A Phenotypic Atlas for Huntington Disease Based on Data From the Enroll-HD Cohort Study.

Background and Objectives: The variable CAG repeat expansion in the huntingtin gene and its inverse relationship to motor dysfunction onset are fundamental features of Huntington disease (HD). However, the wider phenotype (including non-motor features) at particular CAG lengths, ages, and functional levels is less well-characterized. The large number of participants in the Enroll-HD observational study enables the development of a phenotype atlas that summarizes the range and distribution of HD phenotypes, including outliers and possible clusters, with respect to various CAG repeat lengths, age ranges, and declining functional levels. Methods: Enroll-HD is an ongoing prospective longitudinal observational study that collects natural history data, releasing periodic data sets, in people with HD (PwHD) and controls. Core assessments at annual visits focus on behavioral, cognitive, motor, and functional status. Periodic data set 5, used for the development of the first iteration of the Enroll-HD Phenotype Atlas (EHDPA), included all eligible data collected through October 31, 2020. The atlas is based on subsets (cells) of descriptive data for all motor, cognitive, psychiatric, and functional measures that are routinely collected at most Enroll-HD sites, analyzed by single CAG lengths and 5-year age blocks. Results: Data from 42,840 visits from 15,982 unique PwHD were available for analysis. At baseline, participants had a mean ± SD age of 48.9 ± 13.9 years and CAG repeat length of 43.4 ± 3.6 and 54.1% were female. The EHDPA includes 223 age-by-CAG subsets for CAG repeats between 36 and 69 with five-year age brackets starting from 20-24 years up to 85-89 years. The atlas can be browsed at enroll-hd.org/for-researchers/atlas-of-hd-phenotype/. Discussion: The EHDPA summarizes the spectrum and distribution of HD phenotypes, including outliers and possible clusters, in all domains of disease involvement for the range of CAG repeat lengths, ages, and functional levels. Its availability in an easy-to-use online format will assist clinicians in tracking disease progression in PwHD by identifying phenotypic features most associated with loss of function and enabling conversations related to prognosis. The observable patterns in the EHDPA should also catalyze more formal multidomain characterization of motor, cognitive, and psychiatric progression and their relationships to functional decline and disease modifiers. Trial Registration Information: Enroll-HD is registered with clinicaltrials.gov: NCT01574053.

Expanding the Allelic Heterogeneity of ANO10-Associated Autosomal Recessive Cerebellar Ataxia.

Background and Objectives: The term autosomal recessive cerebellar ataxia (ARCA) encompasses a diverse group of heterogeneous degenerative disorders of the cerebellum. Spinocerebellar ataxia autosomal recessive 10 (SCAR10) is a distinct classification of cerebellar ataxia caused by variants in the ANO10 gene. Little is known about the molecular role of ANO10 or its role in disease. There is a wide phenotypic spectrum among patients, even among those with the same or similar genetic variants. This study aimed to characterize the molecular consequences of variants in ANO10 and determine their pathologic significance in patients diagnosed with SCAR10. Methods: We presented 4 patients from 4 families diagnosed with spinocerebellar ataxia with potential pathogenic variants in the ANO10 gene. Patients underwent either clinical whole-exome sequencing or screening of a panel of known neuromuscular disease genes. Effects on splicing were studied using reverse transcriptase PCR to analyze complementary DNA. Western blots were used to examine protein expression. Results: One individual who presented clinically at a much earlier age than typical was homozygous for an ANO10 variant (c.1864A > G [p.Met622Val]) that produces 2 transcription products by altering an exonic enhancer site. Two patients, both of Lebanese descent, had a homozygous intronic splicing variant in ANO10 (c.1163-9A > G) that introduced a cryptic splice site acceptor, producing 2 alternative transcription products and no detectable wild-type protein. Both these variants have not yet been associated with SCAR10. The remaining patient was found to have compound heterozygous variants in ANO10 previously associated with SCAR10 (c.132dupA [p.Asp45Argfs*9] and c.1537T > C [p.Cys513Arg]). Discussion: We presented rare pathogenic variants adding to the growing list of ANO10 variants associated with SCAR10. In addition, we described an individual with a much earlier age at onset than usually associated with ANO10 variants. This expands the phenotypic and allelic heterogeneity of ANO10-associated ARCA.

End of life: Expert care and support, not physician-hastened death.

