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Background Huntington’s disease (HD) is a rare, neurodegenerative disease and its complex motor, cognitive and psychiatric symptoms exert a lifelong clinical burden on both patients and their families. Objective To describe the clinical burden and natural history of HD. Methods This longitudinal cohort study used data from the linked Swedish national registries to describe the occurrence of comorbidities (acute and chronic), symptomatic treatments and mortality in an incident cohort of individuals who either received the first diagnosis of HD above (adult onset HD; AoHD) or below (juvenile-onset HD; JoHD) 20 years of age, compared with a matched cohort without HD from the general population. Disease burden of all individuals alive in Sweden was described during a single calendar year (2018), including the occurrence of key symptoms, treatments and hospitalizations. Results The prevalence of HD in 2018 was approximately 10.2 per 100,000. Of 1492 individuals with a diagnosis of HD during 2002 and 2018, 1447 had AoHD and 45 had JoHD. Individuals with AoHD suffered a higher incidence of obsessive–compulsive disorder, acute psychotic episodes, pneumonia, constipation and fractures compared with matched controls. Individuals with JoHD had higher incidence rates of epilepsy, constipation and acute respiratory symptoms. Median time to all-cause mortality in AoHD was 12.1 years from diagnosis. Patients alive with HD in Sweden in 2018 displayed a pattern of increased clinical burden for a number of years since diagnosis. Conclusions This study demonstrates the significant and progressive clinical burden in individuals with HD and presents novel insights into the natural history of JoHD.

Huntington's disease (HD) is an inherited neurodegenerative disease with motor, cognitive and psychiatric symptoms. Non-motor symptoms like depression and altered social cognition are proposed to be caused by dysfunction of the hypothalamus. We measured the hypothalamic neuropeptide oxytocin in plasma and cerebrospinal fluid (CSF) in a cohort of HD gene expansion carriers (HDGECs), compared the levels to healthy HD family controls and correlated oxytocin levels to disease progression and social cognition.We recruited 113 HDGECs and 33 controls. Psychiatric and cognitive symptoms were evaluated, and social cognition was assessed with the Emotion Hexagon test, Reading the Mind in the Eyes and The Awareness of Social Inference Test. The levels of oxytocin in CSF and blood were analyzed by radioimmunoassay.We found the level of oxytocin in CSF to be significantly lower by 33.5% in HDGECs compared to controls (p = 0.016). When dividing the HDGECs into groups with or without cognitive impairment, we found the oxytocin level to be significantly lower by 30.3% in the HDGECs with cognitive symptoms (p = 0.046). We found a statistically significant correlation between the level of oxytocin and scores on social cognition (Reading the Mind in the Eyes p = 0.0019; Emotion Hexagon test: p = 0.0062; The Awareness of Social Inference Test: p = 0.002).This is the first study to measure oxytocin in the CSF of HDGECs. We find that HDGECs have a significantly lower level of oxytocin compared to controls, and that the level of oxytocin may represent an objective and comparable measure that could be used as a state biomarker for impairment of social cognition. We suggest treatment trials to evaluate a potential effect of oxytocin on social cognition in HD.

Huntington’s disease is a fatal neurodegenerative disorder caused by an expanded CAG triplet repeat in the huntingtin (HTT) gene. Previous research focused on neuropathology in the striatum and its association with a typical movement disorder. Direct effects of mutant HTT (mHTT) in the striatum may cause neuropathology, although non-cell autonomous effects have also been suggested. Important non-motor features of HD include psychiatric symptoms and metabolic dysfunction, which may be linked to hypothalamic neuropathology. As hypothalamic neurons project to the ventral striatum, we hypothesized that expression of mHTT in the hypothalamus leads to disrupted neurotransmission in the ventral striatum and causes pathology. The overall aim of this study was to investigate the impact of mHTT expression in the hypothalamus on ventral striatal neuropathology and its contribution to non-HD motor symptoms. We demonstrate that selective expression of mHTT in the hypothalamus leads to the loss of dopamine and cAMP-regulated phosphoprotein (DARPP-32) immunopositive neurons in the ventral striatum in mice. Contrary to the effects of direct expression of mHTT in the hypothalamus, selective overexpression of mHTT in the ventral striatum does not affect body weight. Selective expression of mHTT in the ventral striatum leads to mHTT inclusion formation and loss of DARPP-32 neurons without affecting motor activity or anxiety-like behavior. We show that DARPP-32 neuron loss in the ventral striatum is recapitulated in the R6/2 mouse model of HD. Chemogenetic activation of hypothalamic neurons projecting to the ventral striatum had a blunted response in the R6/2 mice compared to wild-type mice, indicating a disrupted hypothalamus-ventral striatal circuitry. In summary, the expression of mHTT in the hypothalamus may impact the development of ventral striatal pathology in mice. This opens the possibility that non-cell-autonomous effects in the reward circuitry play a role in HD.

