Huntington’s Disease (HD) is a heritable neurodegenerative disease characterized by significant neuron loss in the striatum, a region of the brain primarily involved in voluntary movement, followed by widespread neuron loss in other brain regions. More information on the basics of HD, including symptoms and genetics, is available here.
The causes of neuronal death in HD are still not fully understood, however postmortem brains of HD patients show reduced levels of brain-derived neurotrophic factor (BDNF), a protein which normally plays an important role in neuronal health. Previous studies have shown that mice that do not express BDNF have HD-like symptoms such as reduced striatal volume, and that BDNF can prevent cell death and stimulate the growth and migration of new neurons in mouse models of HD. Since neuronal death is a major cause of the symptoms of HD, BDNF’s potential to not only maintain neuronal health but also stimulate growth of new neurons has placed BDNF as a promising option for the treatment of HD.
Studies examining the viability of BDNF as a treatment for the underlying neuronal loss seen in HD have been limited by the speed with which BDNF degrades and the lack of effective delivery methods. However, one group found that mouse mesenchymal stem cells (MSCs) engineered to overexpress BDNF significantly slowed disease progression in mouse models. MSCs are a type of multipotent stem cell, meaning that they are able to give rise to many, but not all, types of cells in the body. In addition, MSCs are relatively easy to deliver, and typically secrete cytokines and growth factors in the body to promote cell growth and repair. Due to these functions, MSCs are often described as a sort of “cellular paramedic.”
MSCs are also considered a valuable treatment option due to their extensive safety profile, having been used in various animal models as well as in humans with minimal negative effects. Unlike most other cells, MSCs can be transferred between organisms with minimal rates of immune rejection, typically suppressing immune response and reducing inflammation, making them a good candidate for transplantation or injection.
Given the benefits of MSCs secreted factors, including but not limited to BDNF, their robust safety profile, and ease to engineer, UC Davis researchers expanded on previous studies by engineering human MSCs to overexpress BDNF and then transplanting the cells into mouse models of HD.
This study utilized two different HD mouse models:
YAC128: This model displays reduced striatal volume and a slow motor and behavioral decline, and was therefore used for behavioral and brain volume studies. This slower decline is a good analog for typical adult onset HD.
R6/2: This model presents with early onset and rapid progression of disease symptoms, and has a significantly reduced lifespan. This model is better suited for evaluating neurogenesis potential, the ability to form new neurons, and lifespan extension.
Immune privilege capacities of MSCs did not extend across species in this study. As a result, both YAC128 and R6/2 mice were immunosuppressed in order to slow clearance of implanted human MSCs from the brain. Both YAC128 and R6/2 mice were intrastriatally injected with vehicle (no treatment), MSC, or MSC/BDNF (MSCs secreting excess BDNF).
The YAC128 mice were injected at 8 ½ months of age followed by behavioral testing for 6 weeks and striatal volume measurement post-mortem at 10 months. R6/2 mice were injected at 7 weeks of age and euthanized at 10 weeks of age to measure neurogenesis. Survival was calculated using a statistical method known as a Kaplan-Meier estimator.
The goal of this study was to evaluate the efficacy of a combined cell and gene therapy strategy, in the form of MSC/BDNF, as a treatment for HD. This model of delivery provides both the beneficial effects of MSCs as well as BDNF supplementation.
A common psychiatric symptom of HD is anxiety, and can be tested in mice with a variety of behavioral tests. In this study, researchers found that YAC128 mice treated with MSC/BDNF exhibited lower levels of anxiety when compared to non-treated YAC128 mice.
YAC128 mice that were not treated exhibited a significant amount of striatal atrophy, ~11%, compared to normal, non-HD mice. YAC128 mice treated with just MSCs exhibited a protective effect against neuron death with only ~8.5% striatal atrophy. However, the protective effect was stronger in YAC128 mice treated with MSC/BDNF, which displayed only ~6% striatal atrophy in comparison to wild-type mice, a statistically insignificant difference, suggesting almost complete prevention of striatal atrophy with MSC/BDNF treatment. These results showed MSC only treatment and MSC/BDNF treatment to both be notably protective of neurons.
The benefits to behavior and striatal volumes shown in the YAC128 mice could be caused by a number of underlying mechanisms. One possibility is that MSC/BDNF treatment promotes neurogenesis, or the growth of new neurons, which in turn produces reduced striatal atrophy and lower anxiety levels. Using the R6/2 mouse model, researchers found that those that were treated with MSC or MSC/BDNF exhibited higher levels of doublecortin, a neuronal marker for immature neurons, suggesting increased levels of neurogenesis.
Lastly, researchers found that R6/2 mice treated with just MSCs exhibited ~10% increase in lifespan compared to non-treated R6/2 mice. Mice treated with MSC/BDNF showed ~15% increase in lifespan compared to their non-treated counterparts.
A number of clinical trials have shown that infusion of MSCs into patients is relatively safe and has the benefit of being immunoprivileged, meaning that they are not attacked by the immune system once in the body. It should be noted that although immune privilege between organisms has been observed, it was not in this study. Previous and ongoing studies are evaluating the safety and viability of MSC injection or implantation into the brain or spinal cord for treatment of stroke, TBI, spinal cord injury, and neurodegenerative disorders. Building off of the information UC Davis researchers have gained from their own and others’ positive results in mouse studies, the next step is a clinical trial in human patients. The proposed clinical trial would evaluate the safety of implantation of gene-modified, BDNF secreting, MSCs to treat HD in human patients (HD-CELL). This would largely recruit from an ongoing observational study, PRE-CELL, which has followed patients with HD for 12-18 months conducting physical and neurological examinations, written and verbal tests, and measurements of daily function ability.
In conclusion, this research group asserts that the robust safety record of MSCs in clinical settings, preclinical efficacy data, and a lack of other available treatments for HD patients indicate strong support for a MSC/BDNF treatment clinical trial. Though these results and studies are still young, and many years stand between research and a safe, effective, available treatment for HD, they do offer hope and indicate significant progress in the fields of stem cell medicine and HD research. More broadly, this strategy offers new potential avenues of research and treatment for other neurodegenerative diseases such as Alzheimer’s disease, ALS (amyotrophic lateral sclerosis), and Parkinson’s disease.
Pollock, Kari, et al. “Human mesenchymal stem cells genetically engineered to overexpress brain-derived neurotrophic factor improve outcomes in huntington’s disease mouse models.” Molecular Therapy (2016).
Wheelock, Vicki, et al. “PRE-CELL: Clinical and Novel Biomarker Measures of Disease Progression in a Lead-In-Observational Study for a Planned Phase 1 Trial of Genetically-Modified Mesenchymal Stem Cells Over-Expressing BDNF in Patients with Huntington’s Disease (S25. 004).” Neurology (2016).
May 12th, 2016
Dr. John Whyte, MD, MPH — Director of Professional Affairs and Stakeholder Engagement at the Federal Drug Administration (FDA)
Laurie Haughey — Health Communications Specialist, Professional Affairs and Stakeholder Engagement at the Federal Drug Administration (FDA)
The Federal Drug Administration (FDA) is a public health organization that evaluates the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, food products, cosmetics, and potentially toxic products. In line with this mission, the FDA regulates clinical trials and drug approval. There is currently no cure and limited treatments available for those with Huntington’s disease. As such, the FDA has a consistent presence in the HD community as researchers develop and test potential treatments that are subject to FDA regulation.
The central mission of the Department of Professional Affairs and Stakeholder Engagement at the FDA is to create a culture of engagement between the FDA, patients, advocates, and healthcare professionals. They recognize the challenge of navigating an organization the size of the FDA and hope to promote a culture of communication based on dialogue with stakeholders in addition to dissemination of information.
Towards a goal of true conversation, there are opportunities available for stakeholders to engage with the FDA, including but not limited to: participating in patient-focused drug development meetings, joining an advisory committee as a patient representative or public speaker, encouraging HD experts to work as FDA reviewers, organizing citizens petitions, and generating direct outreach via emails and letters.
However, limitations to engagement are often difficult to overcome and it is valuable for the HD community to be aware of inherent restrictions to information sharing. For example, although the FDA hopes to be as transparent as possible, legal restrictions around confidentiality for knowledge, opinions, identities, and sponsorship during drug development and review may prevent full disclosure. This significantly restricts the FDA’s ability to discuss specific information about a product or research study under review. In addition, the FDA must be consistent in its approaches so as to not show bias to any one company or organization, and therefore often must default to presentation of only the scientific facts.
The presentation closed with a reiteration of the values of the FDA as well as the department of Professional Affairs and Stakeholder Engagement and that when it comes to drug development, patient interests are at the heart of what the organization does. In addition, the presenters expressed a desire for the HD community to know that the FDA does not want to slow research or drug development progress, they in fact want to say yes to new treatment options. However, to protect patients’ and stakeholders’ well being, they must be confident that a certain drug’s benefits outweigh its risks before doing so. For further questions or a desire to become involved, the presenters provided their contact information and encouraged listeners to reach out to them.
Dr. John Whyte MD, MPH — Director of Professional Affairs and Stakeholder Engagement at the Federal Drug Administration (FDA)
Laurie Haughey — Health Communications Specialist, Professional Affairs and Stakeholder Engagement at the Federal Drug Administration (FDA
HDSA Research Webinars can be accessed here. More
On April 9th, HOPESters Natty and Caitlin attended Help4HD’s 3rd annual symposium in Sacramento, California. The all-day event featured a wide range of presentations from speakers representing academic institutions, pharmaceutical companies, and research groups. The event honored the work and retirement of Terry Tempkin, RNC, MSN, ANP. Terry is the Nurse Practitioner at the HDSA Center of Excellence, University of California, Davis Medical Center, and Department of Neurology. The event was attended by HD families, researchers, and advocates and was a full day of education for all.
Sponsors of the event included Raptor Pharmaceuticals, The Griffin Foundation, Teva Neuroscience, Ionis Pharmaceuticals, and Lundbeck Pharmaceuticals. Attending the symposium allowed HOPESters the opportunity to meet with others in the HD community working for therapeutics, a cure, and better patient advocacy for those affected by Huntington’s disease (HD). Below is a summary of each presentation from the day.
Dr. Jan Nolta, Ph.D., Director of UC Davis Stem Cell Program and UC Davis Institute for Regenerative Cures and Dr. Vicki Wheelock, MD, Director of the UC Davis Huntington’s Disease Clinic
“Bench to Bedside; Mesenchymal Stem/Stromal cells Engineered to Produce Brain-Derived Neurotrophic Factor as a Potential Treatment for Huntington’s Disease”
“Pre-Cell: The Path Forward and Findings Along the Way”
Dr. Nolta and Dr. Wheelock presented current updates on UC Davis’s progress in its HD stem cell treatment clinical trial. The proposed treatment uses mesenchymal stem cells (MSCs) engineered by Dr. Nolta and others at UC Davis in order to overproduce brain-derived neurotrophic factor (BDNF) as a therapeutic for HD. In HD, medium spinal neurons of the striatum die out, resulting in many of the symptoms seen in HD patients. Current research has identified lowered levels of BDNF as a key cause of this cell death as the mutant huntingtin protein blocks production of BDNF at the RNA level and reduces axonal transport from cortical cells to the striatum.
MSCs have been developed as a viable candidate for delivery of BDNF into the striatum due to their reliable safety profile and ease to engineer. Mouse models of HD treated with implantation of these engineered MSCs have showed success in decreasing behavioral symptoms such as anxiety and reduced striatal atrophy. Mouse models have also revealed key information about the effectiveness of different dosages of MSC-delivered BDNF. Mouse model studies also showed an extended life span and increased neurogenesis, or production of new neurons, in mice treated with MSC-delivered BDNF. Please see this HOPES article on the UC Davis team’s research. The group at UC Davis has completed the first phase of their project plan, “Pre-Cell”, and are working to prove that delivery of MSCs can be done safely in larger mammals in order to receive approval for the first in-human trial of gene therapy engineered MSCs implanted into the brains of patients with Huntington’s disease. The most recent publication on this research is available here.
Jimmy Pollard, CHDI Foundation
“You Are a Part of the Change — Patient Participation in Clinical Trials”
Jimmy Pollard, HD health educator and advocate, spoke about the origins of Huntington’s disease, specifically with regards to its discovery by Dr. Huntington. However Jimmy spent the majority of his presentation taking about the value of HD families in accelerating research and education around HD. One example he gave was the advocacy work of Marjorie Guthrie when she discovered that her husband Woody Guthrie, renowned folk singer, was afflicted with HD. In addition to starting the Committee to Combat Huntington’s Disease, which eventually became the Huntington’s Disease Society of America, Marjorie Guthrie was also instrumental in the creation of the World Federation of Neurology’s Research Commission of Huntington’s chorea (as it was called at the time).
Jimmy also emphasized the value that sharing of stories, such as those in Life Interrupted, has for HD awareness efforts. Finally, he emphasized and thanked everyone in the room who had ever contributed to a clinical trial on HD, acknowledging the necessity and sacrifice of those who constantly supported research efforts.
Morning Panel: Update on Clinical Trials and Studies in HD
Dr. Victor Abler, Global Medical Director at Teva Pharmaceuticals
Dr. Abler described three current clinical trials that Teva Pharmaceuticals is conducting. The first is Pride-HD, which is a Phase II, double blind, randomized control trial testing the impact of pridopidine on motor impairment in patients with Huntington’s disease. Pride-HD is primarily aimed at testing the safety and efficacy of pridopidine at different dosages compared to placebo controls. This study is closed for enrollment but continuing through September of 2016.
The second trial presented was data from First-HD and ARC-HD, the former of which has been completed and the latter of which has completed enrollment but is still underway. These Phase III studies evaluated the safety and effectiveness of SD-809 (deutetrabenazine) in the treatment of chorea. Results have been positive with transition from tetrabenazine, the current treatment for chorea. The most common adverse side effects, affecting ≥5% of participants, were drowsiness, dry mouth, diarrhea, insomnia, and fatigue. SD-809 was granted Orphan Drug Designation for treatment of HD by the FDA in 2015.
The final trial presented was LEGATO-HD, a Phase II study to study the efficacy and safety of laquinimod in the treatment of HD. Laquinimod is understood to decrease inflammatory responses that occur in the brain of someone with HD. The primary endpoint for this study is measurement of a change from baseline in the Unified Huntington’s Disease Rating Scale- Total Motor Score (UHDRS-TMS) after 12 months of treatment. This study is currently enrolling.