In legal physician-hastened death, a physician prescribes medication with the primary intent of causing the death of a willing terminally ill patient. This practice differs radically from palliative sedation, intended to relieve a patient's suffering rather than cause a patient's death. In this position paper, we argue that the practice of physician-hastened death is contrary to the interests of patients, their families, and the sound ethical practice of medicine. Therefore, the American Academy of Neurology should advise its members against this practice, as it had done until 2018.

Late Onset Huntington Disease: Phenotypic and Genotypic Characteristics of 10 Cases in Argentina.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder that includes motor, psychiatric and cognitive manifestations with typical onset of symptoms is in the forties. A percentage of patients (4.4% - 11.5%) may be exceptions to this and manifest symptoms later (>60 years old). Diagnosis of Late onset HD (LoHD) can be a challenge, due to the low suspicion of the disease at this age. OBJECTIVE: To review the genotype and phenotype of LoHD in an Argentinian cohort. METHODS: We reviewed the medical records and genetic testing of a total of 95 individuals with clinical and molecular diagnosis of Huntington's disease, based on 2 institution's registry. RESULTS: Among our HD cohort, 10 patients (10.52%) had LoHD, with variable results regarding family history. The average of repetitions of the expanded allele was 40 (range 38-44). All cases had mild motor symptoms at onset. CONCLUSIONS: Late onset HD can be a diagnostic challenge, due to its slow progression, unawareness of manifestations among patients and in many cases, mild symptomatology that does not warrant medical attention.

Risk factors for suicidality in Huntington disease: An analysis of the 2CARE clinical trial.

OBJECTIVE: Most suicidality literature in Huntington disease (HD) is based on natural history studies or retrospective reviews, but reports on risk factors from clinical trials are limited. METHODS: We analyzed 609 participants from 2CARE, a randomized, double-blind, placebo-controlled clinical trial with up to 5 years of follow-up, for risk factors related to suicidality. The primary outcome variable was the time from randomization until the first occurrence of either suicidal ideation or attempt. We also considered time from randomization until the first suicide attempt as a secondary outcome variable. RESULTS: Depression, anxiety, bipolar disorder, antidepressant or anxiolytic use, and prior suicide attempt at baseline were associated with time to ideation or attempt. Baseline employment status, marital status, CAG repeat length, tetrabenazine use, and treatment assignment (coenzyme Q10 or placebo) were not associated with suicidality. Time-dependent variables from the Unified Huntington's Disease Rating Scale Behavioral Assessment were associated with time to suicidal ideation or attempt, driven mainly by items related to depressed mood, low self-esteem/guilt, anxiety, suicidal thoughts, irritability, and compulsions. Variables associated with time to suicide attempt alone were generally similar. CONCLUSION: These data suggest psychiatric comorbidities in HD are predictive of suicidal behavior while participating in clinical trials, reinforcing the importance of clinical surveillance and treatment towards lessening risk during participation and perhaps beyond. Designing a composite algorithm for early prediction of suicide attempts in HD may be of value, particularly given anticipated trials aimed at disease modification are likely to be long-term. CLINICALTRIALSGOV IDENTIFIER: NCT00608881.

Huntington Disease: The Complexities of Making and Disclosing a Clinical Diagnosis After Premanifest Genetic Testing.

The management of patients and families affected by Huntington disease (HD) is complicated by several factors, both practical and ethical. It can be difficult to determine the onset of clinically manifest HD (mHD). In addition, it can be challenging to decide when to disclose the diagnosis to the affected individual. Firstly, the features of HD, an incurable, inherited, neurocognitive disorder that often manifests in young adulthood, influence how the person presents and accepts a diagnosis. Secondly, a positive genetic test for HD may result in a genetic diagnosis, sometimes years before the development of clinical features and the diagnosis of mHD. Thirdly, observational studies of unaffected gene expansion carriers documented HD manifestations up to 10 years before the typical presentation for diagnosis. These developments may permit earlier genetic diagnosis and information regarding the patient's likely status with respect to the development of clinical disease. Making the genetic diagnosis of HD and providing information regarding disease status, earlier rather than later, respects the person's right to know and preserves honesty in the doctor/patient relationship. Conversely, delaying the diagnosis respects the right not to know, avoids potential discrimination, and permits the person to live a "normal" life for longer, in the context of a disease without cure. This discussion has implications for other inherited and neurocognitive disorders.

