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