Dr. Ben Cadieux, Senior Director of Clinical Development at Raptor Pharmaceuticals
Dr. Ben Cadieux discussed the investigation of RP-103 by Raptor Pharmaceuticals for the treatment of HD. The current Phase II/III trial is building on previous safety trials as well as findings that RP-103 is able to have effects on glucose metabolism, oxidative stress, and brain-derived neurotropic factor (BDNF) production, all of which are abnormal in the brains of those with HD. Measurements of effectiveness on the UHDRS-TFC and Independence Scale showed mild improvements over time in those taking RP-103 compared to controls. Following this Phase II/III trial, the next steps for Raptor are to continue analyzing the data for effectiveness and long-term safety and to develop a stage III protocol.
Dr. Peg Nopoulus, Professor of Psychiatry, Pediatrics, and Neurology at The University of Iowa, Kids HD and Kids JHD Research Director
Dr. Nopoulus presented her team’s work on the Kids HD and Kids JHD programs. The Kids HD study is a longitudinal study of children, adolescents, and young adults who are at-risk for HD. The goal of this research is to identify early changes in brain structure and development in those that are gene-expanded (GE) and will eventually develop HD compared to their gene non-expanded (GNE) counterparts in the at-risk population. In order to study brain structure and development changes, researchers measure brain structure and function as well as behavioral, motor, and cognitive abilities over time. To separate out the control, or NGE, individuals, researchers also conduct genetic testing of patients to determine their HD gene status, but due to the ethical implications of such information about minors, all information is deidentified.
Results thus far have shown reduced striatal volumes in those individuals that are gene-expanded in comparison to those that are gene non-expanded. As a longitudinal study, Kids-HD is still recruiting and is based out of the University of Iowa.
The Kids-JHD study overlaps with the Kids-HD study in most measurement endpoints, including brain volumes, cognitive and motor abilities. However, due to the current lack of significant research on JHD, Kids-JHD also aims to better understand the brain changes that occur in juvenile-onset, as opposed to adult-onset, of HD. In addition, the Kids-JHD program includes an extra day of clinical assessment conducted by a team of doctors who are experts in JHD. The team is able to assess, and if needed, make recommendations to parents and other physicians for the care of individuals with JHD. Reports with relevant information on the child’s clinical status and abilities are sent to local doctors and schools to help inform those involved in the child’s care and development.
Please see clinicaltrials.gov or this HDSA resource to find up to date information on clinical trials.
Kyle Fink, Ph.D. Post-Doctoral Fellow at the UC Davis Institute for Regenerative
Gene Therapy in JHD
Dr. Fink presented his research on the potential for gene modification using transcription-like effectors (TALES) as a treatment for JHD. The idea behind this research is to get to the root of the problem, the expanded CAG repeats in the Huntingtin gene, that result in production of mutant protein in those with HD. Targeting protein levels is an option but that would require the continuous administration of a drug to keep huntingtin protein levels low. Dr. Fink’s work uses TALES to target single-nucleotide polymorphisms (SNPs), or specific targets in the DNA and cause collapse of the CAG repeat extension or repression of the mutant gene. The collapse model works by using two TALES that target unique SNPS around the CAG repeat extension and cause shortening of the DNA until they reach a certain distance from each other (approximately 16-18 CAG repeats), and are no longer able to function. This results in a mutant HTT gene being shortened to one that has a normal CAG repeat length. TALES can also be used for gene silencing, another approach being investigated. When these TALES are used in patient fibroblasts (skin cells), researchers found a markedly reduced amount of mutant huntingtin protein. They also found a 20% reduction in the amount of RNA production, the precursor to the huntingtin protein. These experiments were also done in primary neuron cultures of transgenic mice, with similar results.
The main limitation to complete silencing or shortening of the mutant HTT gene seem to be delivery into the cells. Current research efforts and collaborations are focused on the development of various delivery options, including viral vectors, synthetic nanoparticles, or mesenchymal stem cells. This research is still in early stages, working in vitro with human cells and mice, but researchers hope to be able to progress to treatment of the striatum and cerebellum of mice.
Dr. Peg Napolous, Professor of Psychiatry, Pediatrics, and Neurology at The University of Iowa, Kids HD and Kids JHD Research Director
Psychiatric Aspects of Huntington’s Disease
Dr. Napolous discussed the extended and varied presentation of psychiatric symptoms in individuals with Huntington’s disease. Extended information on this topic is available here. Dr. Napolous emphasized the importance of understanding psychiatric and behavioral symptoms of HD because they typically appear years before motor symptoms do and early identification is important for the care of an individual both emotionally and medically. In addition, many of the psychiatric and behavioral symptoms are treatable with medications used for other disorders. Treatments for HD symptoms are not curative, but rather symptom management. For some aspects of the disease, such as cognitive abilities, apathy, and issues with balance, speech, and swallowing— currently available medications are minimally effective. However, for symptoms such as chorea, irritability, and depression, treatments can be very effective. Finally, Dr. Napolous emphasized the importance of having a team of care providers that can meet the unique needs of the HD patient and family.
Hurry Up and Wait
To conclude the conference, Jimmy Pollard engaged attendees with a presentation that worked to help build an understanding for the experience of HD. This session included an explanation of the ways in which thinking can be affected in those with HD, such as memory impairment, slower thinking, and difficulty focusing, organizing, and planning. One activity Jimmy had attendees do was to attempt to write their names at a rate of one letter every ten seconds and pay attention to the feelings that arose when they were not able to act more quickly. Participants described the task as frustrating, agitating, and tiring; they also noted that they were easily distracted when forced to move at such a pace. Another activity focused on HD patients’ typical dislike of surprises because of the increased difficulty it adds to their ability to plan. A participant was blindfolded and then told to find an item a few tables away. However, when she was close to her destination, Jimmy spun her around in several circles to cause disorientation. This ‘surprise’ of being spun around, was meant to mirror the way in which HD patients feel when something in their day is not the way the have come to expect it. Finally, Jimmy ended on one take home message, which was to “hurry up and wait”. A seemingly contradictory statement, Jimmy hoped to emphasize to attendees that the various cognitive effects of HD are complicated, and patients are often impatient with themselves and the world around them, especially when they are forced to function at a much slower pace than they want. As someone caring for, or interacting with, an individual with HD, it is important to be aware of their array of emotions and experiences and ‘hurry up’ when they need you to, but to ‘wait’ for them as well. Jimmy’s full presentation is available here.
Huntington’s disease (HD) is an autosomal dominant disorder caused by a mutation known as a CAG repeat expansion in the Huntingtin gene (HTT). A CAG repeat expansion means that the codon ‘CAG’, which can be thought of as one of the words that makes up the book of DNA, is repeated more times that it is meant to be in one particular spot of the genome. The HTT gene typically has 10-35 CAG repeats, however when this number of repeats is expanded to 40 or higher, it causes HD. Repeats in the intermediate range, from 36-40, may or may not cause HD, but account for a very small portion of the population. More information on the background and history of Huntington’s disease can be found here.
Limitations of Studying HD in Animal Models
One challenge to researching Huntington’s disease is the scientific community’s reliance on animal models, particularly mouse models of HD. An animal model, or model organism, is a species that is used to understand the biological processes of humans. Animal models can be bred or genetically modified in order to produce a disease or condition that is similar to a human one, such as Huntington’s disease. In order to study HD many researchers use a mouse model, because mice have a Huntingtin gene that is homologous, or related, to the human huntingtin gene. However, study of an animal model with a homologous gene, though extremely useful, is not exactly the same as study of the disease or gene in a human.
There are several types of mouse models, most being either:
- Knock-outs, meaning the huntingtin gene is either partially or completely prevented from being expressed.
- Transgenic, and therefore contain part of or the whole human mutant huntingtin gene somewhere in the mouse genome, as opposed to the normal location of the mouse huntingtin gene on chromosome five; or
- Knock-in, in which the mouse huntingtin gene is either partially or entirely replaced with the human gene.
Using mouse, and other animal, models allows researchers to study aspects of the disease that would be impossible, and likely unethical, in humans.
However, mouse models cannot provide a completely accurate representation of a human disease because different species have unique cell types, proteins, and toxicity sensitivities. Even though humans share a lot of common genetic material with other animals, there are often significant variations from species to species in how that genetic material is processed, which means that the same DNA sequence can be used to make products which are very different from those in humans. Drug trials in particular can be hindered by differences in how two different species react to the same drug. What is safe in mice may not be safe in humans. More information on animal models in HD research can be found here.
Studying HD in Human Stem Cells
Due to the limitations of animal models, stem cells have offered an opportunity for researchers to ethically and efficiently study disease in human cells. In the paper “Genomic Analysis Reveals Disruption of Striatal Neuronal Development and Therapeutic Targets in Human Huntington’s Disease Neural Stem Cells” (Ring, 2015) researchers use induced pluripotent stem cells (iPSCs) and differentiated neural stem cells (NSC) in order to explore the role mutant HTT plays in neural development and in producing disease phenotypes. Induced pluripotent stem cells (IPSCs), like other stem cells, have the ability to develop into different cell types in the body. IPSCs are unique in that they are originally adult cells that are reprogrammed to an embryonic stem cell-like state. Human iPSCs are capable of generating any type of cell in the body(2).
Differentiated neural stem cells (NSCs) are multipotent and can develop into the cells that characterize the nervous system, including neurons, astrocytes, and oligodendrocytes2. The most significant difference between IPSCs and NSCs is that NSCs are further along developmentally in that they are a more specific cell type and closer to reaching their final cell fate. However, these stems cells are similar in that they both have the potential to be influenced by external cues to become a specific type of cell.
In a previous study, these researchers used iPSCs and NSCs derived from patients with HD and found that iPSCs do not show any of the disease phenotypes of HD, such as cell death, loss of brain-derived neurotrophic factor (BDNF), and reduction of energy production. These types of phenotypes only manifest at the NSC stage. Using the same cell types, researchers built on this information in order to perform an analysis of transcriptional changes that occur in the genome from mHTT. Using corrected iPSCs and NSCs as controls, which are cells that are genetically modified to no longer express mutant HTT; researchers found that 4,466 genes were expressed differently in HD NSCs compared to corrected NSCs. In comparison, HD iPSCs only expressed 370 genes differently from corrected iPSCs. This 10-fold difference in the number of differentially expressed genes between iPSCs and NSCs supports the idea that mHTT affects cells at a later stage on the pathway to neural differentiation.
Further analysis between HD NSCs and corrected NSCs revealed several proteins to be important regulators of these gene expression changes. These proteins, including transformation growth factor β (TGF- β), β-estradiol, and tumor necrosis factor alpha (TNF-α), have been found by previous studies to play a role in HD (3,4,5,6,7).
Researchers also used gene co-expression analysis in order to identify modules of co-expressed genes in HD NSCs that share similar functions or cellular components. They found seven distinct modules that represented co-expressed genes in HD NSCs. They focused on two of these modules, labeled “Red” and “Black”, due to their relevance to the HD phenotype. These two modules were enriched with genes associated with human striatal tissue development, an area of the brain that experiences extensive cell loss in HD.
In addition to these modules, researchers found a number of other striatal-specific genes that were expressed at lower levels in HD NSCs than in corrected NSCs (CTIP2, DARPP-32, ISL1, TBR1, FOXP1, and PAX6).
Finally, researchers explored the question of whether, and how, development sets the stage for early pathophysiology in HD. They also looked into whether there were pathways or genes that could be identified as potential candidates in restoring neuronal health and protecting striatal medium spiny neurons (MSNs) in order to halt disease progression. Medium spiny neurons are the cells most acutely lost from the striatum in Huntington’s disease and play an important role in regulating a wide range of behaviors, including initiation and control of movement, motivation, and reinforcement learning. Researchers focused on two signaling pathways, TGF- β and netrin, as potential therapeutic targets for HD and found both to be altered in HD. They found that TGF- β was expressed at higher levels in HD NSCs than in wild-type controls. TGF- β could also be neuroprotective in HD NSCs, alleviating certain HD phenotypes such as high levels of caspase activity, which is involved in cell death pathways, and low respiratory capacity. This suggests a possible compensation mechanism in which HD NSCs express higher levels of TGF- β in order to compensate for negative effects of the HD mutation.
The other pathway studied was netrin-1, which is typically involved in axonal guidance and was altered in HD NSCs. Axonal guidance is the developmental mechanism through which neurons are able to reach their correct targets in the body. Researchers found that the addition of an axonal guidance molecule similar to netrin-1 was neuroprotective, suggesting that the alteration of netrin-1 and its receptors is a negative effect of the HD mutation.
In conclusion, these researchers brought forward several important details about the effects that the HD mutation has on gene expression and regulatory pathways involved in brain development. They also provide strong support for the use of a neural stem cell (NSC) model in order to study HD. Their HD NSC model provides evidence that early disruption of signaling pathways at the NSC stage is critical for determining striatal development in HD and that restoration of these pathways may be a potential option for developing therapeutics.
1) Original Paper: Ring, Karen L., et al. “Genomic Analysis Reveals Disruption of Striatal Neuronal Development and Therapeutic Targets in Human Huntington’s Disease Neural Stem Cells.” Stem Cell Reports 5.6 (2015): 1023-1038.
2) “What are induced pluripotent stem cells?” Stem Cell Information. National Institutes of Health. stemcells.nih.gov
3) Battaglia, G., Cannella, M., Riozzi, B., Orobello, S., Maat-Schieman, M.L., Aronica, E., Busceti, C.L., Ciarmiello, A., Alberti, S., Amico, E., et al. (2011). Early defect of transforming growth factor b1 formation in Huntington’s disease. J. Cell. Mol. Med. 15, 555–571.
4) Kandasamy, M., Reilmann, R., Winkler, J., Bogdahn, U., and Aigner, L. (2011). Transforming growth factor-beta signaling in the neural stem cell niche: a therapeutic target for Huntington’s disease. Neurol. Res. Int. 2011, 124256.
5) Bode, F.J., Stephan, M., Suhling, H., Pabst, R., Straub, R.H., Raber, K.A., Bonin, M., Nguyen, H.P., Riess, O., Bauer, A., et al. (2008). Sex differences in a transgenic rat model of Huntington’s disease: decreased 17b-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males. Hum. Mol. Genet. 17, 2595–2609.
6) Bjo¨rkqvist, M., Wild, E.J., Thiele, J., Silvestroni, A., Andre, R., Lahiri, N., Raibon, E., Lee, R.V., Benn, C.L., Soulet, D., et al. (2008). A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J. Exp. Med. 205, 1869–1877.
