presented by Clinical Professor Peter K Panegyres MD PhD FRACP
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Factors Influencing the Clinical Expression of Intermediate CAG Repeat Length Mutations of the Huntington’s Disease Gene presented by Clinical Professor Peter K Panegyres MD PhD FRACP www.ndr.org.au
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Factors Influencing the Clinical Expression of Intermediate CAG Repeat Length Mutations of the Huntington’s Disease Gene. presented by Clinical Professor Peter K Panegyres MD PhD FRACP. www.ndr.org.au. Paulsen et al, Progress Neurobio 2013; 110, 4. Neurodegeneration Risk Spectrum. - PowerPoint PPT Presentation
Transcript of presented by Clinical Professor Peter K Panegyres MD PhD FRACP
Factors Influencing the Clinical Expression of Intermediate CAG Repeat Length Mutations of the
Huntington’s Disease Gene
presented by
Clinical Professor Peter K PanegyresMD PhD FRACP
www.ndr.org.au
Paulsen et al, Progress Neurobio 2013; 110, 4
Neurodegeneration Risk Spectrum
Mendelian genes
Genetic risk factors
Non-genetic risk factors
The larger the CAG repeat length, the earlier the Huntington’s disease : the role of gene modifiers
Arning & Epplen, Future Neurol, 2012, 94
Modifier gene products on the age at onset in HD
CAG Repeat Counts on the Huntington gene
Intermediate CAG Repeat Lengths
Intermediate CAG Repeat LengthsControversies exist with interpretation
of intermediate CAG repeat lengths
CAG ≥ 40 PREDICT-HD phenotype
36-39 might develop HD phenotype with reduced severity and risk of offspring developing HD
27-35 might have normal phenotype but offspring might develop HD
Am J Hum Genet 1998
Intermediate CAG Repeat LengthsPrevious studies 2011
Longitudinal evaluation: 10 patients, 5 years
Syndrome chorea (perioral), subtle cognitive defects, ataxia
N=4 formal diagnosis HD
Long-term follow-up essential as the experience suggested that medical disorders, treatments, environmental and other genetic factors J Neurol Sci 2011
EARLY
CAG 38
CAG 39
Intermediate CAG Repeat LengthsCAG 27-35
Some might have significant behavioural abnormalities without cognitive or motor defects
CAG 27-35 Some features of HD with negative work-up for
phenocopies
CAG 32 Had neuropathological evidence of HD
CAG 32-35 Might be at risk of developing HD, especially if
family history
AimTo further elucidate the clinical significance of intermediate CAG repeat lengths using the COHORT database
Study groups: CAG = 36-39; CAG = 27-35
FACTORS
Premanifest HD Manifest HD
Methods COHORT
Global longitudinal prospective study to gather genetic and biological information + socioeconomic status from subjects with HD and their families
2006-2011
N = 2318
Baseline (year 1) demography, medical history, physical exam, neurological exam, vital signs, UHDRS, MMSE, medications, HD gene result
Information collected annually
Univariable logistic regression
Multivariable logistic modelling
Results
The data set of CAG repeat length
CAG group N %
≤ 26 721 33.27
27-35 62 2.86
36-39 59 2.72
≥ 40 1325 61.14
ResultsCAG 36-39
N = 3 conversions premanifest manifest
CAG 27-35 N = 0 no conversions
Probability diagnosis HD CAG = 36-39 = 25 x (95% CI 3-39)
than 27-35
No demographic differences CAG 36-39 vs 27-35
Results
CAG = 36-39
N = 17 manifest at baseline
54.7% mother with HD (p < 0.001)
ResultsTotal motor scoreMaximal chorea scoreMaximal dystonia
scoreTotal functional
assessmentIndependence scaleTotal functional
capacity
Significant difference CAG 36-39 vs 27-35
Base-line
V1 V2 V3 V40.000.501.001.502.002.503.003.504.00 Maximal Chorea Score
Base-line
V1 V2 V3 V40.00
0.20
0.40
0.60
0.80
1.00
1.20Maximal Dystonia Score
Base-line
V1 V2 V3 V40.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00Total Motor Score
Base-line
V1 V2 V3 V4-1.00
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00Stroop Score
Base-line
V1 V2 V3 V40.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
Behaviour Frequency-Severity Score
Base-line
V1 V2 V3 V421.5022.0022.5023.0023.5024.0024.5025.0025.50 Functional Assessment
Total
Base-line
V1 V2 V3 V486.00
88.00
90.00
92.00
94.00
96.00
98.00
100.00
102.00Independence Scale
Base-line
V1 V2 V3 V410.0
10.5
11.0
11.5
12.0
12.5
13.0
13.5 Total Functional Ca-pacity Score
Base-line
V1 V2 V3 V426.5
27.0
27.5
28.0
28.5
29.0
29.5
30.0
30.5MMSE
Interaction of UHDRS measures with time for patients with intermediate CAG repeat lengths over 4 years
ResultsCAG = 36-39
Total motor score
Maximal chorea score
Maximal dystonia score
Total functional assessment
Independence scale
MMSE
Significant differences in manifest HD than those who did not
ResultsMultivariable Logistic Model
MODEL Adjusted OR*
(95% CI) P-value
Age 24-39 1
40-64 0.37 (0.03-5.08)
0.04
≥ 65 5.81 (0.37-90.58)
0.02
Highest education
- Some college (no degree)
1
- Associated degree and higher
0.10 (0.02-0.54)
0.007
Smoking behaviour No
1
Yes (active & non-active)
13.99 (2.03-96.44)
0.007
* The OR was also adjusted for gender and the history of psychiatric disease
ConclusionManifest HD CAG 36-39
Factors increasing risk Age Smoking
AgeingSmoking
Premanifest HDManifest HD
Cognitive Reserve
+
Factor reducing risk Higher
education
Conclusion
CAG 36-39
CAG ≥40
CAGRepeatLength
Age at onset
Prusiner, Science, 2012; 336: 1511Modelling neurodegeneration using the Prion hypothesis
AcknowledgementsEllie Shu
Data collection and analysisTom HY Chen
Statistical analysis and modellingJane Paulsen
Intellectual contentCheryl MacFarlane
Project managementStaff at NDR
Questions & Answers