Aims: To determine the underlying cellular changes and clinical correlates associated with pathology of the hypothalamus in amyotrophic lateral sclerosis (ALS), as hypothalamic atrophy occurs in the preclinical phase of the disease. Methods: The hypothalamus was pathologically examined in nine patients with amyotrophic lateral sclerosis in comparison to eight healthy control subjects. The severity of regional atrophy (paraventricular nucleus: PVN, fornix and total hypothalamus) and peptidergic neuronal loss (oxytocin, vasopressin, cocaine- and amphetamine-regulating transcript: CART, and orexin) was correlated with changes in eating behaviour, sleep function, cognition, behaviour and disease progression. Results: Tar DNA-binding protein 43 (TDP-43) inclusions were present in the hypothalamus of all patients with amyotrophic lateral sclerosis. When compared to controls, there was atrophy of the hypothalamus (average 21% atrophy, p = 0.004), PVN (average 30% atrophy p = 0.014) and a loss of paraventricular oxytocin-producing neurons (average 49% loss p = 0.02) and lateral hypothalamic orexin-producing neurons (average 37% loss, significance p = 0.02). Factor analysis identified strong relationships between abnormal eating behaviour, hypothalamic atrophy and loss of orexin-producing neurons. With increasing disease progression, abnormal sleep behaviour and cognition associated with atrophy of the fornix. Conclusions: Substantial loss of hypothalamic oxytocin-producing neurons occurs in ALS, with regional atrophy and the loss of orexin neurons relating to abnormal eating behaviour in ALS. Oxytocin- and orexin neurons display TDP43 inclusions. Our study points to significant pathology in the hypothalamus that may play a key role in metabolic and pathogenic changes in ALS. (Less)

Aims Huntington disease (HD) is a fatal neurodegenerative disorder with no disease‐modifying treatments approved so far. Ongoing clinical trials are attempting to reduce huntingtin (HTT) expression in the central nervous system (CNS) using different strategies. Yet, the distribution and timing of HTT‐lowering therapies required for a beneficial clinical effect is less clear. Here, we investigated whether HD‐related behaviours could be prevented by inactivating mutant HTT at different disease stages and to varying degrees in an experimental model. Methods We generated mutant BACHD mice with either a widespread or circuit‐specific inactivation of mutant HTT by using Cre recombinase (Cre) under the nestin promoter or the adenosine A2A receptor promoter respectively. We also simulated a clinical gene therapy scenario with allele‐specific HTT targeting by injections of recombinant adeno‐associated viral (rAAV) vectors expressing Cre into the striatum of adult BACHD mice. All mice were assessed using behavioural tests to investigate motor, metabolic and psychiatric outcome measures at 4–6 months of age. Results While motor deficits, body weight changes, anxiety and depressive‐like behaviours are present in BACHD mice, early widespread CNS inactivation during development significantly improves rotarod performance, body weight changes and depressive‐like behaviour. However, conditional circuit‐wide mutant HTT deletion from the indirect striatal pathway during development and focal striatal‐specific deletion in adulthood failed to rescue any of the HD‐related behaviours. Conclusions Our results indicate that widespread targeting and the timing of interventions aimed at reducing mutant HTT are important factors to consider when developing disease‐modifying therapies for HD., Although ongoing Huntington disease clinical trials are attempting to reduce huntingtin (HTT) expression in the central nervous system using different strategies, the distribution and timing of HTT‐lowering therapies required for a beneficial clinical effect is less clear. Here, we investigated whether HD‐related behaviours could be prevented by inactivating mutant HTT at different disease stages and to varying degrees in an experimental model. Our results indicate that widespread targeting and the timing of interventions aimed at reducing mutant HTT are important factors to consider when developing disease‐modifying therapies for HD.

