when does huntington’s disease begin? richard dubinsky, md, mph university of kansas 11/16/12
TRANSCRIPT
When does Huntington’s Disease Begin?
Richard Dubinsky, MD, MPH
University of Kansas
11/16/12
Disclosures Current NIH/NCAM and FDA
OPD 2CARE CRESTE
CHDI ENROLL-HD Facilitator, redefining
HD across the life span
Completed: NIH: CARE-HD,
PHAROS, PREDICT-HD FDA: RID-HD HSG: Longitudinal
database CHDI: COHORT
HD Gene Cloned 1993,from the Venezuela project Trinucleotide repeat, one of the first three
described CAG expansion Gene product
huntingtin htt
Ross C, Lancet Neurology 2011;10:83-98
CAGn Ranges
<26 normal, 17 most common 26-29 rarely expand 30-36 expand, mostly 35 and 36 35-38 unstable expansion
HD in future generations 39 and above: HD
80% of people with 39 repeats will develop HD
What happened?
Founder effect, maternal germ cell mosaicism
Maternal transmission rarely changes CAGn
Paternal transmission usually expands Mean expansion 6.2 Mean contraction 1.3
Lee JM. Neurology 2012;78:690-5
Onset of HD
Traditionally defined as onset of chorea Always gradual, never sudden Cognitive, behavioral and motor changes
can precede chorea
Determining Clinical Onset
Historical data Chorea Other domains:
Behavior Cognition
UHDRS-99
Copyright © HSG Ltd.
HD: Juvenile Form
Predominance of dystonic rigidity Early cognitive problems Prolonged survival
http://promotingexcellence.org/huntingtons/
Is the initial symptom disease onset?
Frequent phenoconversion after predictive testing
4 x > normal population suicide rate around phenoconversion
HD is not protective against other disorders
HD: Progression
Total Functional Capacity Five domains
Occupation (3) Fiscal (3) Activities of daily living (3) Household chores (2) Residence (2)
T
Slope ~ 0.9/y
HD Disease Models
Weir Lancet Neurology 2011;10:573-9
Ross C, Lancet Neurology 2011;10:83-98
Ross C, Lancet Neurology 2011;10:83-98
Ross C, Lancet Neurology 2011;10:83-98
Lee JM. Neurology 2012;78:690-5
Brinkman R Am J Hum Genet, 1997;60:1202-10
Brinkman R Am J Hum Genet, 1997;60:1202-10
Langbehn D, Am J Med Genet B Neuropscyh 2010;153B:397-408
PREDICT-HD
Prospective cohort study of gene +, asymptomatic subjects and gene – controls Near (onset < 9 years) Mid (onset 9-15 years) Far (onset > 15 years)
Yearly neuroimaging, cognitive and psychomotor testing
Paulsen J, JNNSP 2008;79:874-80
Paulsen J, JNNSP 2008;79:874-80
Paulsen J, Brain Res Bull 2010;82:201-7
Aylward E, JNNSP, 2011;82:405
COHORT
Multi-site, international natural history of HD
People with HD, those at risk, family members, some children
2006-2011 Funded by CHDI
Dorsey, PLoS 2012
Dorsey, PLoS 2012
Dorsey, PLoS 2012
Dorsey, PLoS 2012
Dorsey, PLoS 2012
Symbol Digit Modality / Stroop
red green blue blue green red
red green blue blue green red
+ ( ! < & ^ @ )
1 2 3 4 5 6 7 8
@ @ ) ^ ( + ! +
COHORT: Medication Use
Dorsey, PLoS 2012
Dorsey, PLoS 2012
TRACK-HD
Prospective, longitudinal cohort study Manifest HD Gene + (pre-manifest HD)
Burden of pathology scoreAge x (CAG-35.5)> 250
Gene -, non-matched controls
HD Cohorts
PreHD-A and PreHD-B Dichotomized at median predicted years
to diagnosis (Langbehn score) HD1 and HD2
Stage 1 TFC 11-13 Stage 2 TFC 7-10
TRACK-HD Baseline Characteristics
Tabrizi S, Lancet Neurology 2009
Tabrizi S, Lancet Neurology 2009
Tabrizi S, Lancet Neurology 2009
Tabrizi, S Lancet Neurology. 2012,11:42-35
∆ in Brain Volume
Tabrizi, S Lancet Neurology. 2012,11:42-35
Striatal volumes
Tabrizi, S Lancet Neurology. 2012,11:42-35
Tabrizi, S Lancet Neurology. 2012,11:42-35
Tabrizi, S Lancet Neurology. 2012,11:42-35
Neuropsychological Tests
Tabrizi, S Lancet Neurology. 2012,11:42-35
Tabrizi, S Lancet Neurology. 2012,11:42-35
HD Clinical Trials Completed
CARE-HD RID-HD TETRA-HD TREND-HD MINOS CYTE I PHEND-HD DIMEBOND 1 & 2 HSG Database PHAROS COHORT
Ongoing 2CARE CRESTE-HD PRE-CREST REACH-HD PREDICT-HD
Potential Treatments
RNA Silencing Anti-sense oligonucleotides RNA interference
Delivery Mechanisms
RNAi injected into CSF Virus injected into:
CSF Putamen
Virus inserted into bone marrow Inserted via nanotube and heavy metal
through the olfactory bulbs
Bone Marrow Transplantation?
Mutant htt expressed in many cells Inflammatory markers before and at
phenoconversion Bone marrow derived cells get into the brain
Lancet 2004;363:1432-7
Aronin N NEJM 2012;367-1753
Conclusion
Changes that lead to HD start > 10 years before ‘phenoconversion’
Redefining the onset Research Clinical diagnosis
Implications
Huntington Study Group
Sleep and HD
Insomnia is very common Sun downing Delusions of not sleeping
