Huntington’s Disease

Leon S. Dure, MD The University of Alabama at Birmingham

George Huntington and Huntington’s Disease

Huntington’s Disease

 Unique among choreas  Hereditary, presenting in adult or mid-life  Escapees “the thread is broken”  Never skips a generation  Tendency to insanity and suicide  Manifests only in adult life  Distinct from postinfectious or other choreas

Chorea – Historical Aspects

   St. Vitus (Guy) – imprisoned, thrown to lions, later boiled in oil (c. 303 A.D.) Medieval Germany – 14 Holy Helpers  Dancing at the statue would ensure health  Protection against plague, illness Patron saint of dancers, choreics, epileptics, also actors, comedians, those who oversleep

Chorea - Definition

 Adjective-laden involuntary movement  Frequent, brief, sudden  Twitch-like  Chaotic  Flow of movement from one body part to another  Intrusion of “movement fragments”

Sydenham’s Chorea

 Example of a postinfectous chorea  Consequence of Rheumatic Fever

Clinical Features of HD

  Prevalence Inheritance  Age of Onset 4-10/100,000 Dominant (Anticipation) Expansion of part of the htt gene High penetrance 35-40yrs (2-80) 10% present <18yo  Duration 15-30yrs

Clinical Presentation of HD

 Initial signs and symptoms  Chorea, incoordination, personality changes  Psychiatric diagnoses  Later signs and symptoms  Progressive chorea, dystonia  Dysarthria  Dementia, ongoing psychiatric disturbance

“Typical” HD

 Mid 30’s to 40’s  Difficulty with job  Employment  Household management  Behavioral changes  Impulsivity and altered judgment  Mood swings

Adult HD Clinical Features

JHD Clinical Features

     Onset before 18y Paternal inheritance the norm Primarily hypokinetic (Westphal variant)   Dystonia, tremor, dysarthria Rarely, a late juvenile choreic variant Seizures Rapid course, early death

Variability of JHD

HD/JHD Genetics

  Expansion of translated CAG n , chromosome 4p  Huntingtin protein (htt)  Polyglutamate motif (similar to MCD, SCA-1, etc.)  CAG > 39 correlated with clinical disease JHD associated with “large” expansions  Inheritance    affected father JHD mother/father Expansions > 200 have been described

CAG Expansion and Age of Onset

CAG Repeats in Other Disorders

 Correlation with age of onset  Suggests explanation of anticipation

CAG Expansions

 General rule – lower number relates inversely to rate of decline and severity  Younger people with symptoms have higher repeat lengths  Older people present with milder symptoms  Large expansions a phenomenon of meiosis  Unexplained mechanism  CAG n quite unstable in spermatocytes

Genetic Testing - Types

 Confirmatory  Symptomatic adults and children  Predictive  Unaffected adults at risk  Prenatal Testing  Unborn children  Unaffected children are not tested (usually)

Testing for HD

 Presymptomatic testing available since 1980’s  Simple test since 1994  ~16% of at-risk adults opt for testing  HSG (among others) does not recommend testing of at-risk children  Exceptions  Symptomatic children  Competent children

HD Testing in Children

 Should have some of the cardinal features of the disorder (rigidity, dystonia, etc.)  Psychiatric/behavioral manifestations alone are insufficient to warrant testing  Psychiatric disorders common in HD families  Not always in presymptomatic individuals

Treatment of Chorea

 Benign neglect if at all possible  Neuroleptics can temporarily help chorea  Not a permanent solution, and may do more harm than good  OT/PT evaluations  Speech therapy for swallowing issues  Other medications  Atypical antipsychotics  Amantidine  Tetrabenazine

Tetrabenazine in HD

Behavioral and Psychiatric Care

 Emotional lability/dyscontrol  Cause or consequence of the disease?

 Education of family and patient  Other more serious psychopathology 

Treat as you would any other patient!

Management of JHD

 No cure  No recommendations regarding agents used in adults  Symptomatic therapy  Anticonvulsants  Psychopharmacology therapy  Little data on treating movement disorder  Supportive care  OT/PT  Speech/swallowing issues  Psychosocial support

Neurobiology – What have we learned?

 Trinucleotide repeat diseases  Basis for anticipation  Translated proteins  Gain in function  New or impaired?

 JHD vs. HD neuropathology  HD a disease of whole brain    Most extensive neuronal loss in caudate/putamen Earliest cell loss – MSN projecting to LGP JHD – less discrete, more profound

Functional Pathology

Caudate/Putamen

GABA ENK

LGP MGP

GABA SP

STN Thalamus

Cortical Pathology

  Postmortem studies  Profound cell loss  Global distribution Premortem imaging (presymptomatic HD)   Thickened cortical ribbon Suggests consequence of gain of function

From Nopoulos, et al. American Journal of Psychiatry, 2007

Investigative Models of HD

 R6/2 mice  Knock in construct  Stereotypic phenotype  Other mouse variations  Drosophila macular degeneration  Yeast expression  Cell culture

Neuronal Intranuclear Inclusions (NII)  Ubiquitinated aggregates    Initial observations of Kowall and Ferrante Studies from HD knock-in mice Subsequent identification in human HD brain  NII colocalize with htt protein   NII do not correspond to regions of primary cell loss in cortex Question of how/why htt enters nuclear compartment

N-Q18

2.7  m 1.7  m

N-Q82

Shao, J. et al. Hum. Mol. Genet. 2007

Mutant Huntingtin

BDNF Mutant Htt

Mutated Huntingtin – Possible Roles  Transcriptional alteration  Poly Q domains affect CREB, Sp1, other transcriptional regulators  Protein expression altered   Variety of potential markers identified No “leading” candidates  Metabolic dysfunction  Pathology greatest in regions prone to oxidative stress  Clinical observation of HD muscle

Possible Therapeutic Approaches

      Excitotoxicity Mitochondria Oxidative damage Caspases Aggregates Mutant htt NMDA/glu inhibition Enhance function Free radical scavengers Inhibitors Prevention Disrupt expression

Ambiguity vs. Progress

 How to proceed?

 Employment of accepted preclinical assays  In vitro and in vivo models  Hypothesis-driven testing of compounds  Creatine, minocycline, etc.

 High-throughput screening of compound libraries  Move forward into human clinical trials

Clinical Research

 HSG – dedicated to development and administration of clinical trials in HD with promising compounds   Multicenter Phase 1-4 trials Results of studies have been disappointing – no effective agents to date  New evidence indicating early clinical features  Cognitive and behavioral impairments  Need to study younger subjects

Recent/New Studies

 HART  ARC-16 – a dopaminergic modulator  Studies in HD and AD with promise  2 year treatment trial  CREST-HD  Creatine of possible benefit in prior studies  High dose creatine (45-50mg/kg/day)  2 year treatment trial

Research in Younger Subjects

 Scientific rationale  Early cognitive findings  HD is probably a lifelong disease  Problems with inclusion  Family dynamics  Knowledge of disease risk  Consent/assent

Summary

 HD is hereditary and progressive  Genetic research has been productive  Basis for anticipation  Development of screening/diagnostic testing  Has helped drive neuroscience investigations  Neurobiology of HD is less definitive  Clinical research will remain a challenge