Patients with Lynch syndrome (LS) are prone to cancer due to heterozygous germline pathogenic variants in genes encoding DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. LS cancer cells exhibit deficient DNA mismatch repair and microsatellite instability due somatic inactivation of the second copy of the affected gene. To study microsatellite characteristics in non-neoplastic cells in LS we determined CAG repeat size in the huntingtin gene (HTT) microsatellite in lymphocyte DNA from LS patients with germline pathogenic variants in MLH1 (n = 11), MSH2 (n = 9), MSH6 (n = 7) and non-LS controls (n=19). Mean repeat size in LS was 19,55 CAG (MLH1), 19,39 CAG (MSH2), 18.07 CAG (MSH6), respectively compared to 18,42 CAG in controls. Standard deviation for CAG repeat size in LS was 4,183 CAG (MLH1), 5,089 CAG (MSH2), 3,075 CAG (MSH6), respectively, compared to 3,342 CAG in controls. Peak CAG repeat size in LS was 32 CAG (MLH1), 32 CAG (MSH2), 24 CAG (MSH6), respectively compared to 27 CAG in controls. Collectively, our data indicate that HTT CAG repeat size tends to be larger and more variable in individuals with LS caused by pathogenic variants in MLH1 and MSH2.

Context White matter lesions (WML) are caused by obstruction of small cerebral vessels associated with stroke risk. Craniopharyngioma (CP) patients suffer from increased cerebrovascular mortality. Objective To investigate the effect of reduced HT volume and cranial radiotherapy (CRT) on WML in childhood‐onset CP patients. Design A cross‐sectional study of 41 patients (24 women) surgically treated childhood‐onset CP in comparison to controls. Setting The South Medical Region of Sweden (2.5 million inhabitants). Methods With magnetic resonance imaging (MRI), we analysed qualitative measurement of WML based on the visual rating scale of Fazekas and quantitative automated segmentation of WML lesion. Also, measurement HT volume and of cardiovascular risk factors were analysed. Results Patients had a significant increase in WML volume (mL) (P = .001) compared to controls. Treatment with cranial radiotherapy (CRT) vs no CRT was associated with increased WML volume (P = .02) as well as higher Fazekas score (P = .001). WML volume increased with years after CRT (r = 0.39; P = .02), even after adjustment for fat mass and age. A reduced HT volume was associated with increased WML volume (r = −0.61, P

Background Skeletal muscle atrophy is one of the hallmarks of Huntington’s disease (HD), and it correlates with inflammation, mitochondrial dysfunction, and altered energy metabolism. Although improvement in muscle wasting has been shown to slow disease progression and increase life span in animal models, the precise mechanism of overall muscle wasting is not well studied. Aim Using an acute injury model, we aimed to investigate the effects of mutant HTT expression on satellite cell regeneration capacity in the R6/2 mouse model. Methods We used adult and neonatal R6/2 mice and their WT littermates. A chemical injury model was employed using cardiotoxin (CTX) in the tibialis anterior muscle. To assess tissue remodeling, we performed immunohistochemistry using laminin to stain basement membrane and embryonic myosin heavy chain (eMHC) as an indicator of muscle regeneration at 4 weeks and 1 week of post-CTX injection, respectively. Results Body weight and fiber diameter were significantly reduced in both adult and neonatal R6/2 mice compared to WT littermates. At four weeks post-injection, fiber diameter was the same between saline and CTX injected group in WT mice. Yet, fiber diameter was increased in the R6/2 CTX compared to the R6/2 saline group. We found a trend towards increased eMHC positive cells in R6/2 compared to the WT littermates at 1-week post-injection. Conclusion R6/2 skeletal muscle has the ability to regenerate new fibers following an acute injury, and the regeneration process was not profoundly affected by mutant huntingtin expression. We will further investigate HD satellite cell proliferation capacity (i.e., Pax7 positive cells) and inflammatory response (i.e., CD68, CD11b) in response to acute muscle injury.

