when does huntington’s disease begin? richard dubinsky, md, mph university of kansas 11/16/12
TRANSCRIPT
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
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
Onset of HD
Traditionally defined as onset of chorea Always gradual, never sudden Cognitive, behavioral and motor changes
can precede chorea
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
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
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
Symbol Digit Modality / Stroop
red green blue blue green red
red green blue blue green red
+ ( ! < & ^ @ )
1 2 3 4 5 6 7 8
@ @ ) ^ ( + ! +
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
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
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
Conclusion
Changes that lead to HD start > 10 years before ‘phenoconversion’
Redefining the onset Research Clinical diagnosis
Implications