Review: Inside the O’Briens – Lisa Genova

By Lakshini Mendis

This review first appeared in the Scientista Foundation blog

In her new novel, Inside the O’Briens, the New York Times best-selling author of Still Alice, Lisa Genova, presents a moving portrayal about a family struggling with Huntington’s disease (HD).
HD is caused by a faulty gene that leads to the progressive breakdown of brain cells, which results in its hallmark symptom, chorea (uncontrollable dance-like movements). It is known as a ‘family disease’ because every child of a parent with HD has a 50/50 chance of carrying the faulty gene. About one in every 10,000 people has HD, but one in every 1,000 is touched by the disorder, whether they are at-risk of inheriting it, a caregiver, family member or friend. Currently there are about 900 families  affected in Auckland.

The story centres on the O’Briens – Joe O’Brien, his wife, Rosie, and their four grown children, JJ, Patrick, Meghan, and Katie – who live in Charlestown, MA. The O’Briens are just another normal family, sibling rivalries and all, which make them very relatable. The difference is that Joe has HD. We follow Joe from his earliest symptoms, to his diagnosis, and get an insight into what living with HD is like. We see how it affects his job in the Boston PD, and the ramifications (both positive and negative) his diagnosis has on his family.
Given that the faulty gene causing HD was found in 1993, ‘at-risk’ individuals can now choose to find out their gene status by taking a genetic test. We see the O’Brien kids, especially Katie, the baby of the family, grappling with this complex choice. It is not a decision that many of us have to consider in our early 20s, but Genova raises and explores some poignant considerations. Is the constant anxiety of not knowing better than being confirmed gene-positive? What happens if you are gene-positive? Do you choose to marry and start a family, given the risk of passing on the gene to your own kids?
Genova, who holds a PhD in Neuroscience from Harvard, effortlessly educates her audience about the science and genetics behind HD, without the complexities of a clinical textbook. It is one of the reasons I love this book.
The other reason I found this book a riveting read is testament to Genova’s storytelling capabilities. Genova really captures the human essence of being a part of an HD family, and gives us a window into what this feels like. The O’Briens were so compelling… so real! I found myself worrying with the O’Briens, crying with the O’Briens, feeling their pain and going on the same journey with them. I’m sure their story will resonate with many HD families across the world. However, because at its core, this story is about family, resilience, and love, it is relevant to all of us. I highly recommend it for your winter reading!
“Every breath is a risk. Love is why we breathe.”
— Katie O’Brien, Inside the O’Briens

May is Huntington’s disease awareness month… educate yourself here:
Huntington’s Disease Association (Auckland) Inc:
Provides support for those living with HD in Auckland, by educating the community, providing the right support services, and furthering research to manage and cure HD
HDYO: the Huntington’s disease Youth Organization site has tons of information about the disease and resources to help those with juvenile HD or with a parent who has HD (HDYO NZ is currently being set-up and could use your support!)
HDBuzz: Co-founded by Dr Ed Wild and Dr Jeff Carroll, this site reports the latest Huntington’s disease research news, without the jargon

About the Author

LakshiniScientista’s co-Editor-in-Chief, Lakshini Mendis, is doing a PhD focused on how the human brain changes in Alzheimer’s disease at the Centre for Brain Research in Auckland. She is passionate about good science communication and changing the stereotype of women in STEM. She also writes for HDBuzz. When she’s not working, you can usually find Lakshini curled up with a good book, spending time with family and friends, or exploring somewhere new. Find her musings on Twitter here!

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New Zealand’s top Huntington’s disease researchers to speak at national conference

New Zealand’s foremost Huntington’s Disease (HD) research and clinical experts will speak at the national associations’ conference in Auckland on Saturday 18 and Sunday 19 May.

The speaker line-up includes New Zealand’s top neuroscientist Distinguished Professor Richard Faull, an internationally recognised expert on neurodegenerative diseases of the human brain. Professor Faull is the Director of The University of Auckland’s Centre for Brain Research which has had an established HD research programme since 1981. Professor Faull’s presentation is titled Huntington’s Disease – Exciting Human Brain Research with Family Support. Fellow University of Auckland researcher Professor Russell Snell, a member of the global team that discovered the HD gene in 1993, will provide an overview of learnings about HD from a genetics perspective.

Neurologist and HD clinical specialist Dr Richard Roxburgh will discuss the progress of an international clinical trial called CREST E* which is in phase 3 and involves 650 participants from around the world. Neuropsychiatrist and fellow clinical specialist Dr Greg Finucane will outline drug therapies in his lecture titled Calming the Stormy Seas. Patient service and care updates will be provided by national Huntington’s Disease Association staff, and all presentations within the two-day speaker programme are designed for the general public to understand.