Background Given the rarity of Huntington’s disease (HD), large cohort studies are warranted to better understand the clinical burden of disease in routine clinical practice. Aims To describe the incidence of clinical events in patients with HD compared with a matched cohort from the general population, and to describe differences between adult- and juvenile-onset HD. Methods This was a nationwide cohort study linking data from the Swedish National Patient Registry, Prescription Drug Registry, and Cause of Death Registry. Patients of all ages with a first diagnosis of HD (ICD-10: G10) from 2002–2018 were included and matched 1:4 (on age and sex) to a control cohort without HD. Incidence rate ratios (IRRs) and 95% confidence intervals (CI) approximated the relative risk of clinical events occurring in patients with HD vs controls after first HD diagnosis. Incidence rates (IRs) of cases were compared in those aged Results Overall, 1,492 patients with HD were matched to 5,946 controls. Median age at first diagnosis was 56 years (range: 0–96; 50% female; median follow-up: 8 years). Most outcomes were higher in patients with HD vs controls, with the greatest difference for (IRR [95%CI]): acute psychiatric episodes (14.4 [13.6–15.2]), subdural haematoma (7.5 [7.1–7.9]), communication and speech problems (6.4 [6.1–6.8]), depression (6 [5.7–6.4]), obsessive compulsive disorder (5.7 [5.4–6.0]) and anxiety disorders (4.4 [4.2–4.7]) (table 1). IRs for all studied clinical events were higher in adult-onset (N=1,447) vs juvenile-onset HD (N=45), except for epilepsy, asthma, gastrointestinal events, meningitis, and acute respiratory symptoms. Conclusions This nationwide study demonstrates considerable disease burden in HD compared with the general population. Juvenile-onset HD have higher incidence of some clinical events when compared with adult-onset HD. Study sponsored by F. Hoffmann-La Roche Ltd.

BackgroundHuntington’s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, and underlying mechanisms are not fully known. As the IKKβ/NF-κB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-κB in hypothalamus-specific HD metabolic changes.MethodsUsing viral vectors, we expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) fragments in the hypothalamus of mice without IKKβ in the CNS (IKKβ-/-) and control mice (IKKβ+/+). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology.ResultsHypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKKβ prohibited weight gain in females, which was independent of neuroprotection and microglial activation.ConclusionsThe expression of mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKβ pathway attenuates the obese phenotype.

Huntington disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. It is inherited in an autosomal dominant fashion with full penetrance. Around 15% of cases arise from spontaneous expansion of the CAG repeat. The clinical presentation includes involuntary movements (chorea) with dysarthria and dysphagia as well as cognitive and psychiatric symptoms and weight loss. The combination of these symptoms and signs should lead to further investigations regarding HD, even in absence of a known family history. Psychiatric and cognitive symptoms often manifest around 15 years before the motor disorder and the disease leads to premature death. HD is likely underdiagnosed as many individuals present with psychiatric and behavioral problems for a long time. No disease modifying treatment is available today but there are a number of clinical trials ongoing aiming at slowing the disease process. The successful progress of these trials will give urgency to correct diagnosis of HD.

Huntington's disease is an autosomal dominant neurodegenerative disease that leads to premature death. The disease is caused by a pathological CAG triplet expansion in the huntingtin gene. The disease is most common in Western populations, with onset in middle age and causing progressive motor, cognitive, and psychiatric symptoms. Currently, only symptomatic treatment is provided, but new molecular technologies may allow treatments reducing levels of mutated huntingtin.

Neuropsychiatric disturbances with altered social cognition, depression and anxiety are among the most debilitating early features in the fatal neurodegenerative disorder Huntington disease (HD) which is caused by an expanded CAG repeat in the huntingtin gene. The underlying neurobiological mechanisms are not known. Neuropathological analyses of postmortem human HD hypothalamic tissue have demonstrated loss of the neuropeptides oxytocin and vasopressin. The dynamic interplay between these neuropeptides is crucial for modulating emotional and social behavior but its role in HD is unclear. In the present study, we have investigated the effect of expressing the mutant huntingtin gene on the development of behavioral changes using the transgenic BACHD mouse model at different ages. We show for the first time that BACHD mice exhibit deficits in social behavior with parallel aberrations in the balance of the oxytocin-vasopressin system. Importantly, our data also show that restoration of the interplay within the system with an acute dose of intranasal oxytocin immediately prior to behavioral testing can rescue the depressive-like phenotype but not anxiety-like behavior in this transgenic model. These findings demonstrate that imbalances in the oxytocin-vasopressin interplay contribute to the neuropsychiatric component of HD and suggest that interventions aimed at restoring the blunted levels of oxytocin may confer therapeutic benefits for this disease.