Medical management of motor manifestations of Huntington disease.

The motor and movement disorders of Huntington disease (HD) are managed in the context of the other disease features. Chorea and dystonia are the most common HD-associated movement disorders, and they can be assessed on research rating scales. However other motor manifestations have a significant impact. In particular, dysphagia influences choice and tolerance of treatment for the movement disorder, as will comorbidities, patient awareness, and distress related to the motor feature or movement. Treatment for other disease features may aggravate the motor disorder, e.g., increased swallowing difficulty associated with antipsychotic agents. Basic principles in deciding to institute a treatment are outlined as well as treatment of specific motor manifestations and movements. There is a paucity of evidence to support the treatments available for the motor disorder, with only one agent with class 1 evidence, tetrabenazine, for chorea. There are, however, treatments informed by expert opinion which reflect the management of a wider HD phenotype than that represented in clinical trials. Some treatments are based on evidence from use in other conditions. Medical management is usually undertaken later in the disease with concurrent nonmedical interventions after multidisciplinary assessments. Medication review with HD progression is essential.

What do we know about Late Onset Huntington's Disease?

BACKGROUND: Although the typical age of onset for Huntington's disease (HD) is in the fourth decade, between 4.4-11.5% of individuals with HD have a late onset (over 60 years of age). Diagnosis of Late onset HD (LoHD) can be missed, due to the perceived low likelihood of HD in the over 60-year-olds. OBJECTIVE: To review the epidemiology, genotype and phenotype of LoHD. METHODS: We systematically searched MEDLINE, EMBASE and Web of Science (inception-November 2016). Web of Science was then used to search for papers citing identified studies. Content experts were consulted for any additional studies. We included all studies reporting the clinical phenotype of LoHD for more than one participant. RESULTS: 20 studies were identified from a potential list of 1243. Among Caucasian HD cohorts, 4.4-11.5% of individuals have LoHD, and this proportion may be increasing. Proportion of LoHD without a positive family history ranges from 3-68%. 94.4% of reported cases of LoHD had CAG repeat lengths of ≤44. Motor manifestations are the commonest initial presentation, although 29.2% presented with non-motor manifestations as the first clinical feature in one case series. Individuals with LoHD may have slower progression of illness. Cognitive impairment rather than chorea may be the major source of disability in this group. CONCLUSIONS: LoHD represents a substantial proportion of new diagnoses of HD and has some unique features. Further characterization of this population will aid clinicians in diagnosis.

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

OBJECTIVE: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. METHODS: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. RESULTS: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. CONCLUSIONS: These data do not justify use of CoQ as a treatment to slow functional decline in HD. CLINICALTRIALSGOV IDENTIFIER: NCT00608881. CLASSIFICATION OF EVIDENCE: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.

Longitudinal Psychiatric Symptoms in Prodromal Huntington's Disease: A Decade of Data.

OBJECTIVE: Psychiatric symptoms are a significant aspect of Huntington's disease, an inherited neurodegenerative illness. The presentation of these symptoms is highly variable, and their course does not fully correlate with motor or cognitive disease progression. The authors sought to better understand the development and longitudinal course of psychiatric manifestations in individuals who carry the Huntington's disease mutation, starting from the prodromal period prior to motor diagnosis. METHOD: Longitudinal measures for up to 10 years of psychiatric symptoms from the Symptom Checklist-90-Revised were obtained from 1,305 participants (1,007 carrying the Huntington's disease mutation and 298 without [classified as controls]) and 1,235 companions enrolled in the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) study. Participants with the mutation were stratified into three groups according to probability of motor diagnosis within 5 years. Using linear mixed-effects regression models, differences in psychiatric symptoms at baseline and over time between the mutation-positive groups and the controls were compared, as well as between ratings by mutation-positive participants and their companions. RESULTS: Nineteen of 24 psychiatric measures (12 participant ratings and 12 companion ratings) were significantly higher at baseline and showed significant increases longitudinally in the individuals with the Huntington's disease mutation compared with controls. The differences were greatest in comparisons of symptom reports from companions compared with self-reports, especially in participants who were closest to motor diagnosis. CONCLUSIONS: The results indicate that psychiatric manifestations develop more often than previously thought in the Huntington's disease prodrome. Symptoms also increase with progression of disease severity. Greater symptom ratings by companions than by mutation-positive participants suggest decreasing awareness in those affected.