Professor Faull, who is patron of Huntington’s Disease Association Auckland, says “The conference will be an opportunity for patients, families and medical professionals to learn about new global and local research and the latest developments in prospective treatments. It will also be a unique opportunity for the HD community to share knowledge and learn from the experience of others. This will be a very special meeting of those who share the ultimate goal of improving patients’ lives and ending Huntington’s Disease. “

For further details about the conference and to register, please phone: (09) 815 9703 or email conference2013@hdauckland.org.nz 

The conference will be held at the Waipuna Hotel and Conference Centre in Auckland and is supported by the Centre for Brain Research, the Neurological Foundation of New Zealand, and the Lion Foundation.

 

 

Symptoms in genetic brain disease are reflected in brain cell loss

Scientists have wrestled to understand why Huntington’s disease, which is caused by a single gene mutation, can produce such variable symptoms.

An authoritative review by a group of leading experts summarizes the progress relating cell loss in the striatum and cerebral cortex to symptom profile in Huntington’s disease, suggesting a possible direction for developing targeted therapies. The article is published in the latest issue of the Journal of Huntington’s Disease.

Huntington’s disease (HD) is an inherited progressive neurological disorder for which there is presently no cure. It is caused by a dominant mutation in the HD gene leading to expression of mutant huntingtin (HTT) protein. Expression of mutant HTT causes subtle changes in cellular functions, which ultimately results in jerking, uncontrollable movements, progressive psychiatric difficulties, and loss of mental abilities.

Although it is caused by a single gene, there are major variations in the symptoms of HD. The pattern of symptoms shown by each individual during the course of the disease can differ considerably and present as varying degrees of movement disturbances, cognitive decline, and mood and behavioral changes. Disease duration is typically between ten and twenty years.

 Recent investigations have focused on what the presence of the defective gene does to various structures in the brain and understanding the relationship between changes in the brain and the variability in symptom profiles in Huntington’s disease.

 Analyses of post-mortem human HD tissue from the Human Brain Bank suggest that the variation in clinical symptoms in HD is strongly associated with the variable pattern of neurodegeneration in two major regions of the brain, the striatum and the cerebral cortex. The neurodegeneration of the striatum generally follows an ordered and topographical distribution, but comparison of post-mortem human HD tissue and in vivo neuroimaging techniques reveal that the disease produces a striking bilateral atrophy of the striatum, which in these recent studies has been found to be highly variable.

 “What is especially interesting is that recent findings suggest that the pattern of striatal cell death shows regional differences between cases in the functionally and neurochemically distinct striosomal and matrix compartments of the striatum which correspond with symptom variation,” says author Professor Richard Faull, Director of the Centre for Brain Research, University of Auckland.

 “Our own recent detailed quantitative study using stereological cell counting in the post-mortem human HD cortex has complemented and expanded the neuroimaging studies by providing a cortical cellular basis of symptom heterogeneity in HD,” continues Dr Faull. “In particular, HD cases which were dominated by motor dysfunction showed a major total cell loss (28% loss) in the primary motor cortex but no cell loss in the limbic cingulate cortex, whereas cases where mood symptoms predominated showed a total of 54% neuronal loss in the limbic cingulate cortex but no cell loss in the motor cortex. This suggests that the variable neuronal loss and alterations in the circuitry of the primary motor cortex and anterior cingulate cortex associated with the variable compartmental pattern of cell degeneration in the striatum contribute to the differential impairments of motor and mood functions in HD.”

The authors including Dr Henry Waldvogel note that there are still questions to be answered in the field of HD pathology, such as, how and when pathological neuronal loss occurs; whether the progressive loss of neurons in the striatum is the primary process or is consequential to cortical cell dysfunction; and how these changes relate to symptom profiles.

Professor Faull adds; “What is clear however is that the diverse symptoms of HD patients appear to relate to the heterogeneity of cell loss in both the striatum and cerebral cortex,” the authors conclude. “While there is currently no cure, this contemporary evidence suggests that possible genetic therapies aimed at HD gene silencing should be directed towards intervention at both the cerebral cortex and the striatum in the human brain. This poses challenging problems requiring the application of gene silencing therapies to quite widespread regions of the forebrain which may be assisted via CSF delivery systems using gene suppression agents that cross the CSF/brain barrier.”

CBR scientists boosted with support from AMRF

The Auckland Medical Research Foundation has announced its latest round of grants, with several innovative projects funded in the Centre for Brain Research. The research will help to develop new treatments for Huntington’s disease, obesity, visual defects, and hearing loss.

THE SYNAPTIC BASIS OF HUNTINGTON’S DISEASE
– $141,154
Dr Johanna Montgomery, Dr Ailsa McGregor Dept of Physiology & Centre for Brain Research, The University of Auckland

All neurodegenerative diseases have direct or indirect effects on synapses in the brain. Therefore a major step towards understanding what goes wrong in the diseased brain is to understand how synapse function is altered by disease. In this proposal we seek to determine the source of synapse dysfunction in Huntington’s Disease (HD). Previous work on HD mouse models has shown that receptors on the surface of neurons are mis-localised, inducing changes in synapse function. Here we will focus on two synaptic proteins, bSAP97 and aSAP97, which we have recently shown can control the distribution of receptors on neurons (Li et al., 2011, J. Physiology 589, 4491-4510). We will utilise a cellular and an animal model of HD to determine whether changing the expression levels of bSAP97 or aSAP97 can rescue normal receptor distribution, and whether this subsequently rescues normal synapse function. These cellular data will identify whether a and/or bSAP97 are part of the pathological signature for HD and also whether they could be potential therapeutic targets.