Hypothalamic obesity (HO) occurs in 50% of patients with the pituitary tumor craniopharyngioma (CP). Attempts have been made to predict the risk of HO based on hypothalamic (HT) damage on magnetic resonance imaging (MRI), but none have included volumetry. We performed qualitative and quantitative volumetric analyses of HT damage. The results were explored in relation to feeding related peptides and body fat. A cross-sectional study of childhood onset CPs involving 3 Tesla MRI, was performed at median 22 years after first operation; 41 CPs, median age 35 (range: 17–56), of whom 23 had HT damage, were compared to 32 controls. After exclusions, 35 patients and 31 controls remained in the MRI study. Main outcome measures were the relation of metabolic parameters to HT volume and qualitative analyses of HT damage. Metabolic parameters scored persistently very high in vascular risk particularly among HT damaged patients. Patients had smaller HT volumes compared to controls 769 (35–1168) mm3 vs. 879 (775–1086) mm3; P

Muscular dystrophies, including laminin α2 chain-deficient muscular dystrophy (LAMA2-CMD), are associated with immense personal, social and economic burdens. Thus, effective treatments are urgently needed. LAMA2-CMD is either a severe, early-onset condition with complete laminin α2 chain-deficiency or a milder, late-onset form with partial laminin α2 chain-deficiency. Mouse models dy 3K /dy 3K and dy 2J /dy 2J , respectively, recapitulate these two forms of LAMA2-CMD very well. We have previously demonstrated that laminin α1 chain significantly reduces muscular dystrophy in laminin α2 chain-deficient dy 3K /dy 3K mice. Among all the different pre-clinical approaches that have been evaluated in mice, laminin α1 chain-mediated therapy has been shown to be one of the most effective lines of attack. However, it has remained unclear if laminin α1 chain-mediated treatment is also applicable for partial laminin α2 chain-deficiency. Hence, we have generated dy 2J /dy 2J mice (that express a substantial amount of an N-terminal truncated laminin α2 chain) overexpressing laminin α1 chain in the neuromuscular system. The laminin α1 chain transgene ameliorated the dystrophic phenotype, restored muscle strength and reduced peripheral neuropathy. Thus, these findings provide additional support for the development of laminin α1 chain-based therapy for LAMA2-CMD.

Aims: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. Methods: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. Results: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. Conclusions: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus. (Less)

Context Patients with craniopharyngioma (CP) and hypothalamic lesions (HL) have cognitive deficits. Which neural pathways are affected is unknown. Objective To determine whether there is a relationship between microstructural white matter (WM) alterations detected with diffusion tensor imaging (DTI) and cognition in adults with childhood-onset CP. Design A cross-sectional study with a median follow-up time of 22 (6–49) years after operation. Setting The South Medical Region of Sweden (2.5 million inhabitants). Participants Included were 41 patients (24 women, ≥17 years) surgically treated for childhood-onset CP between 1958–2010 and 32 controls with similar age and gender distributions. HL was found in 23 patients. Main outcome measures Subjects performed cognitive tests and magnetic resonance imaging, and images were analyzed using DTI of uncinate fasciculus, fornix, cingulum, hippocampus and hypothalamus as well as hippocampal volumetry. Results Right uncinate fasciculus was significantly altered (P ≤ 0.01). Microstructural WM alterations in left ventral cingulum were significantly associated with worse performance in visual episodic memory, explaining approximately 50% of the variation. Alterations in dorsal cingulum were associated with worse performance in immediate, delayed recall and recognition, explaining 26–38% of the variation, and with visuospatial ability and executive function, explaining 19–29%. Patients who had smaller hippocampal volume had worse general knowledge (P = 0.028), and microstructural WM alterations in hippocampus were associated with a decline in general knowledge and episodic visual memory. Conclusions A structure to function relationship is suggested between microstructural WM alterations in cingulum and in hippocampus with cognitive deficits in CP.