Motor onset and diagnosis in Huntington disease using the diagnostic confidence level.

Huntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive deterioration, and psychiatric symptoms, with progressive motor impairments being a prominent feature. The primary objectives of this study are to delineate the disease course of motor function in HD, to provide estimates of the onset of motor impairments and motor diagnosis, and to examine the effects of genetic and demographic variables on the progression of motor impairments. Data from an international multisite, longitudinal observational study of 905 prodromal HD participants with cytosine-adenine-guanine (CAG) repeats of at least 36 and with at least two visits during the followup period from 2001 to 2012 was examined for changes in the diagnostic confidence level from the Unified Huntington's Disease Rating Scale. HD progression from unimpaired to impaired motor function, as well as the progression from motor impairment to diagnosis, was associated with the linear effect of age and CAG repeat length. Specifically, for every 1-year increase in age, the risk of transition in diagnostic confidence level increased by 11% (95% CI 7-15%) and for one repeat length increase in CAG, the risk of transition in diagnostic confidence level increased by 47% (95% CI 27-69%). Findings show that CAG repeat length and age increased the likelihood of the first onset of motor impairment as well as the age at diagnosis. Results suggest that more accurate estimates of HD onset age can be obtained by incorporating the current status of diagnostic confidence level into predictive models.

Multivariate clustering of progression profiles reveals different depression patterns in prodromal Huntington disease.

OBJECTIVE: Although Huntington disease (HD) is caused by an autosomal dominant mutation, its phenotypic presentation differs widely. Variability in clinical phenotypes of HD may reflect the existence of disease subtypes. This hypothesis was tested in prodromal participants from the longitudinal Neurobiological Predictors of Huntington Disease (PREDICT-HD) study. METHOD: We performed clustering using longitudinal data assessing motor, cognitive, and depression symptoms. Using data from 521 participants with 2,716 data points, we fit growth mixture models (GMM) that identify groups based on multivariate trajectories. RESULTS: In various GMM, different phases of disease progression were partitioned by progression trajectories of motor and cognitive signs, and by overall level of depression symptoms. More progressed motor signs were accompanied by more progressed cognitive signs, but not always by higher levels of depressive symptoms. In several models, there were at least 2 groups with similar trajectories for motor and cognitive signs that showed different levels for depression symptoms-one with a very low level of depression and the other with a higher level of depression. CONCLUSIONS: Findings indicate that at least intermediate HD progression might be associated with different levels of depression. Depression is one of the few symptoms that is treatable in HD and has implications for clinical care. Identification of potential depression subtypes may also help to select appropriate patients for clinical trials.

The many facets of unawareness in huntington disease.

BACKGROUND: Unawareness or diminished awareness is present when a patient's perception of obvious disease manifestations and impact differ from that of observers such as clinicians or family members. METHODS: We examined studies that specifically investigate unawareness in Huntington disease (HD). RESULTS: Unawareness of motor, cognitive, behavioral, and functional aspects of HD has been documented throughout the disease course. This can occur at motor and cognitive onset but is more pronounced as the disease progresses. DISCUSSION: We discuss the implications for diagnosis, symptom report at presentation, timing of diagnosis, acceptance of symptomatic care strategies, and reporting in clinical trials. Assessments of work place competency, discrimination, driving, and the particular challenges of isolated patients without caregivers are described. Engaging with a person who is unaware of their disease or its impact presents a number of conflicts, including maintaining the right to autonomy, privacy, confidentiality, and independence while recognizing concerns for the wellbeing of the vulnerable person with HD and their caregiver when the unaware person refuses assistance. Unawareness is seen increasingly as neurologically based due to the impairment of functional networks, predominantly in nondominant frontostriatal pathways.

Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study.

There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington's disease is a 32-site, international, observational study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7-12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease.

Asymmetric homoenolate additions to acyl phosphonates through rational design of a tailored N-heterocyclic carbene catalyst.

A highly selective NHC-catalyzed synthesis of γ-butyrolactones from the fusion of enals and α-ketophosphonates has been developed. Computational modeling of competing transition states guided a rational design strategy to achieve enhanced levels of enantioselectivity with a new tailored C1-symmetric biaryl-saturated imidazolium-derived NHC catalyst.