7) Hsiao, H.Y., Chiu, F.L., Chen, C.M., Wu, Y.R., Chen, H.M., Chen, Y.C., Kuo, H.C., and Chern, Y. (2014). Inhibition of soluble tumor necrosis factor is therapeutic in Huntington’s disease. Hum. Mol. Genet. 23, 4328–4344.
These stories, following Michelle as she learns of her JHD diagnosis, were never meant to be demonstrative of a “typical” JHD or HD experience, as that does not exist, nor do they represent the experience of any one individual. Rather, their intent was to create a character with which readers could connect, and through her narrative begin to explore the complexities and injustices of JHD. Storytelling is one of the oldest modes of learning in existence, and through Michelle’s story I hope to bring forward themes with important implications for JHD and HD that will create greater awareness and empathy for those affected.
One such theme was the value of having a support network. In the first few stories, Michelle’s only support seems to be coming from Carley. However, the introduction of Dr. Miller brings in a character that Michelle learns to trust, and when she is to receive her genetic test results, she request for Dr. Miller to be there. The value of a compassionate doctor for someone with a diagnosis such as JHD cannot be undervalued, and Dr. Miller is an instrumental connection for Michelle to make early.
Another point of emphasis in these stories is the implication of JHD (and HD) as a genetic disorder. Michelle’s mom’s distress was not only due to her own diagnosis, but also to the fact that she had likely passed on the gene to her daughter. One consequence of her mother’s suicide is seen in the triggering of her father’s alcoholism to a point at which he is not able to care for Michelle, further breaking up her family. The issue of suicide is a serious one in the Huntington’s disease community; however, addressing the topic is crucial for the education and safety of those affected. In the second story, though Michelle does not yet know of her at-risk or gene-positive status, she is haunted by thoughts and dreams of her mother as she begins to show symptoms such as muscle rigidity, difficulty focusing, and mood swings. Though every case of JHD is unique, these symptoms are characteristic of JHD, and parallel those of Michelle’s mother as described by her aunt. Michelle’s thoughts and dreams about her mother serve to foreshadow the implications of the physical and behavior changes we begin to notice at this point in the stories.
The issue of genetic testing is commonly addressed in media, pop culture, and academia. Ultimately, Michelle decides to undergo genetic testing because, for her, not knowing her gene status would be the greater torture. However, an important note to make is that she makes this decision without any consideration for whether there may be others affected by her knowledge. Typically, the weight of knowing one’s gene status falls not only on the shoulders of the at-risk individual, but also those of every close family member. Michelle’s lack of acknowledgement as to how her gene status might affect her father, aunt, or uncle shows her disconnect from them. However, the one person Michelle claims as closest to her, Carley, is also not considered when Michelle makes the decision to get tested. Some would argue this is selfishness on Michelle’s part, but the level of support that Carley provides throughout shows her respect for Michelle’s autonomy in making this decision.
Finally, the process of testing for Michelle is done in a respectful, sensitive manner that unfortunately not every at-risk individual has access to, but that should be strived towards. Spreading the process out over several appointments with multiple individuals, the Duke Neurological Disorders Clinic(1) shows an attention to education, compassion, and discretion that is important for all medical proceedings but especially for the process of JHD/HD genetic testing. In particular, both Michelle’s genetic counselor and doctor offer multiple opportunities for discussion about her desire to know her gene status. In addition, they are transparent about the process, as well as the potential implications, of learning her gene status. Up until the very last appointment, they continuously check-in to make sure that Michelle is confident in her desire to receive the information.
In conclusion, these stories were not written to sugar coat JHD, however they are also not meant to be absent of hope. JHD and HD are diseases that ravage the minds, bodies, families, and communities of those affected. However, the strength, compassion, and as Michelle shows, love, within the HD community is amazing. Michelle faces losing everything that she had previously identified herself with to JHD— strength, independence, running, and freedom. However as the series arches to an end, she begins to take moments of pause to think about the implications of her diagnosis and tries to savor the small moments of joy, freedom, and love left to her. I hope that in these stories I was able to at least partially convey both the pain that Michelle goes through as well as the strength she exhibits in the face of JHD.
- Disclaimer: I have never visited, but The Duke Neurological Disorders Clinic is an Huntington’s Disease Society of America Center of Excellence.
I wake up to a dark sky, having slept through most of the day.
Looking over my shoulder, I smile to see Carley sleeping soundly.
Slowly, I get up, trying to move as little as possible so as not to wake her.
I note that my roommate is not home and then remember that she is at a conference for the weekend. Well that’s convenient, I’m not sure how I could have explained to her the state that I was in yesterday.
Thirsty, I grab my water bottle and chug, focusing on the feeling of cool water running down my throat, trying to keep the thoughts flying around my head at bay.
What are you going to do now?
Is there any point in staying at school?
Maybe it would be better to just run away.
What about Carley?
Looking at her, my heart hurts. I can’t put into words how grateful I am for her love, and her loyalty. I really do think she means it when she says she’ll be with me until the end.
But I’m still afraid.
Not knowing what else to do, and unable to cry anymore, I grab my running shoes.
As familiar as breathing, I pull them on and tie the laces tight.
Outside, the cold air hits me like a wave and I regret the thin layers I am wearing. Facing into the wind I take a deep breath in and swan dive forward, stretching out my legs. It takes longer and longer to get loose nowadays, and I can’t tell if it’s a symptom or just a function of not running as much.
Quitting the team had been tough, but also a relief, and now I’m glad to already have it out of the way. I just couldn’t handle not being at my best, being less then I was capable of. Most days, I was the worst on the team.
That day I cried and cried, feeling like I was losing bits and pieces of myself and there was nothing I could do to stop it.
And I know it will be completely gone soon. If I progress the way Dr. Miller thinks I will, then in a year or two I won’t be able to run and not long after that I’ll lose the freedom of walking.
Rising up from my stretch with another deep breath, I decide to try and enjoy my autonomy while I still have control over my body.
I squat down and feel my quads engage, enjoying the warmth emanating from them as I hop up and down. I feel strong. Last, I make small circles with my feet, working out the stiffness in my ankles. I admire their dexterity as I spell first Carley’s name and then my own with each foot.
Putting my back to the wind, I take off down the sidewalk, going slowly at first to get my bearings. As I warm up I push myself faster, enjoying the pull at the back of my legs as I lengthen my stride. I feel faster than I have in a long time and relish in the experience, easily finding my rhythm and only just noticing the tightness in my lower legs, the desire for them to fall out of line. The mental effort it takes to keep myself moving gracefully is intense, and I feel it begging me to stop, or to slow.
At that moment, I look up from my feet, which I had been carefully studying to help me focus and I see a flurry of birds take flight from a nearby tree, soaring into the sky all at once. The sight is beautiful and I run to them, sprinting, jumping, and flying to be right underneath them. I run along in the same path they fly, picturing myself in the air, free of the shackles that HD is forging for me. Restraints that will keep me here, on the ground, never to feel the rush air beneath my wings or wind in my face as I sprint down a hill.
The birds turn suddenly and I am forced off my path, onto uneven ground covered in the layers of decaying and freshly fallen leaves of late fall. They give way beneath my feet as I work to keep up with the birds overhead. Suddenly, I feel my right foot sink in further than expected, and the groundcover wraps around my calf as my knee buckles.
Then I am falling, first slowly and then all at once. Unable to react quickly enough, my face hits earth with a hard thump, only lightly cushioned by the leaves that had pulled me down.
Looking up, I see the last of the birds flutter away.
Rolling over, I feel my body protest, my ankle and head in pain from the fall. I stare up at the clear blue sky visible through the bare branches above me. Exhausted, I cannot find it within myself to do anything. I cannot cry. I cannot yell. I cannot move.
I want to do all of these things. To sob until my lungs scream for air, protesting at the suffocating grasp of my prognosis. To shout at the injustice of a world that would threaten to take away the decades more I could have spent with Carley. And to run, as fast and as free as I have ever been— far, far away from anyplace that has ever heard even an uttering of the words Huntington’s disease.
I grasp a handful of mulch and throw it angrily, explosively. Hitting the earth with my fists in a futile attempt to fight back. I want to fight back.
Burrowing deep into my mind I think about all the things I could have done. Graduation, a fulfilling job, pets, marriage, children, and a peaceful death — old and wrinkled in my bed, surrounded by loved ones. No matter what I do, my life will not look like that, and I don’t know how I am supposed to just accept that.
Rolling onto my side, I grunt as I prop myself up and then carefully wiggle my right foot to check its status. Definitely not sprained, just a little bit sore. I feel relieved, knowing that I will be able to run again soon.
But for how much longer?
Standing up slowly, I gaze in the direction of my flock of birds, wishing I could just spread my wings and fly away from it all. Turning back, I gaze towards home, towards where Carley is likely still sleeping soundly, hopefully able to forget the horrors of reality for a few more blissful hours.
Thinking of her I can’t help but feel guilty — guilty that I would ever consider leaving, even if it were merely a daydream.
She deserves better than a dying girlfriend who runs away. She deserves to be happy.
And that’s when I see it: I see how I can fight back against HD, futile as the effort may be. I can’t fight my symptoms, and I can’t stop the progression. I may not even be able to control how I will behave through all of this. But I can do one small thing. I can love, and I can be loved.
And it won’t fix anything. But at least for today, it will carry me through.
Taking a step, I start my journey back towards home, towards hope. And in this moment, I feel strong again. More
Today’s the day.
Time to flip the coin.
That’s the metaphor that was first used to explain HD to me, and it’s deceptive. Supposedly, heads you live, tails you die — slowly and painfully. But I’ve flipped a hundred coins and the act is too simple to accurately describe what is happening. Any comfort lent by the quarter landing face up is cancelled out by the fear of seeing that same face hit the tabletop.
I want to live.
I read a bunch of stuff about people not wanting to know their gene status, or feeling guilty for being gene negative because they have a family member who is positive. But I think HD already gave me more than my fair share of misery when it took my mom. What sense is there in me dying too?
I look up from the bench I’m sitting on and watch as an elderly couple walks by, hands intertwined. My heart reaches out to them in yearning. The couple turns off from the main road and meanders down a path framed by maple trees, eventually wandering just out of view. No matter how much I strain, the trees obscure them from my sight, as though the world is trying to tell me I will never see such a scene again.
Sighing, I look the other direction in search of Carley. I wouldn’t be able to face today without her. I can’t imagine facing any day without her, especially if the odds are against me. She has been so much stronger than I have, staying calm in my sea of chaos.
But I’m afraid.
What if she doesn’t want to take on a dying girlfriend? And even if she will, I can’t ask that of her. She’s here now, and has been amazing. But I can’t ask her to go through this hell with me. My genetic counselor, Andrew, made us talk about what this disease looks like at the end — and it’s my worst nightmare. I’ll likely lose control over my body, as though I’m possessed, unable to ever be still. Eventually, I won’t be able to feed myself. I’ll be in a wheelchair. Then I’ll be bed ridden. And then, less than 10 year from now, I’ll die.
One of the most common ways HD patients die is from choking on their food, and not being able to control swallowing. If I wanted to have a feeding tube it could extend my life, but at that point I won’t be able to make my own decisions.
Arguably even worse than the physical torture, are the behavioral changes — the list of psychiatric symptoms is long enough to make anyone break: anger, impulsivity, depression, and compulsiveness to name a few. And much as I deny it, I think it’s already happening. I can it in the rollercoaster that is my moment-to-moment emotional state, and in the way I lash out at those around me. I’ve never been a particularly sweet person, but never have I as cruel as I have been in the last 6 months. When I look in the mirror, I hardly recognize the person I see anymore. I try to convince myself that it’s just the sleep deprivation, but my reflection looks back at me knowingly, unmoved by my protests.
I watched a documentary about HD and all I could see was this new face of mine in the writhing, pained looks of those affected. The world tells me my results are just chance but I can feel that something is wrong.
I think I have it.
I see Carley walking towards me, and it brings me back to the present. I can tell she’s working hard to stay calm through the layer of worry that has enveloped her all week.
Ever since my last appointment, we have both been on edge. The neurologist said that I had showed some indications of symptoms, but they were slight enough that it was not yet possible to confirm. She also said that HD presents differently in younger patients, and the usual tests are not always completely accurate and I would need to get the genetic test to be sure.
But deep down… I already know. I’ve devoured literature on HD day and night, and at this point I’m informed enough to consider pursuing research on the topic. In every science review and patient narrative I can feel the truth of my fate, I can see myself. But I have to hope — for Carley, for myself, for our future.
Why is this happening?
Looking at the clinic, I imagine seeing through the walls, straight into Andrew’s office. And I see the envelope on his desk. Waiting. My results are in there. A single sheet of paper holds my entire fate.
I look down at my feet, willing them to never lose their ability to carry me for miles, free and swift as a bird.
“Hi there” says Carley.
Looking up, I offer my best attempt at a smile, and so does she, mutually acknowledging each other’s feelings in this moment.
She sits down and holds my hand. “Are you sure you want to go in there?”
“Yes. I’m sure. I feel like the only thing worse than knowing would be not knowing.”
“Okay, if that’s what you want. Either way I’m here, I hope you know that. Through everything, I’m here.”
Looking at her, my eyes water— in love, in fear, in guilt. My whole self wants only to fall into the warmth of the comfort she’s offering. But I can’t put this weight on her. I just can’t.
Sensing my resistance, Carley looks me in the eyes and says, “Hey I mean it. I know what you’re thinking and I’m not going anywhere. You can’t make me. And you know what, if it’s bad news, we’re getting the hell out of here anyways.”
I laugh bitterly, “Where exactly are you proposing we go?”
“Well, we both have a lot left to see of this world, and I want to see it with you. Let’s blow our savings and live out our daydreams. We’ll go to all the places we talked about growing up—New Zealand, South Africa, Brazil— we can even do the touristy stuff and make some stops in Paris, Rome, and London.”
“I don’t know about making it to all of those, but I guess if I’m dying, what do I have to lose?”
“We’re not going to go because you’re dying; we’re going to go because you’re living. So focus on now, focus on what’s left. Whether that’s seven or seventy years, we both have so s lot to look forward to. Whichever way this goes, we’re going to make the best of it. And I will be here. Do you hear me? I’m not leaving you.”
Crying now, I embrace her and sob freely.
“I’m so scared. I’m just so scared.”
“I know, I know”, she breathes, holding me tighter.
We enter the clinic hand in hand.
The receptionist recognizes me and smiles. But I see her hesitation. She knows why I’m here.
Trying not to tremble, I approach and give her my name “Michelle Thompson.”
“Hi Michelle, please wait just outside Andrew’s office, Dr. Miller will also meet you there.”
“Alright, thank you.”
