Transcript Juvenile Huntington’s Disease

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
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Hereditary, presenting in adult or mid-life
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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
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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
4-10/100,000
Dominant (Anticipation)
Expansion of part of the htt gene
High penetrance
 Age of Onset
35-40yrs (2-80)
10% present <18yo
 Duration
15-30yrs
Clinical Presentation of HD
 Initial signs and symptoms
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Chorea, incoordination, personality changes
Psychiatric diagnoses
 Later signs and symptoms
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Progressive chorea, dystonia
Dysarthria
Dementia, ongoing psychiatric disturbance
“Typical” HD
 Mid-30’s to 40’s
 Difficulty with job
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Employment
Household management
 Behavioral changes
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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
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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
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Younger people with symptoms have higher
repeat lengths
Older people present with milder symptoms
 Large expansions a phenomenon of meiosis
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Unexplained mechanism
CAGn quite unstable in spermatocytes
Genetic Testing - Types
 Confirmatory
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Symptomatic adults and children
 Predictive
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Unaffected adults at risk
 Prenatal Testing
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Unborn children
 Unaffected children are not tested (usually)
Testing for HD
 Presymptomatic testing available since
1980’s
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Simple test since 1994
~16% of at-risk adults opt for testing
 HSG (among others) does not recommend
testing of at-risk children
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Exceptions
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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
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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
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Cause or consequence of the disease?
Education of family and patient
 Other more serious psychopathology
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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
GABA
SP
LGP
MGP
STN
Thalamus
Cortical Pathology
 Postmortem studies
Profound cell loss
 Global distribution
 Premortem imaging (presymptomatic HD)
 Thickened cortical ribbon
 Suggests consequence of gain of function
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From Nopoulos, et al. American Journal of Psychiatry, 2007
Investigative Models of HD
 R6/2 mice
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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
N-Q82
2.7 m
1.7 m
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
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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
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In vitro and in vivo models
Hypothesis-driven testing of compounds
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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
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Multicenter Phase 1-4 trials
 Results of studies have been disappointing –
no effective agents to date
 New evidence indicating early clinical
features
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Cognitive and behavioral impairments
Need to study younger subjects
Recent/New Studies
 HART
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ARC-16 – a dopaminergic modulator
Studies in HD and AD with promise
2 year treatment trial
 CREST-HD
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Creatine of possible benefit in prior studies
High dose creatine (45-50mg/kg/day)
2 year treatment trial
Research in Younger Subjects
 Scientific rationale
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Early cognitive findings
HD is probably a lifelong disease
 Problems with inclusion
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Family dynamics
Knowledge of disease risk
Consent/assent
Summary
 HD is hereditary and progressive
 Genetic research has been productive
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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