disease occur gradually over time - there is no sudden loss of abilities and. May 12, Huntington disease is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition). Adult-onset Huntington disease, the most common form of this disorder, usually appears in a person's thirties or teknoderas.comg: dating. In Huntington disease, the length of CAG repeat is inversely related to age of onset. This relationship is shown with approximations of age of onset based on repeat length. JHD, juvenile Huntington diseaseMissing: dating.
However, multiple lines of evidence support the theory that abnormal brain development may play an important role in the etiology of HD, as well as other degenerative brain disorders. Abnormal development and degeneration are not mutually exclusive.
There is no doubt that HD is a neurodegenerative disorder. However, persuasive work in molecular biology has supported the theory of neurodevelopmental mechanisms of degeneration.
This theory suggests that neurodegenerative diseases such as Alzheimer disease and HD may represent a novel class of developmental disorders in which subsets of neural populations are vulnerable because of abnormal development, and exist in a mutant steady state before succumbing to environmental stressors or toxins that normally would not promote cell death.
Normal HTT is necessary for brain development; embryos of HTT knock-out mice have major abnormalities in central nervous system development and die shortly after birth. Although the classic theory of HD etiology is that mutant HTT mHTT results in a gain-of-function toxicity that results in neural damage, there is also compelling evidence that in addition to this mechanism, loss of function of normal HTT may also be an important mechanism in the disease.
More recent work by Nguyen et al 37 has shown that HTT is essential for the program of neural induction, progressive specification of neural progenitor cell types, and the subsequent elaboration of neural lineage species. Moreover, mHTT was shown to cause impairments in multiple stages of striatal development, supporting the notion that the selective vulnerability of striatal neurons may have a developmental etiology.
One of the benefits of the HTT gene discovery was the opportunity it afforded to study presymptomatic HD subjects, also known as preHD. This allows the measurement of brain structure and function in people who are years from the onset of disease. One large multisite study with more than at-risk adults enrolled has shown that preHD subjects exhibit abnormalities in brain structure, cognition, behavior, and motor function long before up to 20 years a clinical diagnosis is made.
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If it is true that HD has a vital portion of its pathophysiology based in abnormal development, a conceptual shift in our understanding of this disease and other degenerative disorders will be in order. The current etio logic dogma of HD is that the disease process lies within the toxic effects of mutant huntingtin encoded by mHTTwhich accumulates in the cell, is toxic, and causes degeneration.
An alternative theory is that HTTs vital role in development is compromised in the mHTT form, leading to abnormal development, which is, in and of itself, part of the disease process. This mutant neuronal circuit is initially able to compensate and remain relatively functional, though with subtle abnormalities mutant steady state.
Later, maturation and aging processes and toxic effects of mutant huntingtin eventually tip the faulty circuit toward degeneration.
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A schematic of the model is shown in Figure 2. Evidence of abnormal brain development in human research includes one large magnetic resonance imaging study showing that pre-HD males had smaller intracranial volumes ICV than healthy controls. Also, a unique study of children at risk for HD has shown that children who are preHD average age 12 have lower BMI and smaller head circumference values than healthy controls, again supporting the notion that abnormal growth may be a vital part of the pathologic process in HD.
Longer expansions of HTT cause early onset of the disease. When this occurs prior to age 21, it is termed JHD. JHD is similar to adult-onset HD in many ways, with the same triad of motor, cognitive, and psychiatric symptoms. Most common in childhood-onset JHD diagnosed before the age of 10seizures can be severe and difficult to treat.
Of the symptoms of JHD, the psychiatric and behavioral symptoms are far more consistent and prominent. That is, most patients will have behavioral symptoms. Although there is a perception that JHD patients may have a more rapid disease course than those with adult onset, the literature has conflicting reports, leaving it a question that has yet to be fully explored. By far the most exciting and promising advances in research on HD have been made in the work toward treatment with gene therapy.
A potential therapeutic for dominant genetic disorders, silencing of mutant genes provides the opportunity for treatment with major impact.
In general, the promise of gene therapy could be twofold: i restoration of function by returning to health neuronal circuits that are not yet dead, but dysfunctional and ii neuroprotection with a lack of disease progression.
In fact, the ultimate use of gene therapy would not be in treatment, but in prevention of disease - avoidance of symptoms entirely.
The approaches of gene therapy are based on targeting the processes of DNA information being copied into messenger RNA or mRNA a process called transcription and on the synthesis of proteins using the information in mRNA a process called translation.
Gene-silencing techniques have three general approaches, as follows: repression of transcription using zinc finger proteins, repression of translation of mHTT by antisense oligonucleotides ASOsand blocking protein translation using RNA interference techniques.
HD, a single-gene degenerative disorder of the striatum, has seen more than two decades of intense research, spurred by the identification of the gene in This research has led to a better understanding of the pathoetiology of the disease; however, there is much still to be studied, especially in the context of understanding the role of abnormal development.
In addition, very little is known about the normal function of HTT, which is vital to brain development.
Despite these areas of uncertainty, much progress has been made, particularly regarding the promise, and now reality, of new methods of treatment and potential prevention in the context of gene therapy approaches. National Center for Biotechnology InformationU. Journal List Dialogues Clin Neurosci v.
Huntington's Disease Testing - Michelle's Story \u0026 Impact on Life
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