Carley and I walk down the hall to the office of my genetic counselor, the hallway seems to lengthen as we walk, Andrew’s door getting further and further away. I walk faster.
Last time I was here, when they did the blood draw, they asked whom I would like to deliver the results. I surprised myself by asking for both Andrew and Dr. Miller.
We sit in the chairs just outside of Andrew’s office, still holding hands, refusing to let go for as long as possible.
I stare out a window at the now bare trees that once sheltered the building. I try to imagine the new buds of springtime emerging along with the sun, and watching as the once empty trees fill back up with life, only to be lost again to the winds of fall. What seems like an eternity later, seasons coming and going during my wait, Andrew emerges from his office, smiling softly and beckoning us inside. I try not to read into his behavior — I know that he has not opened the envelope yet either. However, I can’t help but hope that his small smile is a sign of good news. Hope is all I can do.
“Patricia is on her way right now, sorry for the delay.”
I’m surprised by the first name reference to Dr. Miller, and wonder if it’s meant to be comforting. As though to say that the impending reveal of my fate places us at an intimacy level that calls for at least a momentary respite from formalities.
“No problem, I know we’re a little early.”
Our hands separate as we sit in the chairs opposite Andrew. I grasp at empty air, feeling suddenly alone.
Sitting quietly for a few moments, I appreciate that Andrew doesn’t try to ask any routine questions. Even a gentle “How are you?” might tear down the wall I’m trying to hurriedly build around myself.
Dr. Miller walks in no more than a minute later and pulls up a chair from across the room.
“Hi Michelle, hi Carley”, she greets us both.
“Hello,” we say in unison. Carley reaches back over for my hand.
I had agreed at my last appointment to being asked about my desire to hear my results one more time before getting them. But I’m still a bit surprised when Andrew addresses me.
“Michelle, do you want to know your Huntington’s gene status?”
I pause for a moment.
I hadn’t harbored much doubt before this. I had been sure I wanted to know. So much was hidden from me growing up that I didn’t want anything else left unknown. But it could be nice to pretend I’m okay… To just go on, hoping that my symptoms never progress.
And there it is.
I know it’s happening, I know something is wrong. I can feel it deep down in my core.
I remember the falls — rare and spread out, but happening nonetheless.
The tightness in my calves as I attempt a sprint.
The angry outbursts I try to tell myself are normal. My emotions constantly laid bare for the whole world to see.
Looking up from my lap, I clearly state, “Yes. I need to know.”
“Okay,” he says as he opens the envelope.
Dr. Miller reaches over to rest her hand on my shoulder. Carley leans closer to me.
Knowing exactly where to look, it takes only seconds for Andrew to read the paper and clearly say, “You’re gene positive. Your CAG repeat is 62.”
I have Huntington’s.
The world fades out and I feel as though I’m falling.
Carley and I walk out of Andrew’s office a little while later. I didn’t hear anything they had said. An apology. Support. Something about making an appointment with Dr. Miller.
As we exit the clinic, I ignore the receptionist. Carley leaves her number and asks her to call tomorrow.
Everything is numb. The world feels blurry and indistinct, like a camera unable to focus.
I’m afraid to move. As though the horrors of my disease will descend upon me all at once if I show any sign of life. Carley urges me forward, and carefully, trying not to disturb a single leaf, I put one foot in front of the other. I’m not paying attention to where we are going. Not paying attention to anything but the sound of my footsteps and the feeling of Carley’s hand in mine.
At home now, I curl up in my bed, Carley holding me tight.
I still haven’t cried. That’s weird.
“I don’t want to move,” I explain to Carley, realizing I hadn’t said anything since we left the clinic.
“Okay, then we won’t”
I roll over to face her.
“You don’t have to do this. I won’t ask you to stay,” I tell her again. I have to give her a chance to leave. This isn’t fair.
“I’m not going anywhere. And I’m not being selfless. I can’t lose you yet. You’re stuck with me for as long as possible.”
Looking in her eyes, I pray that she means it. But I also pray that she doesn’t. I don’t want her to suffer with me.
I manage to choke out a “Thank you,” before burying my head in my pillow and finally crying— wracked sobs that fill up my lungs and claw at my chest. Everything hurts.
Eventually my tears run out, and I’m tired. Just so tired. I close my eyes, and allow myself to drift away. The last image I see before slipping into a dreamless night is of a single bare tree, begging for the beautiful shelter of its now lifeless foliage. More
Huntington’s disease is a dominant autosomal inherited genetic disorder, meaning that the child of any parent with Huntington’s disease has a 50% chance of inheriting the disorder. The mutation that causes Huntington’s disease is a CAG repeat extension in the HTT gene on chromosome 4. If someone is born with a repeat number of 40 or higher, an individual will develop Huntington’s disease, typically around the age of 40 with an average life expectancy of 17-20 years after onset. In about 10% of cases, onset occurs before the age of 21, and is referred to as Juvenile Huntington’s disease. There are several key differences between adult and juvenile onset Huntington’s disease, including symptom presentation and life expectancy; JHD patients present with behavioral changes, muscle stiffness, clumsiness, decline of mental ability, difficulty with speech and swallowing, and bradykinesia (slowness of movement). Those with JHD also tend to have a CAG repeat number above 60 and a family history of early onset. JHD also progresses more quickly than adult onset HD, and life expectancy after diagnosis is on average 10 years(1). More information about Juvenile Huntington’s disease can be found here.
Treatment for JHD, much like HD, is limited to symptom management, and in many cases the implications of patients’ neuropsychiatric symptoms, such as impulse control, agitation, aggression, and obsessive behaviors, make it difficult for the patients to engage with in occupational activities such as therapy groups, family visits, and social interactions. Sensory modulation is the neurological function through which the body receives and processes incoming stimuli — smells, sight, sounds, taste, and touch. With this information, individuals can self-regulate and respond appropriately to their environment. Sensory modulation dysfunction (SMD) is when a person has difficulty processing sensory input, which leads to sensitivity as well as changes in arousal and emotional reactivity to an experience. This abnormal processing has been observed in JHD patients, suggesting that they may experience sensory input differently than non-affected individuals, and therefore be more likely to experience SMD. The ways in which a JHD patient may respond to sensory stimuli is therefore different from how one might expect. For example, this could manifest as being under reactive to touch, which may result in a person layering their clothing excessively and intruding on the personal space of others. It could also result in over reactivity to visual processing, leading to complaints of a messy environment and rearrangement of their surroundings.
In two case studies at the University of Melbourne, sensory modulation intervention strategies (SMIS) were used in order to reduce the prevalence of neuropsychiatric symptoms in two patients diagnosed with juvenile Huntington’s disease. The aim of these case studies was to explore the potential for SMIS in helping combat the consequences of sensory modulatory dysfunction in order to allow for JHD patients to engage in a wider range of occupational activities.
Names changed for privacy
The first case study was a 22-year-old female, Carrie-Anne, who had been diagnosed with JHD at the age of 16 and was living in a supportive care community. Her impulsive verbal and physical aggression had shown minimal response to medications or other behavior strategies. Due to these symptoms, she had restricted interactions with others and limited access to the community. Carrie-Anne’s sensory assessment showed that she had a lowered understanding of her sensory sensitivities and was unable to control her sensation satisfying behaviors; this led to physical aggression. Prior to physical aggression Carrie-Anne would show precursors such as pacing, voicing hunger, verbal aggression, and intrusiveness. She would also seek out activities that satisfied her sensory compulsions, such as dressing in layered clothing, standing close to people, and vocalizing hunger as well as dissatisfaction with the flavor of her food. The sensory modulation intervention implemented for Carrie-Anne used strategies that she indicated she preferred — a weighted blanket and vibrating massager, as well as added condiments to Carrie-Anne’s food to enhance the taste experience as recommended by her occupational therapist. Carrie-Anne was able to successfully use these SMI strategies in order to regulate her reaction and emotional stability. Instead of pacing or becoming verbally aggressive, Carrie-Anne would rest with her weighted blanket, after which she would occasionally resume pacing, but the risk of escalation to physical aggression was dramatically diminished. In addition, after implementation of these sensory modulation intervention strategies, Carrie-Anne was able to more frequently engage in meaningful activities and with the community.
The second case study is of a 31-year-old male, Christopher, who had exhibited symptoms of JHD since his late teens but was not formally diagnosed until he was 29. This happens most often because many of the symptoms of JHD, such as behavioral changes, can be confused with normal adolescence or a psychiatric disorder. Christopher was living in a supported community but frequently needed emergency services to address his risk of aggression despite medication. A sensory assessment showed that Christopher was over-reactive to auditory processing; essentially he was sensitive to sound. This sensitivity manifested itself in verbal and physical aggression when the television was on or if another resident was speaking. Before SMIS, Christopher would be given medication and removed to his own room to avoid any risk to others. The chosen SMIS for Christopher consisted of those that he had an affinity for. This included a click-clack ball (a hollow, soft, apple sized ball with hard objects inside), a hand held vibrating massager, and a weighted blanket. Upon employment of these strategies in situations in which Christopher would usually become agitated, Christopher’s complaints and involuntary movements would lessen. In addition, the risk of him escalating to verbal or physical abuse was drastically lowered. This allowed Christopher to stay in communal areas and interact with other residents in a group setting.
In conclusion, these two case studies indicate a potential role for sensory modulation intervention strategies (SMIS) as an effective occupational therapy tool for those suffering from neuropsychiatric symptoms of JHD. Both patients assessed had previously been unable to engage in community spaces due to their increased amount of neuropsychiatric disturbance. However, with SMIS, both Carrie Anne and Christopher were able to participate in meaningful activities such as group therapy and events. As these case studies only discuss two patients, the effectiveness of SMIS cannot be generalized as an appropriate strategy for all JHD patients. However, with further research and practice, this strategy may be a valuable tool for improving the quality of life of JHD patients.
(1) Brown, Anahita, and Caroline Fisher. “Optimising occupational performance through sensory modulation interventions: Case reports of two young adults diagnosed with juvenile Huntington’s disease.” British Journal of Occupational Therapy (2015): 0308022615569249.
HOPESters Natty and Caitlin headed down to Southern California on August 22nd for Help4HD’s 2nd annual symposium in Riverside, California. The event was hosted at The Mission Inn and featured an array of guest speakers and presenters representing research groups, caregiver organizations, pharmaceutical companies, and advocacy groups. Keynote speakers included Dr. Donald Cleveland of UC San Diego, Dr. Leslie Thompson of UC Irvine, and representatives of the Inland Caregiver Resource Center and Riverside Community Health Foundation. This symposium was a full day of education, resource sharing, and community building for those who attended.
Sponsors of the event included Auspex Pharamceuticals, Teva CNS, Lundbeck Pharmaceuticals, Raptor Pharmaceuticals, and the Griffin Foundation. Attending as a representative of HOPES was a wonderful opportunity to meet some of the dedicated individuals and organizations working to raise awareness and support for Huntington’s disease and those that it affects. The HD community is truly astounding in the amount of compassion and dedication individuals have for each other and I am grateful to have played even a small role in Help4HD’s goal to create a world “where everyone knows what HD and JHD is; a world in which compassion is a normal response to the devastation that this horrific disease [causes].”
Below is a brief summary of each presentation.
Terry Tempkin, NP-C, MSN— University of California, Davis HDSA Center of Excellence
“Preparing for a stem-cell based treatment for HD: Pre-Cell and Beyond”
Terry Tempkin presented current updates on UC Davis’s progress in its HD stem cell treatment clinical trial. The proposed treatment uses mesenchymal stem cells engineered by Dr. Jan Nolta of UC Davis to overproduce BDNF as a therapeutic for HD. In HD, medium spinal neurons of the striatum die out, resulting in many of the symptoms seen in HD patients. Current research has identified lowered levels of BDNF as a key cause of this cell death as the mutant Huntingtin protein blocks production of BDNF at the RNA level and reduces axonal transport from cortical cells to the striatum. Mesenchymal stem cells have been developed as a viable candidate for delivery of BDNF into the striatum due to their reliable safety profile and ease to engineer. Mouse models of HD treated with implantation of these engineered mesenchymal stem cells have showed success in decreasing behavioral symptoms such as anxiety and reduced striatal atrophy. The group has completed the first phase of their project plan, “Pre-Cell”, and are now seeking FDA approval for the first in-human trial of gene therapy engineered mesenchymal stem cells implanted into the brains of patients with Huntington’s disease.
Dr. Don Cleveland — University of California, San Diego
“Therapeutic strategies in HD: developing a gene silencing therapy for neurodegenerative disease”
Dr. Cleveland presented on a potential treatment for HD that is currently in mouse models and was initially designed for Amyotrophic Lateral Sclerosis (ALS). The treatment uses antisense oligonuceltides (ASOs), which are chemically similar to DNA and mRNA and are able to base pair with the mutant huntingtin mRNA and signal the cell to degrade it, preventing the production of huntingtin protein. In partnership with Isis Pharmaceuticals, Dr. Cleveland’s work builds on this technology with a designer DNA infusion into the spinal cord targeted against the Huntingtin gene. Success in mouse models shows reduced Huntingtin expression for more than 3 months and partial disease reversal. Trials for safety in human patients have begun and consist of four monthly doses. Efficacy trials are expected to begin in 2017.
Heather Hare, Director of Communications and Outreach at Huntington Study Group (HSG)
Heather Hare discussed the role that the Huntington Study Group (HSG) is playing in current HD research. HSG is a network of investigators, scientists, and HD experts who work to find viable HD treatments, expand the global HSG network, and design and facilitate clinical trials. As of August, they are enrolling in Legato-HD and Signal. HSG is also working to raise clinical trial participation by partnering with sponsors and research sites to cover travel expenses and make sites more accessible. They have also created a Future Contact Database, which notifies subscribers when a new trial is open for enrollment. They hope to streamline the relationship between sponsors, trial participants, and research groups to improve the success and accessibility of clinical trials.
Contact info: www.huntingtonstudygroup.org Heather.Harg@hsglimited.org
Sonia Slevinski: University of Iowa Department of Psychiatry, Napolis Lab
Kids HD + Kids JHD Studies
Sonia Slevenski attended as a research group representative from Iowa. Her group is working on two studies for kids affected by Huntington’s disease (HD) and Juvenile Huntington’s disease (JHD). The first is an ‘at-risk’ study, which follows children who are at-risk for HD in order to track their brain structure and function with MRI and computer analysis. They also test thinking, memory, movement, balance, self-awareness using quizzes, brain tests, and behavior questionnaires. The intent is to identify how early changes begin to occur for those who eventually develop HD. Researchers also use genetic analysis to aid in this research and match early changes with gene status. However, due to the ethical implications of research studies with minors, all information is deidentified out of respect for allowing those in the study to decide whether they want to know their gene status once they become of legal age. Preliminary results have found some evidence for brain changes happening as far as 30 years from expected onset, including reduced putamen and increased thalamus volumes.
