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Intermediate CAG repeats: Analysis of the Cooperative Huntington’s Observational Research Trial (COHORT) Ainhi D. Ha, MBBS 1, Christopher A. Beck, PhD.

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Presentation on theme: "Intermediate CAG repeats: Analysis of the Cooperative Huntington’s Observational Research Trial (COHORT) Ainhi D. Ha, MBBS 1, Christopher A. Beck, PhD."— Presentation transcript:

1 Intermediate CAG repeats: Analysis of the Cooperative Huntington’s Observational Research Trial (COHORT) Ainhi D. Ha, MBBS 1, Christopher A. Beck, PhD 2, Joseph Jankovic, MD 1 1 Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas 2 Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York No Relevant Financial Disclosures

2 The American College of Medical Genetics/American Society of Human Genetics (ACMG/ASHG) Huntington Disease Genetic Testing Working Group Category DescriptionCAG Repeat Range Predicted Phenotype Normal allele<=26Normal Mutable normal allele (Intermediate) 27-35Normal HD allele with reduced penetrance 36-39Normal/HD HD allele>=40HD

3 Can Intermediate Repeats Cause Clinical Manifestations of Huntington’s Disease? Age of Onset CAG Repeat Size Clinical Manifestations Family History of HD 60 1 29, 20 Chorea, depression, motor impersistance Negative 68 2 33,- Jerky ocular pursuit, increased latency saccade initiation Positive 60 3 34, 17 Chorea, dystonia, interrupted ocular pursuit, dysarthria, dysphagia Negative 48 4 34, 16 Chorea, dysarthria, slow saccades, depression Positive 68 5 31, 18 Chorea, tremor, interrupted ocular pursuit, memory impairmentPositive 1 Kenney et al (2007), 2 Squitieri et al (2011), 3 Andrich et al (2008), 4 Herishanu et al (2009), 5 Groen et al (2010),

4 Aim  To define the clinical characteristics of individuals who possess intermediate length CAG repeats in the Huntingtin (HTT) gene.

5 Methods  Analysis of COHORT 1985 subjects  HD (CAG >=36): 1290 (65%)  Intermediate (CAG 27-35): 50 (2.5%)  Normal (CAG <=26): 645 (32%) Investigators blinded to CAG repeat length Baseline data

6 Distribution of Subjects with Intermediate CAG Repeats (N=50)

7 Unified Huntington’s Disease Rating Scale (UHDRS)  Motor Oculomotor function Dysarthria Chorea Dystonia Gait Postural stability  Cognitive Verbal Fluency Symbol Digit Modalities Stroop Interference Test  Behavioral Depressed mood Apathy Suicidal thoughts Anxiety Delusions Hallucinations  Functional Independence scale Functional capacity Functional assessment

8 UHDRS: Motor Domain Comparisons Normal (N=645) Intermediate (N=50) p-value (Norm vs. I) HD (N=1290) p-value (HD vs. I) Total UHDRS motor assessment 1.72 (2.91)2.16 (3.14)NS 30.11 (21.96) <.0001 Total maximal chorea score 0.08 (0.41)0.16 (0.59)NS7.72 (5.99)<.0001 Total maximal dystonia score 0.01 (0.14)0.10 (0.42)0.00142.64 (3.60)<.0001 Mean (SD)

9 UHDRS: Behavioral Domain Comparisons Normal (N=645) Intermediate (N=50) p-value (Norm vs. I) HD (N=1290) p-value (HD vs. I) UHDRS Behavioral frequency 4.39 (4.33)5.06 (4.48)NS6.94 (6.25)0.0273 UHDRS Behavioral frequency x severity 6.27 (9.12)8.28 (10.87)NS 13.5 (15.87) 0.0186 Mean (SD)

10 UHDRS: Cognitive Domain Comparisons Normal (N=645) Intermediate (N=50) p-value (Norm vs. I) HD (N=1290) p-value (HD vs. I) UHDRS Verbal fluency 40.25 (11.84) 38.44 (11.51)NS26.43 (14.88)<.0001 UHDRS Symbol digit modalities test 47.3 (10.91)45.65 (9.79)NS30.11 (15.28)<.0001 UHDRS Stroop color naming 74.6 (15.32)72.27 (12.58)NS52.05 (20.86)<.0001 UHDRS Stroop word reading 95.7 (18.36)89.96 (16.67)0.018767.39 (26.10)<.0001 UHDRS Stroop interference 43.4 (13.35)41.79 (11.59)NS30.43 (14.74)<.0001 Mean (SD)

11 Comparison of Individual UHDRS Motor Items between Normal and Intermediate Groups

12 Comparison of Individual UHDRS Behavioral Items between Normal and Intermediate Groups

13 Comparison of Intermediate Vs Normal and HD Normal (N=645) Intermediate (N=50) p-value (N vs. I) HD (N=1290) p-value (HD vs. I) History of at least one suicide attempt [%] 1.46.00.04866.41.0000

14

15 Summary: Intermediate vs. normal  Comparison of Means: Total Maximal Dystonia Score (p=0.001) UHDRS Stroop word reading (p=0.019) Comparison of Distributions Across Individual UHDRS Scores:  Motor  Vertical Saccade Velocity (p=0.045)  Maximal Dystonia RUE (p= 0.004)  Maximal Chorea LLE (p=0.026)  Behavior  Depressed Mood – Severity (p=0.019)  Suicidal Thoughts Severity (p= 0.013)  History of at least one suicide attempt (p=0.049)

16 Conclusions Differences in UHDRS scores were identified between normal and intermediate groups on exploratory analysis. The presence of intermediate CAG repeats may influence the phenotype of these individuals.

17 Acknowledgements  Huntington Study Group  Dr. Ray Dorsey  Dr. Ira Shoulson  Anthony Davidson  Statistical analysis conducted by Dr. Christopher A. Beck

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