Huntington’s Disease

Leon S. Dure, MDThe 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

Duration

4-10/100,000

Dominant (Anticipation)Expansion of part of the htt gene

High penetrance

35-40yrs (2-80)10% present <18yo

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 CAGn, 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 CAGn 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

MGP

Thalamus

LGP

STN

GABAENK GABA

SP

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

2.7 mN-Q18

1.7 mN-Q82

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

BDNF

Mutant Htt

Mutant Huntingtin

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