The other study is for those affected by JHD. The research is attempting to identify the brain changes that occur in JHD in contrast to adult-onset as well as what potential biomarkers can be identified. The JHD protocol is similar to the at-risk protocol, and researchers are hopeful that this study will result in a better understanding of JHD in order to make progress on potential treatments. This is one of the first studies to look at exclusively JHD and, in combination with the at-risk trial, is trying to understand how HTT plays a role in the developing brain.
Carmen Estrada, Executive Director of Inland Caregiver Resource Center
Note: Carmen was not able to attend and another representative from the organization spoke in her stead.
The final presentation was from a representative of the Inland Caregiver Resource Center. HD and JHD affects not just those with the diagnosis but also those who care for them. These caregivers are typically under a lot of stress, trying to balance work and caring for their loved one. Caregivers face many challenges including a lack of preparation, lack of support, lack of self-care, and loss of identity. The ICRC works to provide services for caregivers not limited to HD, such as information and referrals to other agencies, family consultation, vouchered services like respite care and supplemental services, and short-term counseling. They also run support groups, educational conferences, and support and bereavement programs. A particular concern of the ICRC is a lack of self-care that caregivers often suffer from. Of the population that they serve, about 2/3 have identified having symptoms of depression. In order to alleviate some of this stress, ICRC helps caregivers develop a care plan, both for the patient and caregiver, provides short term counseling, respite care, and recommends a variety of strategies and services to help caregivers. Caregivers do not lack in resilience and love, but providing support for them is critical to prevent burnout. More
The hall is silent as I slowly shut the door behind me, careful not to wake up my roommate. Though she is as much a stranger now as she was on move-in day, we coexist well. Double-checking that I have my key, I turn around and sling my backpack up onto my shoulders, hoping it will protect me from the day.
As I step outside I can smell the first hints of fall, though the temperature is still relatively warm and the humidity is a constant companion. I pass through my building’s parking lot as I walk to my bike— a less than glamorous form of transportation but appreciated all the same. Almost six weeks into classes now, I’ve become accustomed to not having a car and can bike to just about anywhere in less than ten minutes.
Besides, I like biking— it makes me feel strong.
Today’s ride is to the Duke Neurological Disorders Clinic about 15 minutes away. It irks me that the clinic is so close to the center of campus, I feel as though it should be miles away and sealed off with a warning “Caution: For damaged people only”. Its proximity suffocates me.
I can’t get away.
My heart feels heavy, and suddenly every rotation of the pedals requires extra effort.
I think back to my first appointment, a visit I would never have made if Carley had not practically dragged me there. The building was cold and sterile, offering little comfort and no answers. It seems ridiculous that such a clinical setting is necessary to determine my fate.
I still think this is all just a dream. After my aunt and uncle broke the news of my mom’s Huntington’s disease diagnosis, I spent the summer in a haze, unwilling to address the implications of this new information.
After that first day of obsessively researching the disease, I figured out just about everything I needed to know. 1) If my mom had it, I have a 50% chance of also having it; 2) there is currently no treatment or cure; and 3) it has been described as a combination of Alzheimer’s, Parkinson’s, and Schizophrenia. To sweeten then news even further, since I am still under 21, if I am diagnosed it will be classified as ‘Juvenile Huntington’s Disease’, which typically progresses more quickly and unpredictably.
That was when I tried to shut it all out, blatantly ignoring my aunt, uncle, and Carley as they tried to convince me to get the genetic test or at the very least talk to someone. I just wanted to pretend nothing had happened. That nothing had changed.
But everything has changed, and I can’t go back now.
That first appointment broke the dam I had built to contain my fears and questions, now I need to know— do I have the gene? How bad is this going to get? Will I even be me anymore? Am I destined to die before I’ve really lived?
I stop my bike outside of Carley’s building. The genetic counselor I spoke to during my first trip to the clinic told me that they highly recommend I bring someone with me to all of my appointments, usually a family member or close friend. Carley offered before I could ask. She also wanted to call my aunt and uncle and update them so that they could be here for me. I refused. I can’t trust them anymore, not after all the years of secrecy.
Carley is bundled up in a peacoat, boots, and scarf, not having adapted to a climate with real seasons quite yet. She takes the stairs two at a time, every breath forming a tiny puff of condensation in front of her. How does she always have so much energy?
I suspect she is trying to stay upbeat for my sake, I’m certainly doing a poor job of it.
She gives me a bubbly “Good morning!” as she unlocks her bike and rides over to meet me. A quick kiss on the cheek is followed with the usual ”How are you doing today?”
This small, seemingly benign question means much more than it suggests. Underneath those 5 words are a host of hidden fears. “How has your temperament been?” “Have you felt any more muscle stiffness?” “Have you had any chorea?” “Are you dying?”
I try for a cheerful “I’m good”, but can tell from the look on her face that I failed to mask my mood. I wish I could hide some of the fear, if only to make her feel better.
Trying to move past the moment, I suggest we get going, claiming that I don’t want to be late. Getting through the genetic testing process is the only way either of us has to cope, so I’m trying to be a model patient.
As we bike along, I ask Carley about her night.
“Oh, it was good. I spent most of it after you left working on that terrible essay for 18th century literature. I honestly don’t know why I thought this class was a good idea.”
“You’re becoming cultured remember?” I tease.
“Culture-schmulture, if anything, I’m becoming dumber. All we talk about are dead white guys’ writing. Where the heck is the other 50% of the world? And what about a country outside of Europe and North America? Are you seriously telling me that the only substantial work to come out of an entire century was from like 15% of the world’s population?”
Unable to resist, I laugh at her rant. Not because she is wrong, but because it feels good to laugh.
She throws me a look that says ‘not funny’, but the smile afterwards tells me that she knows exactly what I’m thinking. Amazing really, seeing as I hardly ever know what I’m feeling or thinking anymore.
We arrive at the clinic and our laughter evaporates like a morning mist, the dread of what this appointment could mean settling in. Today is my neurological exam, during which I will be prodded and tested in order to determine if I am showing symptoms of HD.
It’s a little weird that they would put this exam before the actual genetic one, like some cruel preview of my fate. Either I get to live a normal life, or I’m receiving a death sentence. There is no third door to choose from.
I turn to Carley, “What if this goes badly?”
”If you’re showing symptoms you mean?”
“Yeah, what the heck else would I mean? That’s what we’re here for.”
Carley flinches. My brief and irrational frustration fades.
“I’m sorry. That was unfair.”
“It’s okay, I’m worried too,” she grabs my hand and suddenly I am calm.
“Thank you”, I smile gratefully, “well, if I’m symptomatic that means I’m gene positive. And… and… I don’t know if this is how I want to find out. But I do have to find out eventually. I just— I’m afraid.”
She pulls me in for a hug, “This is terrifying, and I’m not going to tell you that you shouldn’t be afraid because I know I am. But I’m here no matter what happens. I love you.”
“I love you too” I hold the embrace for another moment before letting go and looking towards the door.
“Alright let’s go in.”
I fidget in my seat waiting for the doctor to arrive, staring at a poster titled “Caring For Your Loved One”. It features an attractive middle-aged white couple; the husband seated with his wife embracing him from behind, both gently smiling.
Cool, I think, hugs are key, thanks for the advice.
The door opens and I’m surprised to see an older woman greet me with a smile, her eyes wrinkling the same way they had surely done thousands of times before.
“Hello, I’m Dr. Miller, you’re neurologist”, focusing in on me immediately, even though we have never met before.
“Hi, I’m Michelle. This is Carley,“ I introduce us, purposely leaving out any details about our relationship. This woman seems kind, but I’m not in the mood for any judgment today.
“It is very nice to meet you both, thank you for coming in as well, Carley”, looking at her now.
“Oh, yeah, of course,” Carley responds, surprised at the sudden attention.
“I suppose we should get started. But first I’d like to tell you a little bit about myself. It seems unfair that I get to know so much about you but you don’t know anything about me,” Dr. Miller explains.
“Um, okay, thanks,” I respond unsurely.
“Alrighty then, so my first name is Patricia, and I’m part of the team of neurologists, counselors, physical therapists, and nurses we have here, all of whom specialize in movement and memory disorders. I’ve been married for almost 20 years to my second husband, and I have two sons from my first. My eldest is 25 and my youngest is graduating from college this year. I did my undergrad at Pomona College and went to medical school at Johns Hopkins. I have two dogs that I dote on and I love to knit. Mmmm, those are the basics. Is there anything more you would like to know?” she asks us both.
“Uh no, no I’m okay. Thanks for, um, sharing,” I mutter.
“Of course! Like I said, you deserve to know who I am. Please let me know what I can do to make you feel more comfortable going through this process. So, when did you meet with the genetic counselor?” she asks, diving in abruptly.
“I met with him about a month ago, on the 31st”, I respond.
“And how did that go?”
“Well I guess it went fine, but to be honest it was mostly information I had already figured out”, I confess.
“That makes perfect sense. With the Internet nowadays, I’m sure you’ve done a lot of research already” she predicts.
“I mean yeah, I guess I have. I needed to know”, I reply.
“Yes, of course you did. So what are you expecting today?” she asks.
“Um, well I read that you’ll do some tests to check my neurological function and see if I am displaying symptoms yet. The counselor sort of told me the same, and also that if I have symptoms I can decide to stop the testing,” I answer.
“Right, that’s just about all of it. One other thing that is important for you to know is that if at any point you don’t want to know or do something— for example the test and results of today, or the blood test later on, you can always say no. Please don’t feel obligated to continue or find out something you don’t want to know. We want to make sure that you are completely comfortable with your decisions in this process” Dr. Miller expands, looking at me carefully.
“Alright, but if I’m showing symptoms that means I’m positive right?” I ask.
“Most likely yes” Dr. Miller responds.
“Okay, well let’s just do this. I want to know. It’s my body, and I want to know,” I say emphatically, Dr. Miller not the only one in the room I am trying to convince.
“Okay then, if you’re sure?” she probes.
“Yes I’m sure” I retort.
“Okay, then to begin we’ll do a simple motor test. It works like this, please hold up both of your hands and copy me,” she says as she raises her own palms to face me.
Quickly, I glance over at Carley; she smiles and nods but I can see concern in the way her smile does not quite reach her eyes. I smile back in an attempt to reassure her before turning back to face Dr. Miller’s upraised hands.
I feel like I’m confessing to a crime I didn’t commit as Dr. Miller touches her forefinger to her pinkie and nods for me to do the same.
Edited by Sharon McClellan Thomason
Published by Help4HD International
Published: July 2015
Life Interrupted is a collection of 12 autobiographical stories written by individuals who have or are impacted by Huntington’s disease (HD). The book was published by Help4HD International, a non-profit dedicated to raising awareness and providing support for those affected by HD, particularly in underserved areas. Often described as a combination of Alzheimer’s, schizophrenia, and Parkinson’s, HD has been called the “worst disease known to mankind”.
As an autosomal dominant genetic disorder, HD wreaks havoc within the families that it exists. Several of the authors are not only coping with their own or a partner’s diagnosis, but also have parents, children, aunts, uncles, and cousins fighting the same battle.
Life Interrupted was published in order to raise awareness about Huntington’s disease; and does so by allowing the reader to briefly witness the journeys of twelve incredibly strong individuals as they face the monster of HD, bringing the reader intimately into the lives of the authors and their families. Life Interrupted serves as a valuable awareness tool in helping the public understand the ways and extent to which HD turns lives upside-down.
The book opens with a foreword by Sharon McClellan Thomason, the managing editor of Help4HD International’s online newspaper The Huntington’s Post. Her first husband died of complications from HD and her son is currently symptomatic, a story which she details in Chapter 11, titled “Into the Storm.” A dedicated activist, in her foreword Sharon expresses the difficulty she encountered not only in telling her own story but also in reviewing the stories of others for the editing process. She also communicates hope that the book will help achieve Help4HD’s mission of creating a world “where everyone know what Huntington’s disease and Juvenile Huntington’s disease is; a world in which compassion is a normal response to the devastation that this horrific disease bestows on everyone”.
The book closes with an afterword by Jimmy Pollard, an HD activist and expert in specialized care for those with HD. He also works with the Cure Huntington’s Disease Initiative (CHDI) Foundation and travels worldwide to raise awareness and teach about how to care for those with HD.
Every story presented in Life Interrupted is as sincere and candid as the last, hiding no details of the horrors of this disease. Major issues within the HD community, such as genetic testing, assisted living, public benefits, family dynamics, and end-of-life care, are raised again and again by the families living through it all. The honesty of it all sends an undeniable message: this book matters, these stories matter, pay attention world.
The authors in Life Interrupted are presented as follows. Please note that some names have been changed for the protection of those who have or are at-risk for HD and may therefore suffer from discrimination in the workplace, care facilities, and in public.
Foreword: “Life Interrupted” by Sharon McClellan Thomason
Chapter One: “Through the Eyes of a Love Child” by Lisa Davenport
Chapter Two: “Written Descent” by Sarah Foster
Chapter Three: “Just Listen” by Ben Lamoreau
Chapter Four: “Three Stolen Futures” by Jeannie Grundborg
Chapter Five: “Marrying into a Family with Huntington’s Disease: A Fight to End a Generational Disease” By Frances Sandaña
Chapter Six: “I’m Not Sick… I Just Have HD” by Vicki Owen
Chapter Seven: “Accidental Discovery” by Roberta Brink
Chapter Eight: “Woody, My Wife-in-Law, and Me” by Pat Wolf
Chapter Nine: “Turning Tears into Hope” by Margaret D’aiuto
Chapter Ten: “Love in Action” by Brenda A. Vega Fonseca (Translated from Spanish by Daniel Medina)
Chapter Eleven: “Into the Storm” by Sharon McClellan Thomason
Chapter Twelve: “When Strength and Resilience Are Your Only Option” by Katie Jackson
Afterword: “Appreciations and Lessons from a Fellow Traveller” by Jimmy Pollard
More information about Life Interrupted can be found here. More
You can purchase a printed or digital copy at these sites:
The brain is a complex and energy demanding organ. In order to prosper it needs a constant flow of nutrients, oxygen, and stimulation. In the developing brain for example, neuronal connections, called synapses, that are not used will eventually be pruned away, resulting in highly specific neural networks. Nutrients and oxygen are delivered to the brain the same way they are delivered to other organs — in the blood stream. However, there is an important difference in how blood flows through the brain in comparison to the rest of the body. Instead of oxygen and nutrients easily crossing from the blood vessels and into the cells of the brain as is done in other organs, brain vasculature has an extra layer of protection known as the blood-brain barrier (BBB). The blood-brain barrier is made up of brain endothelial cells held together by tight junctions (TJs) that form a highly selective barrier between the blood supply and the cerebral spinal fluid (CSF). The BBB regulates the passage of certain molecules necessary for brain function while keeping out potential toxins(1). This is a very important job because substances that can easily enter the peripheral bloodstream (such as botulin toxin) would wreak havoc if they easily diffused or were transported into the CSF.
