Huntington’s Disease

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Brief Overview of Huntington’s Disease

  • 30,000 affected in US; 200,000 at risk
  • Affects striatum/basal ganglia (esp. caudate nucleus)
  • Triad of clinical symptoms:
    • motor (unsteady gait, involuntary movements; slurred speech; difficulty in swallowing; intoxicated appearance)
    • cognitive and behavioral (personality changes, depression, mood swings,impaired judgment)
    • diagnosis relies on emergence of chorea (traditional);
    • progressively disabling, adult-onset, lethal
      • usual onset is 30-50, but can be from 2-80
      • average age of onset is 38
      • average length of life from diagnosis to death is 19 years
      • no effective treatment to delay onset or slow decline is currently available

Neuropsychological manifestations: subcortical dementia

  • decreased attention,
  • impaired executive functioning,
  • memory retrieval deficits
    • Neuropsychiatric manifestations common (affective disorders) – 50% of all patients
    • depending on study, motor, cognitive, or behavioral symptoms may appear first; also, some of the early features might be related to “being at risk” rather than carrying the gene
    • Diagnosis made by DNA marker of CAG repetitions:
      • CAG trinucleotide repeats <36 – no HD, 36-39 – questionable, >39 – HD;
      • repeat length accounts for half of the variance in determining age of onset (more repetitions = earlier onset)
    • this is also affected by how onset is defined (mood, personality or chorea, e.g.)
    • Also, the repetition length can change during transmission (e.g. from parent to child); it usually lengthens with a particular tendency to lengthen when passed from father to child
    • gene (huntingtin) found in 1993; HAP-1 (protein that works with huntingtin) found in 1995
  • Huntington Study Group (international coalition) formed in 1993 – coordinates research efforts – developed the UHDRS (motor, cognitive, behavioral, functional measurement of disease)
    • UHDRS battery uses Stroop, Symbol Digit, and Verbal Fluency – sensitive to basal ganglia dysfunction (study showed all declined in at-risk who eventually developed HD, not so in at-risk without gene)
    • Possible environmental modifiers: enriched environment; no other studies have produced convincing results

Recent Findings/Developments

  • First, HDSA is VERY active, has designated “Centers of Excellence” (U of R is one), and created “Coalition for the Cure” (1997) – 14 top labs in North America and Europe – will award 2 million in 2000/2001; ave. 2-yr award of 200,000 per investigator
  • NINDS and HDSA formed a partnership – “Screening FDA Approved Drugs for Neurodegenerative Disease” pilot project – joint sponsorship between goverment and voluntary health agency – will help speed research from lab to clinical trials – govt will supplement HDSA funding
  • 3/01 – report in Science detailing how gene attacks and kills cells – mutant huntingtin “hijacks” a key molecule termed CBP, which is necessary for activating genes necessary for neuronal survival. Without CBP, a pathway crucial for cell survival can’t get turned on. The molecular “hijack” makes direct use of the expanded polyglutamine stretch in huntingtin. Therefore, this mechanism can provide an elegant explanation for the pathology of the whole family of diseases – currently about 8 – caused by expanded glutamine stretches in different disease proteins.
  • Currently awaiting results on clinical trials involving Co-enzyme Q10, remacemide, and creatine
  • Human fetal nerve cell implants have had mixed findings – when they take, they appear to offer improvement; not yet an accepted treatment (goal would be to use human stem cells); genes do not appear to invade the transplants; small n
  • Reversible mouse model of HD created in 2000 – inserted a genetic switch that allows regulation of the protein (i.e., on or off) – found that a continuous influx of the mutant protein is required to maintain inclusions and symptoms; therefore, treatment might be aimed at preventing protein from being made or increase the removal of the protein – however, maybe huntingtin is crucial for normal brain functioning (i.e., turn off completely disrupts this function); don’t yet know what huntingtin (the gene) does in normal brain
  • Minocycline (antibiotic) found to delay mortality in HD mice (also, delays ALS and reduces size of injury post-CVA); implications for role of oxidants and stress in HD

Ongoing Studies

  • Broadly accepted criteria for clinical diagnosis/onset are lacking – MUST HAVE THIS prior to initiation of clinical tx trial
  • Neuroprotective interventions being studied aren’t implemented until manifest disease – this is rather late in the game for neuronal degeneration
  • We know lots about manifest HD and the gene defect, little about signs, symtoms, experiences, and attitudes of at-risk persons

