presented by Clinical Professor Peter K Panegyres MD PhD FRACP

1. 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

2. Paulsen et al, Progress Neurobio2013; 110, 4

3. Neurodegeneration Risk Spectrum Mendelian genes Genetic risk factors Non-genetic risk factors

4. The larger the CAG repeat length, the earlier the Huntington’s disease : the role of gene modifiers Arning & Epplen, Future Neurol, 2012, 94

5. Modifier gene products on the age at onset in HD

6. CAG Repeat Counts on the Huntington gene

7. Intermediate CAG Repeat Lengths

8. Intermediate CAG Repeat Lengths • Controversies 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

9. Intermediate CAG Repeat Lengths • Previous 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 EARLY J NeurolSci 2011

10. CAG 38

11. CAG 39

12. Intermediate CAG Repeat Lengths • CAG 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

13. Aim To 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

14. 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

15. Results

16. Results • CAG 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

17. Results • CAG = 36-39 • N = 17 manifest at baseline • 54.7% mother with HD (p < 0.001)

18. Results • Total motor score • Maximal chorea score • Maximal dystonia score • Total functional assessment • Independence scale • Total functional capacity Significant difference CAG 36-39 vs 27-35

19. Interaction of UHDRS measures with time for patients with intermediate CAG repeat lengths over 4 years

20. Results • CAG = 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

21. Results * The OR was also adjusted for gender and the history of psychiatric disease

22. Conclusion Manifest HD CAG 36-39 • Factors increasing risk • Age • Smoking • Factor reducing risk • Higher education Ageing Smoking Premanifest HD Manifest HD Cognitive Reserve +

23. Conclusion CAG 36-39 CAG Repeat Length CAG ≥40 Age at onset

24. Modelling neurodegeneration using the Prion hypothesis Prusiner, Science, 2012; 336: 1511

25. Acknowledgements • Ellie Shu • Data collection and analysis • Tom HY Chen • Statistical analysis and modelling • Jane Paulsen • Intellectual content • Cheryl MacFarlane • Project management • Staff at NDR

26. Questions & Answers