Figure One (2)
The root cause of Huntington’s disease (HD) is a genetic mutation resulting in an extended CAG repeat in the Huntingtin gene (HTT). The mutation that results in HD was isolated in 1993 and research since then has worked to further understand the inheritance patterns and implications of this genetic disorder. However, an aspect of HD that has been less well researched is HD pathophysiology, essentially the way in which HD interrupts normal brain function. In other neurodegenerative diseases, such as Alzheimer’s disease, there have been reports of impairments in cerebral vasculature as well as the BBB (3). Knowing the role that cerebral blood flow deficiency can play in neurodegenerative diseases, researchers from the University of Cambridge, the Hospital Center University of Quebec, the University of Nottingham, and the University Laval, collaborated on a project investigating potential vascular impairments in HD.
Researchers used magnetic resonance imaging (MRI) as well as post-mortem tissue analysis in order to explore any potential vascular or BBB impairments in HD patients. Researchers also used the R6/2 mouse model, a mouse line that has been genetically engineered to represent human Huntington’s disease. Using a mouse model allows the researchers to use a wider range of experimental techniques in order to glean further details of HD pathophysiology.
Several differences were identified between cerebral blood vessels and the BBB of healthy controls in comparison to HD patients and R6/2 mice. Researchers found mHTT aggregates, the mutant form of the Huntingtin protein, in the cerebral blood vessels as well as the BBB of HD patients. These mHTT aggregates were also found in the blood vessels and BBB of R6/2 mice. Image 2 shows where these aggregates were seen as well as how they are able to move between cells. The effect of mHTT aggregates remains unclear —previous studies linked them to oxidative stress and impairment of brain cells’ ability to produce energy; however, recent research suggests that mHTT inclusions in neuronal cells may be protective. Regardless, mHTT aggregates are a deviation from the norm and this study found their presence in the cells making up the brain blood vessels and BBB, a fact of unknown consequence (4,5,6).
Figure Two. Used With Original Author’s Permission (5)
Researchers also identified changes in the structure of brain blood vessels. Both post-mortem tissue analysis of HD patients and R6/2 mice showed an increased density of blood vessels — so there were more of them in the same space. However, this increased number of blood vessels was accompanied by a decrease in the average size of the vessel. In addition, the increased density of blood vessels was negatively correlated with the amount of putaminal atrophy— the more brain cells that died the more of these smaller blood vessels there appeared to be.
This change in number and size of blood vessels does not sound too disastrous until you consider the massive amount of oxygen and nutrients that needs to be carried through the cerebral vasculature — about 750mL of blood per minute (3). With such a high demand for blood flow, small changes in blood vessels could affect the ability of those vessels to deliver the needed oxygen and nutrients.
In addition, researchers found significant changes in the BBB structure. There was a decrease in the expression of two of the proteins that form the tight junctions between the endothelial cells that make up the BBB. Decreased expression of these two proteins, occludin and claudin-5, has been found to be associated with increased permeability (6). Image 1 shows the locations of the tight junctions between the endothelial cells that surround blood vessels. Image 2(upper insets) shows how claudin-5 and occludin help hold together these tight junctions of the BBB. Finally, to check the effects of these structural changes, researchers looked for any leakage across the BBB by measuring the amount of fibrin, a protein in the blood that aids in clotting, outside of the blood vessels. These analyses showed an increased amount of extravascular fibrin. Fibrin’s role in clotting means that the majority of it is usually located within the blood vessels, higher levels outside of the blood vessels indicates leakage through the BBB. Furthermore, the amount of leakage through the BBB in the right-side caudate region of the brain was correlated with disease burden; meaning that the further progressed a patient was, the “leakier” their BBB appeared to be.
This research is significant because it identifies clear structural and functional changes in the cerebral vasculature and BBB in Huntington’s disease patients. Although it remains unclear exactly how these various changes affect or are affected by brain cell survival and disease progression, there is evidence that significant changes are happening in the HD brain’s circulatory system. In addition, this information about HD is valuable to researchers as they continue to work towards development of treatments because in order to fix something, you first need to know what’s going wrong.
2) http://neuroscience.uth.tmc.edu/s4/chapter11.html (Image 1)
3) Roher, Alex E., et al. “Cerebral blood flow in Alzheimer’s disease.” Vascular health and risk management 8 (2012): 599.
4) Xu J, Chen S, Ku G, et al. Amyloid beta peptide-induced cerebral endothelial cell death involves mitochondrial dysfunction and caspase activation. J Cer eb Blood Flow Metab 2001;21:702–710
5) Rizzo MT, Leaver HA. Brain endothelial cell death: modes, signaling pathways, and relevance to neural development, homeostasis, and disease. Mol Neurobiol 2010;42:52–63.
4) Jiao H, Wang Z, Liu Y, et al. Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood-brain barrier in a focal cerebral ischemic insult. J Mol Neurosci 2011;44:130–139.
5) Drouin‐Ouellet, Janelle, et al. “Cerebrovascular and blood–brain barrier impairments in Huntington’s disease: Potential implications for its pathophysiology.” Annals of neurology (2015).
6) Slow, Elizabeth J., Rona K. Graham, and Michael R. Hayden. “To be or not to be toxic: aggregations in Huntington and Alzheimer disease.” Trends in Genetics 22.8 (2006): 408-411.
CJE 09/15 More
Huntington’s disease (HD) is a genetic disorder caused by a mutation in the huntingtin gene (HTT). The mutation is identified as an extended number of CAG repeats where 40 or more repeats results in mutated huntingtin protein production and Huntington’s disease. The condition is inherited in an autosomal dominant fashion— meaning that only one copy of the mutated allele, known as the “HD disease allele”, is necessary for development of HD. Consequently, if one parent has the mutated gene, then all children of that parent have a 50% chance of inheriting a mutated allele. The normal, healthy copy of the gene is known as the “wild-type allele”. More information on the genetics of HD is available here.
Determining whether an individual has the HD disease allele has become a relatively accessible process due to the development of accurate genetic testing. More information on genetic testing can be found here. However, one major factor that remains elusive is when an at-risk individual will become symptomatic, often referred to as the age of onset (AO). The AO is when an individual begins to show obvious motor, behavioral, or cognitive symptoms, and it is often predicted based on the number of CAG repeats an individual has — the more repeats, the sooner they will develop symptoms. However, this correlation only accounts for 67% of variation in age of onset(1). This means that two individuals with the same number of repeats can develop symptoms up to 20 years apart. So what about the other 33% of variation? Although the answer to this question remains unclear, the remaining variation has been found to have a heritability of about .56, suggesting additional genetic factors that modify AO(1).
An international and collaborative research effort looked to the regulatory components of gene expression in order to better understand variability in AO. The researchers hypothesized that a potential factor in the variability of AO might be the levels of HTT expression, a process in which the promoter region of a gene plays a significant role. For this reason, the researchers chose to look into the role of the promoter region of the HTT gene in HTT production. Before a gene is “read” and transcribed into mRNA in order to eventually become a protein, it must have a certain array of active regulatory elements in order to initiate the process. One such element is known as the promoter, which when targeted by transcription factors, stimulates transcription. Transcription factors are an array of proteins that bind to DNA in order to regulate gene expression and consequently, protein production. For more information on DNA structure and how it results in proteins please refer here. In this recent 2015 study, researchers looked at the sequences of the HTT promoter region from a range of HD patients(2). In order to investigate the effects of gene variation in the HTT promoter on gene expression, researchers used luciferase reporter assays. This is a biochemical test that allows for measurement of differences in transcription levels by using the promoter of a gene of interest, in this case the promoter of HTT, to drive expression of a luciferase reporter gene. The luciferase reporter gene codes for a protein that emits light when produced, which can then be directly measured. The amount of light emitted serves as a measurement for the amount of promoter activity and consequently gene of interest expression. So, the more light emitted, the higher level of promoter activity and consequently transcription. Using this technique, researchers identified a relatively common SNP (present in about 16% of HTT alleles) that resulted in a 50% reduction of transcriptional activity. A SNP is a small change in the DNA sequence due to the swapping of one nucleotide for another
Next, researchers used transcription factor binding site (TFBS) prediction tools in order to identify an overlap between the SNP and a NF-κB binding site. NF-κB, which stands for “nuclear-factor-kappa-light-chain-enhancer of activated B-cells”, is a protein that regulates gene transcription. They found that the SNP was in a location where NK-κB would possibly bind, and as such could potentially to play a role in how NF- κB interacts with the promoter.
With this information, researchers hypothesized that the SNP altered the ability of NF-κB to bind to the HTT promoter and consequently reduced transcription. Researchers investigated this hypothesis and confirmed their prediction that the identified SNP reduced the ability of NF-κB to bind to the HTT promoter. This was confirmed in multiple systems, including in vitro rat striatal cell line and human cell line (LCL), as well as in vivo mouse brain tissue.
Furthermore, researchers found higher levels of NF-κB binding in mouse striatum than in other brain regions. This is significant because the striatum is an area where HD patients experience significant neuron loss and since binding of NF-κB to the HTT promoter resulted in increased HTT expression, the authors suggest that this may be related to the increased levels of neurodegeneration seen in the striatum. In summary, the hypothesis is that increased binding of NF-κB, resulting in increased HTT expression, may be causing more mutant Huntingtin protein to be produced in striatal neurons and therefore make them more susceptible to degeneration.
So, at this point the researchers knew that NF-κB binding to the HTT promoter typically results in increased HTT transcription. They also knew that the identified SNP lowers HTT promoter activity. Putting the two together, the researchers proposed that the mechanism by which this SNP acts is by inhibiting NF-κB binding to the promoter region, therefore lowering HTT transcription. And this is exactly what the researchers found: the SNP is in fact located in the binding site of NF-κB, and can act by inhibiting the ability of NF-κB to bind to the HTT promoter, consequentially reducing HTT transcription.
In order to investigate the disease-modifying effects of this molecular mechanism, researchers turned to genetic analysis of HD patients and their ages of onset. Patient cohorts consisted of those who had either very late or very early AO. This sampling strategy of extreme AO increases the efficiency in testing for the SNP’s effect because if it is true that the SNP affects AO then it should be more common in those at the ends of the AO spectrum.
The researchers found that the identified SNP in the HTT promoter acts as a bidirectional genetic modifier in HD, meaning that it can be associated with an increase and a decrease in age of onset, depending on which allele it is located. As you might remember, HD patients have two copies of the HTT gene— typically, one is the mutant allele and the other is the normal, or “wild-type”, allele. When the SNP was found on the mutant HTT, patients developed motor symptoms on average ten years later than patients without the SNP— a “protective” effect. On the other hand, patients who had the SNP on the normal allele typically developed motor symptoms four years earlier — a “detrimental” effect. The ability of this SNP to cause both an increase and decrease in age of onset, depending on which allele it is located on, makes it a “bidirectional” genetic modifier.
It should be noted that the patient cohort in this study is not an accurate representation of the entire HD population. In addition, the variant investigated that was associated with later age of onset has not been found in high frequencies outside of the Danish HD population that was used.
Why does this matter?
Genetic modifiers such as the SNP investigated in this paper are interesting because they provide more information on AO and symptom development, giving doctors the ability to better predict when a patient may become symptomatic. In addition, genetic modifiers such as this SNP can be used as potential therapeutic targets for HD patients. In this case, a drug that could “mimic” the effects of the SNP could be used to delay symptom onset. Another important implication is the detrimental role that the SNP played when located on the WT allele. Current therapies such as antisense oligonucleotides (ASOs) are designed to reduce total Huntingtin protein. These findings suggest that reduced expression of normal HTT may cause earlier age of onset, and therefore reducing all Huntingtin protein, mutant and normal, may have undesirable effects.
It is important to keep in mind that although this is exciting information that gives us new insight into how the HTT gene is regulated and the potential relationship between HTT levels and AO, the studies were restricted to an extreme patient population and use of this knowledge for therapeutics may still be years away. Nevertheless, a better understanding of the factors that influence HD provides valuable insight for researchers as they continue to search for potential treatments and cures.
- (2) Becanović, Kristina, et al. “A SNP in the HTT promoter alters NF-kB binding and is a bidirectional genetic modifier of Huntington disease.” Nature201: 5
The following is a series of fictional short stories from the perspective of someone with Juvenile Huntington’s Disease. These works do not represent the experience of any one individual, nor do they aim to encompass the entirety of an illness experience such as JHD. Rather, these stories strive to capture and explore themes presented across different JHD and HD experiences through a collection of punctuated narratives. Hopefully, engaging with JHD through storytelling will allow readers to better empathize with, and understand the nature of, the experience of this illness.
It’s the first day of classes and I’m late. I’m running both towards and away from my destination, unable to nail down a sense of direction. Suddenly I arrive, unsure how I managed to find the room. The door swings open to reveal a huge lecture hall full of people. I trip on my way in. Darn it. I look around and see an ocean of faces all trained on me. I don’t recognize any of them, their features blurry and indistinct. Then a few gazes lock with mine and suddenly they are familiar. My high school classmates. I don’t even question their presence at the same college as myself, but instead sit down in a desk immediately in front of me and hurriedly dig out a notebook. When I look up the room has changed and my backpack is gone. I’m at a round table with people I don’t know, blank faces that look somehow identical and radically different from each other. I have a feeling we are waiting for someone, a professor perhaps? When did I sign up for this class anyways? The door opens and someone enters the room. The furniture and people disappear, and I’m standing right in front of the newcomer. She introduces herself and reaches out to give me a hug. Where did everyone else go? Stepping back, I look into her face and see my own eyes staring back at me.
My 5am alarm jolts me awake. Smacking at my phone a few times, I finally manage to hit the snooze button, but it has already done its job. Lying in bed, I attempt to stay in my dream haze as long as possible. I grasp at memories just at the edge of my mind, trying to recall the scene I was pulled out of. A room. A different room. That face.
