presented by clinical professor peter k panegyres md phd fracp
DESCRIPTION
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 PresentationTRANSCRIPT
![Page 1: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/1.jpg)
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
![Page 2: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/2.jpg)
Paulsen et al, Progress Neurobio 2013; 110, 4
![Page 3: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/3.jpg)
Neurodegeneration Risk Spectrum
Mendelian genes
Genetic risk factors
Non-genetic risk factors
![Page 4: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/4.jpg)
The larger the CAG repeat length, the earlier the Huntington’s disease : the role of gene modifiers
Arning & Epplen, Future Neurol, 2012, 94
![Page 5: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/5.jpg)
Modifier gene products on the age at onset in HD
![Page 6: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/6.jpg)
CAG Repeat Counts on the Huntington gene
![Page 7: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/7.jpg)
Intermediate CAG Repeat Lengths
![Page 8: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/8.jpg)
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
![Page 9: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/9.jpg)
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
![Page 10: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/10.jpg)
CAG 38
![Page 11: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/11.jpg)
CAG 39
![Page 12: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/12.jpg)
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
![Page 13: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/13.jpg)
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
![Page 14: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/14.jpg)
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
![Page 15: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/15.jpg)
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
![Page 16: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/16.jpg)
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
![Page 17: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/17.jpg)
Results
CAG = 36-39
N = 17 manifest at baseline
54.7% mother with HD (p < 0.001)
![Page 18: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/18.jpg)
ResultsTotal motor scoreMaximal chorea scoreMaximal dystonia
scoreTotal functional
assessmentIndependence scaleTotal functional
capacity
Significant difference CAG 36-39 vs 27-35
![Page 19: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/19.jpg)
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
![Page 20: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/20.jpg)
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
![Page 21: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/21.jpg)
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
![Page 22: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/22.jpg)
ConclusionManifest HD CAG 36-39
Factors increasing risk Age Smoking
AgeingSmoking
Premanifest HDManifest HD
Cognitive Reserve
+
Factor reducing risk Higher
education
![Page 23: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/23.jpg)
Conclusion
CAG 36-39
CAG ≥40
CAGRepeatLength
Age at onset
![Page 24: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/24.jpg)
Prusiner, Science, 2012; 336: 1511Modelling neurodegeneration using the Prion hypothesis
![Page 25: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/25.jpg)
AcknowledgementsEllie Shu
Data collection and analysisTom HY Chen
Statistical analysis and modellingJane Paulsen
Intellectual contentCheryl MacFarlane
Project managementStaff at NDR
![Page 26: presented by Clinical Professor Peter K Panegyres MD PhD FRACP](https://reader037.vdocuments.mx/reader037/viewer/2022102909/56812e5a550346895d940174/html5/thumbnails/26.jpg)
Questions & Answers