Neurobiological PREDICTors of HD

  • Study name is PREDICT HD
    • Status: reviewed favorably and awaiting formal notice of funding; enrollment to begin this summer or fall
    • Goal: examine nature and pattern of progression of behavioral neurobiological changes that occur in the period leading up to the diagnosis of HD and to investigate the relations between the progressive prodromal changes, the degree of CAG expansion, and age of onset. (all are critical to design/implementation of future clinical trials)
    • Subjects: (1) 425 CAG expansion >40 (2) 75 At-risk No expansion; 30-55 y/o
    • Design: yearly evals X7 (UHDRS, criteria for disease onset, MRI, neurobehavior/cognition)
    • Inclusion: CAG known via predictive testing and >39; 30-55 y/o, involved sig other
    • Exclusion: any abnormal mvmt d/o, psych illness, EtOH/drug problem 1 yr pre, h/o LD/MR, h/o CNS dz/event, h/o antipsychotics, use of phenothiazine-derivative antiemetics, pacemaker/metallic implants
    • Primary Measures: Disease Onset, MRI (basal ganglia volume), Cognition
    • Secondary Measures: UHDRS, Neurobehavioral Rating Scales (BDI, FLOPS, Neuropsychiatric Inventory, Awareness Interview), CAG repeat length
  • PHAROS (Prospective Huntington At Risk Observational Study):
    • we know nothing about the 97% who have not undergone testing
    • PHAROS is a multi-site, double-concealed observational study
    • Status: reviewed, not funded, revised, resubmitted 3/1/01. In interim, funded by the HDSA to enroll. So far, 450 Ss at 25 sites (beginning 7/99). 19 at U of R (Peter is site PI) – half have returned for a second study visit. Expect completed enrollment of 1000 by 11/01; data analyses completed by 11/06; expect 400 to be HD+
    • Goal: Overall: observational study to find way to reliably measure onset of HD in untreated gene carriers so that therapies (when developed) can be tested. Have to determine when to begin therapy. Also, need to examine ethical issues and feasibility of conducting research in at-risk persons. Specifically:
      • define objective criteria for an early phenotype of HD
      • understand genetic and environmental variables that may influence the onset of the early phenotype of HD
      • clinical research methodology pertaining to the design and conduct of controlled therapeutic trials aimed at postponing onset of the early phenotype of HD
      • counseling and caring for adults at risk for HD
      • care and research of other adult-onset genetic diseases
      • Subjects: 30-55 y/o, 50:50 risk, never tested, can give consent (will enroll people with obvious signs who ‘don’t want to know’, but won’t analyze their data)
    • Design: undergo UHDRS every 9mos
    • Exclusion: dx with manifest HD; neuroleptics within past 6 months; phenothiazine-derivative antiemetics; psychosis or severe depression at screening
    • Primary Outcome Measures: early, HD gene-specific clinical precursors predictive of manifest HD; inter-rater agreement of manifest HD; association of CAG with onset of clinical precursors predictive of manifest HD; relationship between onset of clinical precursors with potential environmental modifiers; characterization of Ss personal beliefs and attitudes re: HD; feasibility of conducting long-term longitudinal research in adults at risk; feasibility of maintaining confidentiality of genetic risk status and genotype and characterization of potential consequences of disclosure of this information; willingness of research participants to consent to future use of DNA samples
    • Predictors: Motor (chorea, dystonia, oculomotor, rapid alternating movements), Cognitive (Stroop, Symbol Digit); will also look at environmental modifiers (diet, caffeine, medications, nutritional supplements, head injury, alcohol, tobacco use, hormone replacement tx)
      • in essence, looking for the other half of the variance in predicting age of onset
      • will gain info re: perceptions of risk, attitudes towards genetic testing, psych well-being, and clinical outcomes of the ‘other’ 97% who elect NOT to know gene status
      • will create a DNA bank for future research

PHAROS vs. PREDICT-HD: The Pharos Advantages

  • PHAROS will allow detection, in a double-concealed fashion, of subtle clinical signs that are specific for HD gene-carrier status and will have immediate application as potential therapeutic outcome measures
  • will also allow for the prospective assessment of the attitudes and beliefs of individuals who wish to remain unaware of their HD gene status.

Genetic Testing

  • despite gene test since 1993, only 3% of persons at-risk have elected testing
  • women seek testing more than men (2.5:1)
    • Current status: presymptomatic, prenatal, confirmation
    • Protocol:
      • initial phone contact,
      • 3 pretest evals (genetic counseling, neurological eval, psych eval)
      • disclosure session
      • post-test counseling
        • should take a good month
        • should identify a support person
        • identify a local counselor for follow-up
  • Pre-testing considerations: is testing necessary, opportunity to defer, informed decision
  • Reasons for declining to pursue:
    • child’s risk status may be revealed
    • lack of cure/tx, health insurance
    • no plans for more children
    • financial costs
    • inability to undo knowledge
    • could lose job/ insurance
    • inability to cope
    • lack of support
    • concerns re: privacy invasion
  • Reasons to deny
    • symptomatic
    • under 18
    • psychiatric instability
    • requesting testing for adoption purposes
  • Reasons to postpone
    • past psychiatric instability
    • poorly thought out reasons for pursuing
    • unstable living situation
    • unwillingness to involve a companion
    • lack of understanding (of disease, of risks, etc)
    • inability to give informed consent
    • recent diagnosis in family member
  • Consequences of HD+:
    • initial difficult adjustment period (many)
    • prolonged emotional distress (few)
    • few regret decision,
    • depression/anxiety common
    • no increase in suicide
    • increase in psychosocial problems (overall, past hx is best predictor)
    • individuals become more present-centered
  • Consequences of HD-: (60% of those tested)
    • most will have improved psych functioning
    • up to 10% may have adverse psych consequence
      • result contradicts expectation
      • consequences of past decisions (e.g., sterilization, finances)
      • survivor guilt
      • contradicts family members’ beliefs
      • psych dysfxn in spouse/sig other – these consequences happen later (2mos-2yrs)
  • Psych effects of prenatal testing: low demand; may disclose parents’ gene status; should definitely have parent tested first (prior to conception)
  • Ethical issues: unauthorized labs/no proper screening/follow-up; advice re: CAG length despite no compelling evidence, privacy/confidentiality (insurance), no tx available, pregnancy termination/voluntary sterilization, knowledge of unsolicited information (e.g., paternity issues), identical twin