Nothing, it all slips away. Except for those eyes, the same ones that have been haunting me all week. Big, brown eyes with flecks of gold in them, the same as my own.
Their owner never says a word. She appears, attempts an affectionate gesture, and meets my gaze for just a moment before I am pulled back to reality. I know it makes the most sense to say that this woman is my mother, showing up in my dreams as I prepare to embark on ‘adulthood’. But I have long since adapted to living without her and my high school graduation doesn’t seem like a good enough reason for her sudden presence.
You can’t miss what you never had right?
I rotate onto my back and stare at the ceiling, contemplating the significance of the day — I’m almost free. Graduation day is bittersweet for a lot of people, but I feel only relief at its arrival. Once today is over, only a single summer stands between me and the rest of my life.
As Valedictorian and Athlete of the Year, I am giving a single double-length speech, the two titles usually going to separate individuals. I attempted to turn down the offer to speak, not feeling much excitement about speaking to a group of individuals I was hoping to never see again. However Carley talked me into it and helped me write the speech, so I guess I’ll put on the bunny ears for a day.
Luckily we are both heading off to Duke, her on pure merit, me on running. It’s actually a miracle I pulled off good enough grades to stay Valedictorian and not have my offer rescinded; second semester was tough once the burnout caught up with me and I could not focus in any of my classes. Senioritis is not something I had expected of myself.
All right, I’ve wasted enough time staring at the ceiling, time to get going. I slowly stand up. My body resists the movement, straining at the change in position. I’ve been remarkably stiff in the mornings lately, my muscles tightening almost to the point of pain. Maybe I should stretch more.
Walking to the bathroom, I can hear my aunt and uncle snoring in their room down the hall, their dog Elvis padding towards me to say good morning, and the soft coos of the mourning doves out back. I close my eyes and enjoy the pre-dawn sounds— this has always been my favorite time of day. On autopilot now, I throw on shorts and a sports bra before grabbing my favorite Nikes. In June, even the early mornings are warm enough to build up a sweat, and I remember to throw on sunscreen before chugging some water and heading out the door.
Outside, the horizon is a blooming shade of coral above a still dark landscape, a new day just moments away. I set off at a leisurely pace on my usual path, enjoying the pain in my legs as they work out the tension from the night.
The beginning of this run is flat and bare, a few Joshua trees the only greenery, but I remind myself to stay focused so I don’t lose speed or trip. When I reach the top of a nearby hill, I pause, needing a breather. I gaze out at the now brightly lit view.
Without the pre-dawn shadows to hide behind, I can see the entirety of the town. There is the high school whose fences I have fought for the last four years. There is the single street of downtown where adults go for a night out and kids go to get into trouble. There is my dad’s house, only a few miles away from my aunt and uncle’s.
There is the Old Mill Bridge, crossing 50 feet over a long ago dried-out riverbed— maybe my mom thought there was still water in it to catch her when she jumped. I turn away from the sight and take off down the hill, hoping to put some distance between my thoughts and my body.
Why is she on my mind again?
I need to stop obsessing over someone long gone and buried. For the most part what had happened was thoroughly swept under the rug — or in my dad’s case drowned in gin. But throughout the years rumored mental health problems have been brought up by more than one of my peers. Whatever the reason, at the age of only 20, Denise Thompson took a swan dive that left her husband in a 17-year tailspin and her year-old daughter without a mother.
She was not that much older than me.
Disturbed, I push myself to move faster, but quickly falter. Still panting, I am overcome with exhaustion and have to stop again. Shoot, I need to get back to a normal training schedule; I am getting way out of shape. I have not been able to finish my morning trail at a decent speed in weeks. I need to kick it up a few gears if I am going to be ready for the fall.
I’m still tired but have caught my breath, so I continue the descent at a slow pace, watching the ground to avoid any slipping— my hands are still raw from where the gravel cut my palms last week and my knees have scars from the months before.
Hot and sweaty in my dress and graduation gown, I struggle to keep my cap on against the wind. Everyone is lined up on the soccer field adjacent to the stadium, waiting for the ceremony to begin. A class of only 57, I can recite all of our names in alphabetical order in my sleep. The music finally starts and that is our cue. We walk into the stadium single file, trying to look as though we don’t all have minor heat exhaustion. I arrive at the front row and take my seat next to Carley, resisting the urge to hold her hand. Once everyone is seated, we say the Pledge of Allegiance and someone’s little sister sings the national anthem. Our principal starts the speeches with a few non-specific words about school pride and tradition. The District Superintendent follows him, rambling on for a solid 20 minutes before it is inevitably time for student speakers. Going first is Joey Anderson, the student body president and town’s future mayor to hear him tell it. He stumbles over a few cheesy words about our accomplishments thus far and our impending entry into adulthood before closing with our (only) school cheer.
I know I am next but still futilely hope that I’ll be saved the pain of giving the fluffy, inspirational speech written on my notecards. When the last ‘Go Bulldogs’ has finally faded away, Joey smirks and sarcastically introduces me as the school’s “star student”. No one else seems to pick up on his tone but me— does everyone think he is praising me?
No. The little rat is taunting me. I feel a boiling rage begin to build up inside of me as I stand to walk the few steps to the stage. I want to throw Joey off of it with every fiber of my being, but he returns to his seat before I get to him.
How dare he mock me? Yes, I am the star of this mediocre school and town. And I worked incredibly hard for it. Screw him and everyone else like him in this town— telling me my whole life that I was crazier than my mom, that my plans were nothing but a pipe dream. This town has given me wall after wall to tear down on my way to success and now that I have finally done it, I am being teased as though I’m just some third-grade brownnoser. Not a pat on the back, not an apology for doubting me— for holding me back.
Forget them, I don’t need this.
Standing at the podium, I look out and realize that my face must be betraying my emotions.
Good. They should know how I feel.
The speech Carley and I wrote flies out of my head and I have nothing left to say but the truth. “I have hated the last 17 years here and I hope to never come back. Good-bye and good luck. Actually, just good-bye.”
I stalk off the stage, across the turf, and straight out the main gates, leaving shocked silence behind me. Still fuming, I kick at a trash bin and knock it over, scaring a flock of birds out of a nearby tree. As I watch them fly away, my anger dissipates and all I feel is emptiness.
Arriving back at my aunt and uncle’s, I look around my room unsure what to do.
Should I pack?
No I guess that’s a bit extreme.
But staying is going to be exceptionally miserable now that I have basically flipped off the entire town. I feel a twinge of guilt for my aunt and uncle, who are probably embarrassed after my stunt. They don’t deserve that. They took me in when I had nowhere to go and they’ve always been kind to me, hell they even showed up to a few races. I hear the front door open and cringe at the thought of facing them, but I know it is inevitable.
They knock on my door before entering. Standing there, they look worried, exceptionally so actually. This strikes me as odd, I had anticipated anger.
“Michelle, we need to talk to you,” my aunt says.
Ominous, but expected.
“Yeah okay. Look, I’m sorry about what I did back there, I was angry at Joey and it got me rolling,” I explain.
“That’s okay, we get it. You have some right to be angry— the kid was being petty. But it was just a dumb comment. What made you so mad?” my uncle tentatively asks.
“I mean he was being a jerk. And it’s not fair that he can just get away with that.” I see the look in my Uncle’s eyes and feel guilty; I must have really embarrassed them.
“And okay yeah I guess I overreacted. But I was just so angry— I can’t explain it. I’m… I’m sorry guys.”
“We forgive you,” my aunt responds, “but we’re worried about you.”
Do they think I have anger management problems or something?
“Look, I’m sorry I worried you, but I’m okay. I just got a little angry,” I say in defense.
My aunt looks at my uncle before responding, “Michelle we know, but you seem to get a little angry a whole lot lately.”
“What are you talking about, no I don’t,” I snap.
My uncle steps in now, “What about after that final race earlier this year? You almost bit off your teammates’ heads.”
“My last race? You mean the one where I came in second? Of course I was angry I had a right to be! I shouldn’t have lost,” I say.
Thinking back I remember that day. I had fallen and twisted my ankle. I kept running but didn’t stand a chance at taking State after my mistake. It killed me to lose.
“Alright, what about last month when you couldn’t find your shoes? You tore this room apart,” my aunt says.
“Ugh, okay, maybe I overreacted then. But you know those are my favorites, I thought Elvis had eaten them. Look why are you bringing this up, do you want me to go to anger management classes or something?” I ask.
My aunt glances down, “No Michelle nothing like that, we don’t think it’s your fault… You, you may want to sit down, we need to tell you something.”
All right, this is weird.
“Um okay… what is it?” I ask.
“Well, it’s about your mom…” my uncle answers.
Looking at my aunt, I see something that looks like fear in her eyes. Or maybe it’s grief; she has never been willing to talk about her sister.
Why do they want to talk about my mom?
I can’t help but think about my recent dreams, my obsession with the Old Mill Bridge. Maybe they know about the dreams.
Have I been talking in my sleep?
Hesitantly, I perch myself on the edge of my bed.
“My mom? Um, okay, what do you want to tell me?” I ask.
“Has your dad ever told you what happened?”
“You already know that I know. She died. She jumped off the Old Mill Bridge and killed herself when I was one”, I try to say calmly.
My aunt pushes back on my explanation, “but did he ever tell you why she did it?”
I carefully respond, “No, he didn’t. I thought she went crazy, people have said she was… distressed,” trying to save my aunt’s feelings.
My uncle looks at my aunt and she nods, her eyes glazed over with tears.
Confused, and more than a little afraid, I shoot off a stream of questions, “What the hell is going on? Why are you both acting so weird? What do you want to tell me about my mom?”
My uncle looks at me and says, “I don’t know how to tell you this Michelle, but your mom was sick. That’s… that’s why she jumped off that bridge.”
“Sick?” I ask, “ Like she was insane?”
Are they trying to say she was schizophrenic or something?
What does this have to do with me?
My aunt suddenly jumps back into the conversation, “No, no, she wasn’t insane. Michelle, your mom was diagnosed with early-onset Huntington’s.” She looks visibly ill as she forces the words out.
Surprised I reply, “Huntington’s… I’m sorry what, what is that? Why does that sound familiar?”
“It’s a brain disease, we don’t know that much about it but… it’s fatal” my uncle answers, my aunt too choked up to say anything more.
After a moment I ask, “Wait, so she killed herself because she was going to die anyways? How long did she have left?”
I feel surprised and hurt, old wounds I thought long ago healed opening up. My mom chose to die. I always thought it wasn’t her fault… she had a mental illness or something. She went crazy— you can’t blame someone not in their right mind for their actions, for abandoning their child.
“No, no that wasn’t it. I mean partly yes, but it was the guilt that killed her. Michelle, this disease— it’s genetic,” my uncle responds.
All the blood drains from my face as I realize what they are trying to tell me.
Even my one biology class had taught me enough to realize what that meant. I might get it.
“Why are you telling me this now?” I ask them, not wanting to hear the answer.
My aunt can’t look me in the eye.
My uncle answers, “Because the doc told Denise that there was a 50% chance she passed the gene on to you. We, we always hoped that you wouldn’t get it. That maybe it was a mistake, or that you would beat the odds. But today… well, your mom was angry a lot before she was diagnosed. She… couldn’t control it.”
My aunt finds her voice again and continues, “She got clumsy too. She had been a dancer, but all of a sudden she was tripping over doorways.” Overwhelmed, she buries her head into my uncle’s chest and the floodgates open. But her sobs feel miles away.
My runs. I fall all the time.
No, there is no way.
I realize that my hands will not stay still.
50% chance, that’s a coin flip.
Looking up at my aunt and uncle, I realize that they are horrified at the sight of my shaking hands.
“Please get out,” I say.
My uncle hesitates, but looking at his sobbing wife, decides otherwise and gently guides her out the door. Before he closes it he looks at me and says, “Please talk to us. You can get a test done to check. You might not have it,” trying to infuse his words with hope. They ring hollow.
Quietly, they exit the room. The moment the door shuts, I jump across the room to my old desktop and open up the web browser. I type in “Huntington’s Disease”.
Almost 3 million hits.
The first is the HDSA site — Huntington’s Disease Society of America.
Shoot, this is real.
Reading quickly, I see “fatal genetic disorder,” “deteriorates physical and mental abilities,” and “no cure.”
Do I have this thing? No way. There’s no way.
“Symptoms usually appear between the ages of 30 to 50.”
I’m too young.
Then I see a header “JHD Overview,” followed by a short paragraph. “In approximately 10% of cases, HD affects children or adolescents.”
There’s no way, I have to be too old for that. I’m 17.
Opening a new search bar I type in “Juvenile Huntington’s Disease.” I find a different site.
“20 years or younger.”
Too shocked to move, I stare at the screen. I’m looking for something — anything — that will confirm this isn’t me. I come up empty. Frustrated, I stand up and grab my backpack on my way out. I don’t know where I am going but I need to get away from here. More
Photo Credit to Lucy Walker Film http://www.lucywalkerfilm.com/
Initially Released: 2014
Publicly Available: June 2015
Run length: 28 minutes
“I’ve always felt like I don’t have it”.
This sentence is how Marianna Palka, both subject and producer, begins the new documentary The Lion’s Mouth Opens. This short documentary, directed by Lucy Walker, known for The Waste Land and The Crash Reel, tells Palka’s story of deciding to undergo genetic testing for Huntington’s disease. At just 28 minutes, an expansion from the initial 15-minute version that was premiered at the Sundance Film Festival, The Lion’s Mouth Opens brings viewers into Palka’s circle of friends as they bear witness to her decision to know her HD gene status. The film begins with Palka hosting a dinner party for close friends the night before finding out the results of her genetic testing. As the story continues, viewers are given an insight to Palka’s life, specifically her experience with her father’s HD progression and the impact on her family. The dinner party scenes are interspersed with interviews of Palka, her mother, and Palka’s friend Jason Ritter, as well as home-movies from Palka’s childhood. These scenes seamlessly take readers back and forth between the community space of the dinner party and the painful past of Palka and her mother. The last 10 minutes of the film are dedicated to the hospital visit, and the reactions of Palka and her close friends as they discover her gene status.
As an autosomal dominant disorder, Huntington’s disease in one parent gives every child a 50/50 risk of having the gene mutation that results in HD. Despite this coin-toss statistic, only about 5-10% of those at-risk choose to undergo genetic testing. As one of the few, Palka’s decision to share her genetic testing experience in the form of a documentary is a valuable addition to existing HD literature and film. In her early 30’s and non-symptomatic, Palka expresses disbelief that her gene status is simply a 50% chance. Although the science says the odds are 50/50, for Palka it does not feel that way. The subtlety of this distinction is an important one for clinicians, caregivers, and advocates to consider in regards to genetic testing. For those at-risk, 50/50 is much more than a number, and in no way as simple as the flip of a coin. Palka describes the difference between gene-positive and gene-negative as two completely diverged roads with no middle option. Down one road is a death sentence and down the other is the ability to be “just like everybody else”.