International audience; Objective: Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers.Methods: High-resolution three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age. Correlation analyses were performed with clinical and metabolic outcomes. Pathologically defined ALS stages were determined in vivo by diffusion tensor imaging (DTI).Results: We observed a severe atrophy of the hypothalamus both in patients with sporadic ALS (-21.8%, p

Gene transfer is a promising drug delivery method of advanced therapeutic entities for Parkinson's disease. One advantage over conventional therapies, such as peripheral delivery of the dopamine pre-cursor L-DOPA, is site specific expression of proteins with regenerative, disease-modifying and potentially neuroprotective capacity. Several clinical trials have been performed to test the capacity of glial-cell line derived neurotrophic factor and neurturin to rescue degenerating dopaminergic neurons in the substantia nigra and their axon terminals in the striatum by delivery of these neurotrophic factors either as purified protein or by means of viral vector mediated gene delivery to the brain. Although gene therapy approaches tested so far have been shown to be safe, none met their primary endpoints in phase II clinical trials designed and powered to test the efficacy of the intervention. Within the scope of this review we aim to describe the state-of-the-art in the field, how different technical parameters were translated from pre-clinical studies in non-human primates to clinical trials, and what these trials taught us regarding important factors that may pave the way to the success of gene therapy for the treatment of Parkinson's disease. (C) 2016 Elsevier Inc. All rights reserved.

Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded cytosine-adenine-guanine triplet repeat in the huntingtin gene. The current diagnosis is based on the presence of typical motor signs in combination with a positive gene test. The motor onset of the disease is usually between 30 and 50 years of age, and the disease then progresses over around 20 more years. Nonmotor symptoms and signs such as cognitive decline, metabolic dysfunction, sleep disturbances, as well as psychiatric symptoms are common and can occur many years before motor onset. Psychiatric symptoms include irritability, apathy, depression, anxiety, and OCD. Although there exist no disease-modifying treatment, available pharmacologic drugs often offer significant symptom relief and improve quality of life. Today, there are only two drugs that are approved by the US Food and Drug Association for the treatment of HD. These are the dopamine-depleting drugs tetrabenazine and deutetrabenazine that both target motor symptoms. The current status of best clinical practice for HD is based on expert opinions as well as evidence and/or experience of treating similar symptoms in other conditions. In this chapter, we provide an overview of the complex clinical manifestations of HD and the commonly used psychopharmacologic treatments.

Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded cytosine-adenine-guanine triplet repeat in the huntingtin gene. The current diagnosis is based on the presence of typical motor signs in combination with a positive gene test. The motor onset of the disease is usually between 30 and 50 years of age, and the disease then progresses over around 20 more years. Nonmotor symptoms and signs such as cognitive decline, metabolic dysfunction, sleep disturbances, as well as psychiatric symptoms are common and can occur many years before motor onset. Psychiatric symptoms include irritability, apathy, depression, anxiety, and OCD. Although there exist no disease-modifying treatment, available pharmacologic drugs often offer significant symptom relief and improve quality of life. Today, there are only two drugs that are approved by the US Food and Drug Association for the treatment of HD. These are the dopamine-depleting drugs tetrabenazine and deutetrabenazine that both target motor symptoms. The current status of best clinical practice for HD is based on expert opinions as well as evidence and/or experience of treating similar symptoms in other conditions. In this chapter, we provide an overview of the complex clinical manifestations of HD and the commonly used psychopharmacologic treatments.

Background: A predictive genetic test for Huntington’s disease can be used before any symptoms are apparent, but there is only sparse knowledge about the long-term consequences of a positive test result. Such knowledge is important in order to gain a deeper understanding of families’ experiences. Objectives: The aim of the study was to describe a young couple’s long-term experiences and the consequences of a predictive test for Huntington’s disease. Research design: A descriptive case study design was used with a longitudinal narrative life history approach. Participants and research context: The study was based on 18 interviews with a young couple, covering a period of 2.5 years; starting 6 months after the disclosure of the test results showing the woman to be a carrier of the gene causing Huntington’s disease. Ethical considerations: Even though the study was extremely sensitive, where potential harm constantly had to be balanced against the benefits, the couple had a strong wish to contribute to increased knowledge about people in their situation. The study was approved by the ethics committee. Findings: The results show that the long-term consequences were devastating for the family. This 3-year period was characterized by anxiety, repeated suicide attempts, financial difficulties and eventually divorce. Discussion: By offering a predictive test, the healthcare system has an ethical and moral responsibility. Once the test result is disclosed, the individual and the family cannot live without the knowledge it brings. Support is needed in a long-term perspective and should involve counselling concerning the families’ everyday life involving important decision-making, reorientation towards a new outlook of the future and the meaning of life. Conclusion: As health professionals, our ethical and moral responsibility thus embraces not only the phase in direct connection to the actual genetic test but also a commitment to provide support to help the family deal with the long-term consequences of the test.