In this chapter, we review the evolution of our understanding of the genetic aspects of HD, and the applications of our understanding in the management of Huntington's disease patients and families ...over the last 150 years. Important aspects of the clinical genetics and epidemiology of Huntington's disease are discussed, such as the definition of "normal" and "abnormal" numbers of CAG (cytosine-adenine-guanine) repeats in the critical spot within the huntingtin gene, meiotic instability of CAG repeat numbers, common Huntington's disease genetic haplotypes, compound heterozygosity for an abnormal gene, and somatic mosaicism for CAG repeat expansions. We touch only briefly on the creation of multiple animal models for Huntington's disease that have profoundly impacted our understanding of the disease and permitted the development of potential disease-modifying treatments, and end with what is, at the time of writing, the dawn of a new era: the advent of gene-based therapies (gene silencing, gene editing) for Huntington's disease.
To improve our understanding of sex differences in the clinical characteristics of Parkinson's Disease, we sought to examine differences in the clinical features and disease severity of men and women ...with early treated Parkinson's Disease (PD) enrolled in a large-scale clinical trial.
Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between men and women using t-test statistics. Sex differences in clinical features were evaluated, including: symptoms at diagnosis (motor) and symptoms at randomization (motor, non-motor, and daily functioning).
1,741 participants were enrolled (62.5% male). No differences were detected in mean age at PD onset, age at PD diagnosis, age at randomization, motor symptoms, or daily functioning between men and women. Differences in non-motor symptoms were observed, with women demonstrating better performance compared to men on SCOPA-COG (Z = 5.064, p<0.0001) and Symbol Digit Modality measures (Z = 5.221, p<0.0001).
Overall, men and women did not demonstrate differences in clinical motor features early in the course of PD. However, the differences observed in non-motor cognitive symptoms suggests further assessment of the influence of sex on non-motor symptoms in later stages of PD is warranted.
Death anxiety, represented by the HDQLIFE™ Concern with Death and Dying (CwDD) patient-reported outcome (PRO) questionnaire, captures a person's worry about the death and dying process. Previous work ...suggests that death anxiety remains an unremitting burden throughout all stages of Huntington disease (HD). Although palliative interventions have lessened death anxiety among people with advanced cancer, none has yet to undergo testing in the HD population. An account of how death anxiety is associated with longitudinal changes to aspects of health-related quality of life (HRQoL) would help optimize neuropalliative interventions for people with HD.
HDQLIFE collected PROs concerning physical, mental, social, and cognitive HRQoL domains and clinician-rated assessments from people with HD at baseline and 12 and 24 months. Linear mixed-effects models were created to determine how baseline death anxiety was associated with follow-up changes in HRQoL PROs after controlling for baseline death anxiety and other disease and sociodemographic covariates.
Higher baseline HDQLIFE CwDD is associated with 12- and 24-month declines in HDQLIFE Speech Difficulties, neurology quality of life (NeuroQoL) Depression, Suicidality, HDQLIFE Meaning and Purpose, and NeuroQoL Positive Affect and Well-being.
Death anxiety may be a risk factor for worsening mental health and speech difficulty. A further prospective study is required to evaluate whether interventions on death anxiety or mental health generally can reduce declines in HRQoL for people with HD over time.
Hereditary spastic paraplegia (HSP) comprises a group of clinically and genetically heterogeneous diseases that affect the upper motor neurons and their axonal projections. For the novel
SPG31 locus ...on chromosome 2p12, we identified six different mutations in the receptor expression–enhancing protein 1 gene (
REEP1).
REEP1 mutations occurred in 6.5% of the patients with HSP in our sample, making it the third-most common HSP gene. We show that REEP1 is widely expressed and localizes to mitochondria, which underlines the importance of mitochondrial function in neurodegenerative disease.
Huntington's disease is a slowly progressive neurodegenerative disorder with wide-ranging effects on affected individuals and their families. Until a cure is found for the disease, patients and their ...families will continue to need care over years, even generations. The ideal care for HD is provided by a team, led by a physician, with input from rehabilitation therapists, nurses, psychologists, genetic counselors, social workers, and other health care providers. The goals of care are to maximize the quality of life at all points through the course of the disease, in part by anticipating problems that are likely to arise at the next stage of the illness. We describe below an approach to comprehensive care, and introduce the concept of the "Huntington disease molecule", in which the patient, in the center, is surrounded by a shell of immediate and extended family members, with bonds extended in multiple directions to provider who can give appropriate medical care, education, crisis management, research opportunities, address family issues, maximize function, and prepare for the future.
As of 2012, almost 20 years after the discovery of the causative gene, clinical research has yet to find a disease-modifying treatment for Huntington’s disease. However, both pharmacologic and ...nonpharmacologic therapies are available for many of the common symptoms of the disease. Recent studies of gene-positive patients in the prodromal, not clinically diagnosable, stages of the disease, are changing our perception of when the process of neurodegeneration begins. Once disease-modifying therapies become available, the approach to the diagnosis of Huntington’s disease will likely shift from an examination-based clinical diagnosis, to one that includes a more complex combination of imaging, examination, and biomarker analysis.
Background and purpose
Huntington disease (HD) is a progressive neurodegenerative disorder. There are no HD-specific measures to assess for end-of-life (EOL) preferences that have been validated for ...clinical use. The purpose of this study is to demonstrate reliability and validity of three HD-specific EOL measures for use in and clinical research settings.
Methods
We examined internal reliability, test–retest reliability, floor and ceiling effects, convergent and discriminant validity, known groups’ validity, measurement error, and change over time to systematically examine reliability and validity of the HDQLIFE EOL measures.
Results
Internal consistency and test–retest reliability were > 0.70. The measures were generally free of floor and ceiling effects and measurement error was minimal. Convergent and discriminant validity were consistent with well-known constructs in the field. Hypotheses for known groups validity were partially supported (there were generally group differences for the EOL planning measures, but not for meaning and purpose or concern with death and dying). Measurement error was acceptable and there were minimal changes over time across the EOL measures.
Conclusions
Results support the clinical utility of the HDQLIFE EOL measures in persons with HD.
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