There are many factors that go into an individual’s decision to be genetically tested, including his or her age, family situation, and personal ability to cope with the information. This makes the process of genetic testing a very complicated one, involving multiple appointments as well as counseling. The entire process takes at the very minimum one month, but typically longer. More information on the process of genetic testing can be found here. In addition, issues of confidentiality, discrimination, and the effect on personal relationships are all implicated in an at-risk individual’s decision to discover their HD gene status. As a result, one’s decision to be tested or not is an intensely personal one, and with both options the at-risk individual needs as much support as possible. This level of support is made clear in the dinner scene with Palka and her friends as they share the night and their care with her. During dinner Ritter expresses that, “we’ll all still be here tomorrow and we’ll all still love each other as much as we love each other now.” The Lion’s Mouth Opens shows how difficult it is to go through the process of genetic testing even with an extremely supportive circle of friends and family.
Another theme that The Lion’s Mouth Opens brings up is the nature and implications of Huntington’s disease as a familial disorder. Palka’s father became symptomatic when she was only 8 years old. Palka describes those years of her life as though going from a paradise to hell. Although her father is still alive, he is now a “ghost” of his past self. Palka and her mother describe the disease as cruelly and randomly taking certain members of the family, a genetic “Russian roulette”. For the Palka family, Marianna’s father, sister, and two cousins have all been taken as victims. Towards the end of the film Palka ruminates on the fact that she, her sister, and her cousins — with whom she has shared everything her entire life — may also share this burden of HD. The familial nature of HD often means that there can be multiple symptomatic individuals at one time. This results in an incredible amount of stress and strain on every aspect of a family’s life — emotionally, socially, and financially. Those family members that are early-stage or at risk may be forced to also play the role of caregiver for a late-stage relative. In addition, gene-positive and at-risk individuals must consider decisions around reproduction. Some may already have at-risk children, others may choose to undergo fetal testing, and others may abstain from having children. Reproductive issues and decisions around them are incredibly sensitive and must be addressed with compassion and understanding on the part of family members, friends, and healthcare providers.
A key and intriguing component of The Lion’s Mouth Opens is its title. The phrase comes from a poem titled “Last Thoughts on Woody Guthrie,” written by Bob Dylan for Woodie Guthrie, who died due to complications of Huntington’s Disease and was a long-time inspiration of Dylan’s. The poem itself is about 5-pages long and can be found here. Palka is able to recite the poem verbatim and does so in the film as a series of video clips of individuals affected by HD plays. This moment, about half way through the film, is an emotionally charged one as it brings together visual images of the experience of HD with the powerful lyrics of Dylan’s poem.
This film touches on genetic testing and the familial nature of HD, in addition to several other themes. Despite its range, the film manages to engage deeply with each topic while simultaneously connecting viewers with Palka’s story. Films such as The Lion’s Mouth Opens, which was aired on HBO during HD Awareness Month(June 2015), are essential tools in the continued struggle for widespread HD awareness. Awareness helps decrease discrimination against those affected with HD, and can also help increase research funding for better treatments and hopefully, a cure.
Find Local Resources through the HDSA
Information on Genetic Testing
Resources for youth affected by HD
CJE 07/16/2015 More
Length: 88 pages
This handbook, written by Dr. Martha Nance and published by the Huntington’s Disease Society of America, is a comprehensive overview of the typical issues faced by caregivers of those at-risk for or with Juvenile Huntington’s disease (JHD). A total of eight chapters, the book goes through the progression of care for everything from before the diagnosis of a child to end-of-life care.
Chapters One and Two begin with a description of the process of diagnosis of a child with JHD, which is typically longer for children than adults due to variation in symptom presentation as well as ethical barriers to genetic testing in minors. The authors also provide advice and guidelines for caregivers to use as they begin assembling a team of health care professionals for their child’s care. Chapter Three is an overview of medical care, including what to expect with regards to the behavioral, cognitive, and movement components of the disease as it progresses. Chapter Four provides considerations for daily life of someone with JHD such as school, meals, transportation, and hygiene. Chapter 5 explains how the later stages of the disease will affect both the patient and caregiver(s) and provides a functional scale for assessing JHD using school attendance, academic/developmental performance, chores, activities of daily living, and living situation as metrics.
A major challenge for many JHD families is navigating and accessing the financial, legal, and social services needed in order to care for someone with JHD. Chapter 6 provides an introduction to these issues and information on relevant resources, including planning for disease progression, Supplementary Security Income (SSI), Medicaid, and disability. Chapter 7 proceeds with a discussion about the importance of caring for caregivers, including parents, professionals, and siblings. The final chapter offers hope on research efforts being made as well as a realistic explanation of the research pipeline.
This book offers guidance in all of the above topics as well as an extensive appendix of different resources for JHD families, including HDSA Centers of Excellence, legal resources, publications, and other HD organizations.
Available through the HDSA website here.
CJE 7/6/2015 More
An update to the review of “Understanding Behavior in Huntington’s Disease” by Jane S. Paulsen (1999)
Length: 66 pages
This book, written for health care professionals caring for those affected by Huntington’s Disease(HD), is an update on Paulsen’s first book “Understanding Behavior in Huntington’s Disease” published in 1999. A review on the earlier edition of this text can be found here. Since the first publication, much has been learned about the physiological and behavioral aspects of HD. One major research update is on individuals at-risk for, but not yet diagnosed with, HD. In the last 15 years, studies of this group of pre-diagnosis (also referred to as preclinical or prodromal) individuals have resulted in a better understanding of how early stages of the disease affect behavior. More information about the stages of HD can be found here.
Within this book the authors provide an overview of HD, including genetics, neurodegeneration, and the stages of HD — from those at-risk to post-diagnostic stages. In Chapter 3, the authors detail common behavioral issues of those with HD. Topics covered include: communication, learning and memory, perception, executive functions, depression, suicide, anxiety, psychosis, sexuality, and sleep disturbances. For each behavioral concern, the authors provide an explanation of how the behavior may be altered in those with HD as well as hypothetical examples of how this behavior may manifest in different patients. In addition, the authors provide common medical treatments as well as an extensive list of behavioral strategies for caregivers to consider implementing at home. The book also provides considerations for other factors that could influence behavior, such as underlying medical conditions, fatigue, or grief. The authors close with a general 7-step approach to working with HD-related behavioral problems.
Overall, this book serves as a good resource for physicians making recommendations to caregivers and patients, as well as for caregivers, who are typically the first to identify behavioral issues. In addition, the focus on behavioral interventions, as opposed to medications, makes this a more readily usable resource for caregivers.
This publication is available through the Huntington’s Disease Society of America’s website here.
CJE 6/30/2015 More
I stand at the starting line alongside the other competitors, stretching and jogging in place, contemplating the race ahead. Just shy of six miles long, the course winds through the desert relentlessly, pulling runners further into the heat until every ounce of moisture is drawn from their bodies. This is easily one of the most difficult runs in the area, but I am always ready for a challenge. Past successes confirm my knowledge that I am stronger than everyone else.
Out here in the middle of nowhere it is easy to get lost. The trail we will follow, lined with mismatched rocks of various shades of reddish-brown, offers no comfort or guidance in the face of this lifeless climate. Without obvious landmarks or pretty scenery to keep one company, runners have to rely on the fortitude of their minds to push through.
In spite of the bleak road ahead, or perhaps because of it, I am excited. This stretch of land off of Highway 62 is familiar to me and I thrive in the heat in a way that my coastal counterparts can not. When you say “Southern California,” most will immediately conjure up images of the beach and palm trees, 70-degree weather, and vibrant cities full of beautiful and interesting people. That is not the case for my small town. Here, the drought is old news and most people live lives about as full as the reservoirs. But I have hardened myself against the harsh conditions of such monotony and after suffering through this place for years, I anticipate a landslide win in my territory.
My thoughts continue to wander and, willingly or not, I land on my favorite topic—Carley. I secretly hope that she will make it from work in time to see the race, though I would never consider asking her to come. Thankfully, despite my stubbornness, she always knows when I need her and shows up anyways. Carley is the one distraction I appreciate and winning feels better when she is there to see it.
I have often wondered if it is wise to allow myself to care so strongly for her, but despite efforts over the years, I have never been able to distance myself. We both have college dreams and are well on-track to achieve them — I run fast and she is the smartest person I know. But I constantly worry that I will be forced to choose between her and my dreams. If we are split up, or God forbid one of us ends up stuck here, long-distance is definitely not an option.
Shaking off my anxieties about the future, I try to refocus. I need to stop letting myself be so easily distracted, especially during races. Senior year is my last chance at recruitment and I need to dominate. I take a deep breath of dry desert air, clear my head, and ease into my pre-race routine.
Preparing myself, I block out the rest of my thoughts and focus on the race specifics. Seeing the twists and turns of the path in my mind, I make a plan for the run. First, a smooth and strong takeoff, launching into the race with perfect form. Then I will settle into a comfortable speed at about 6th or 7th place for the following four miles. At around the two-third mark I’ll kick it up a gear and move ahead a few spots. Finally, in the last stretch of the race, I’ll take the lead and win by a solid 50 to 100 meters. It’s the perfect formula for victory.
With a couple of minutes to go, I systematically begin flexing and relaxing my muscles in preparation. The temperature makes loosening up easier, but I still have some trouble shaking out my calves— a chronic issue that my coach claims is due to not weight training enough. Since I am the strongest runner as well as team captain, he feels the need to give me advice, warranted or not. I have never exactly trusted his judgment though, given his status as a mediocre former athlete and my old man’s long-time drinking buddy. When neither of them made an appearance this morning, one not invited and the other abandoning his coaching responsibilities, I was forced to organize the carpool and bring all the food and drinks for the rest of the team. I suppose I shouldn’t be shocked at the incompetency of someone put in charge of minors — after all I lived with it for about a decade with dear old dad.
Darn it, my mind is wandering again. But I can’t help being bothered by the whole situation. Although I care for my team, I am frustrated by anything that pulls my attention away from my own needs, my own race. I can’t afford to be distracted.
I know I will win. I see the course in my mind again and am certain. Victory is not a question but an expectation. Not just because I know I am better than everyone else, but rather because I have to win. Barring death, few ever leave our town. Caught up in young marriages or family-owned businesses, there is never any encouragement to work for better, to hope for more.
People tell me my mom was smart, I wonder if she ever had an escape plan. I guess even if she did it was foiled by her pregnancy with me. My plan is to make a run for it, literally. Victory is a standard I have set for myself ever since I realized that running could be my ticket out. The goal is an elite Division I school. A place where I can take advantage of the countless opportunities that will be laid out for me in a neat little row, one after the other.
The gun goes off.
I am embarrassed beyond belief but hastily regain my footing and launch into the first phase of the run. What the hell just happened? I’m not concentrating and it ruined my start. A rookie mistake, I need to do better.
I steady my breathing and lengthen my stride, working to make up the lost ground. After a few minutes I find 6th position and resist the urge to take the lead of the pack in retaliation for my earlier blunder. Instead, I find a comfortable pace that will keep me poised to overtake those ahead of me while simultaneously conserving energy. Self-control is the key to my wins. Even in a pre-season training race such as this one, I never stray from my mantra.
Start slow and steady.
Beat ‘em to the finish line.
I always find a certain sort of pleasure in that final surprise. As I run, alert for anyone creeping up behind me, I visualize myself pulling up to the front of the pack, still calm and breathing steadily, perfectly in control. Feeling me on their heels, others will quickly lose morale and I know that I have won.
The desert passes by unremarkably for the next couple of miles, the pounding of my feet and the sound of my breath all I can hear, the puffs of dirt with every step all I can see. My mind is the clear, still surface of a seemingly endless lake and I feel strong.
About three miles in I wobble and almost fall, a rut in the dirt my feet do not react quickly enough to. I lose no time but my meditation is broken, and the slight error strikes me as odd. I typically respond to the irregularities of the dirt path reflexively, without thought. I am not paying attention again. I must be letting myself become too relaxed.
Focus, focus, focus.
My ability to command my body to continue, to push further despite the screaming of every muscle fiber, is my greatest pride— complete self-control.
My father used to tell me that the key to success in life is power. “Powerful people can have what they want, do what they want, control their own destiny.” I now know this for what it was: the angry rants of an unemployed alcoholic with absolutely no authority over anyone or anything. However, there is a certain truth to the old fool’s words, and I value my power over myself extremely highly.
Almost five miles in now. I am still towards the front of the group, hovering just behind the current leaders and feeling strong. My shoulder feels weird though, stiff and sore as though I had slept in an odd position. I try to rub the ache out.
The final stretch is my favorite part of a race. Most runners feel a rush of exhilaration as the finish line approaches, but I feel a rush of almost inhuman energy. My body filled to the brim, I feel as though I have been given a good scare and all of my basic instincts are yelling, “run!”
I throw myself forward, ready to strike everyone in that last half-mile. I at my strongest, they at their weakest. I pass a few runners, briefly indulging in the looks of exasperation that flash across their faces before I move onwards. About a minute later though, with just over a quarter-mile left, something odd happens— I can feel my legs weakening. Suddenly, they feel as though they are made of lead, drained of all the power they contained only a moment ago. Despite my best efforts, I cannot will them to run any faster and I know I am falling behind. Looking forward, I see that there are still two runners ahead of me and not enough dirt left. Steeling my mind, I practically scream in my attempt to catch up and manage to pass one of them, but seconds later the other cruises across the finish, a full 10 seconds ahead of me.
The spectators are cheering as my teammates pat me on the back, saying how great I ran and that I had State in the bag this year. I’m not listening to any of them. I look down at my legs and they shake, as though the shear effort of holding me up is too much for them anymore. The post-race exhaustion hits me like a wave. Usually a bearable feeling, this is much worse than anything else I have ever endured. It is the sensation of all my dreams crashing around me, pushing me down into the dry desert ground. I stare at the earth as though I am afraid it will swallow me whole. Looking up I see people cheering, including Carley, who managed to make it to the end of the race. She looks at me with concern, but I find no comfort in her gaze. Slowly, I sink to the floor and grab my ankles, too drained to move any further. I ran my race and I lost.
Why did my body disobey me?
Something is wrong.
My usually infallible confidence fails me and suddenly I am afraid.
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