THE EFFECT OF NEONATAL HYPOGLYCAEMIA ON VISUAL DEVELOPMENT
– $97,250 Mr Nabin Paudel
Dept of Optometry & Vision Sciences, The University of Auckland

Newborn babies commonly experience low blood sugar, a condition known as neonatal hypoglycaemia.  As glucose is the brain’s main energy source, this condition may impair neurological function, however, at present, very little is known about the effect of neonatal hypoglycaemia on brain development.  As a consequence, the level of neonatal hypoglycaemia that requires treatment in early infancy is currently unknown.  This PhD project forms part of a large multidisciplinary study known as the Children with Hypoglycemia and their Later Development (the CHYLD study) which aims to assess the developmental effects of neonatal hypoglycaemia in a cohort of 500 children whose blood glucose levels were measured continuously for several days after birth.  The aim of this specific project is to assess visual function in these children at the ages of 2 and 4.5 years.  Vision is of particular interest as neonatal hypoglycaemia may preferentially affect visual brain areas.  The assessments include a range of vision tests targeting specific regions of the visual cortex and will therefore provide new insights into the effect of neonatal hypoglycaemia on the rate and extent of visual cortex development.  The study will also provide important information regarding the treatment and management of hypoglycaemia in newborns.

MELANOCORTIN TREATMENT FOR OBESITY
– $166,636
Dr Kathy Mountjoy, Dr Ailsa McGregor Dept of Physiology, The University of Auckland

Stress, weight gain and glucose metabolism are influenced by a group of hormones called melanocortin peptides. These peptides comprise chains of amino acids, of varying length, and are derived from one large precursor protein found in the brain and pituitary gland, called proopiomelanocortin (POMC). Special enzymes chop-up POMC to form the melanocortin peptides, according to the body’s requirement. We have developed a mouse that lacks a particular 13 amino acid melanocortin peptide called adrenocorticotropic hormone (ACTH1-13). These mice can be used to study what effects of ACTH1-13 on physiological function. The mice appear normal until they reach puberty and then they develop obesity, but not diabetes. Treatment of these obese mice with ACTH1-13 or a natural variant that is slightly chemically altered, called -melanocyte stimulating hormone (-MSH), reduced mouse body weight and fat mass when mice were fed a normal diet. In light of the worldwide obesogenic environment, we will now test whether obesity and diabetes in these mice is exacerbated by a feeding a high-fat diet, and whether melanocortin hormone treatment can reverse obesity while animals feed on a high-fat diet. These studies should aid the development of improved tests and treatments for obesity and type 2 diabetes.

OTOPROTECTION BY ADENOSINE RECEPTORS
– $146,752 Dr Srdjan Vlajkovic, Prof Peter Thorne, Dr Detlev Boison, Prof Gary Housley
Dept of Physiology, The University of Auckland

Hearing loss affects 10-13% of New Zealanders and this prevalence will increase with the aging population. Exposure to noise and drugs toxic to the inner ear are major contributing factors to this disability. Prosthetic rehabilitation via hearing aids and cochlear implants is the only current treatment for hearing loss. Hence, it is essential to develop therapies that can ameliorate or repair injury to the delicate structures of the inner ear. We have shown that hearing loss in experimental animals exposed to traumatic noise can be substantially restored by administration of drugs acting on adenosine receptors. Here we propose a set of studies that will utilize transgenic mice that lack genes for the two main types of adenosine receptors found in the inner ear to assess their responses to aging, noise stress and drug toxicity. This is critical translational research for therapeutic management of noise, age and drug-induced hearing loss.

Genetic research hits the global headlines

Research from the CBR has made the international news with advances in genetic therapies.

The transgenic Huntington’s sheep developed by Professors Richard Faull and Russell Snell has been featured in the prestigious magazine Scientific American. The article highlights how the sheep model was developed over many years of painstaking research, supported by the Freemasons of New Zealand.

Now 5 years on, the sheep is being used to study Huntington’s disease, which causes devastating movement and psychological symptoms which get worse as patients age. The sheep will hopefully be used to develop new drugs for this debilitating disease. The article can be viewed here.

Research into another genetic disease, Canavan disease, has also been published in the top-class journal Science Translational Medicine. The gene therapy breakthrough was developed by Associate Professor Debbie Young and Professor Matt During’s team, who research viral vectors as a way to alter disease progression in humans.

Canavan disease is a rare hereditary disorder which affects children, causing their entire nervous system to stop working. Long-term follow-up after the gene therapy has shown that patients had less seizures and slower brain shrinkage. The exciting research may mean that the children have better health as they grow up.

These important clinical developments both came about through painstaking preclinical research, and highlight just how important support for basic research is. You can read more about the need for basic research here.