When does Huntington’s Disease
Begin?
Richard Dubinsky, MD, MPH
University of Kansas
11/16/12
Disclosures
 Current
 NIH/NCAM and FDA
 Completed:
 NIH: CARE-HD,
OPD
 2CARE
 CRESTE
 CHDI
 ENROLL-HD
 Facilitator, redefining
HD across the life
span
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
Slope ~ 0.9/y
 Five domains
 Occupation (3)
 Fiscal (3)
T
 Activities of daily living (3)
 Household chores (2)
 Residence (2)
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
+
(
!
<
&
^
@
)
1
2
3
4
5
6
7
8
@
@
)
^
(
+
!
+
red green blue blue green red
red green blue blue green red
COHORT: Medication Use
Dorsey, PLoS 2012
Dorsey, PLoS 2012
TRACK-HD
 Prospective, longitudinal cohort study
 Manifest HD
 Gene + (pre-manifest HD)
 Burden of pathology score
 Age 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
∆ 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
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