Intermediate CAG repeats: Analysis of the Cooperative Huntington’s Observational Research Trial (COHORT)

Ainhi D. Ha, MBBS1, Christopher A. Beck, PhD2, Joseph Jankovic, MD1

1Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas 2Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York

No Relevant Financial Disclosures

The American College of Medical Genetics/American Society of Human Genetics (ACMG/ASHG) Huntington Disease Genetic Testing Working Group

Category Description CAG Repeat Range Predicted Phenotype

Normal allele <=26 Normal

Mutable normal allele (Intermediate)

27-35 Normal

HD allele with reduced penetrance

36-39 Normal/HD

HD allele >=40 HD

Can Intermediate Repeats Cause Clinical Manifestations of Huntington’s Disease?

Age of Onset

CAG Repeat Size Clinical Manifestations

Family History of

HD

601 29, 20 Chorea, depression, motor impersistance Negative

682 33,- Jerky ocular pursuit, increased latency saccade initiation Positive

603 34, 17 Chorea, dystonia, interrupted ocular pursuit, dysarthria, dysphagia Negative

484 34, 16 Chorea, dysarthria, slow saccades, depression Positive

685 31, 18Chorea, tremor, interrupted ocular pursuit, memory impairment Positive

1Kenney et al (2007), 2Squitieri et al (2011), 3Andrich et al (2008), 4Herishanu et al (2009), 5Groen et al (2010),

Aim

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

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

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

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

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) NS 7.72 (5.99) <.0001

Total maximal dystonia score 0.01 (0.14) 0.10 (0.42) 0.0014 2.64 (3.60) <.0001

Mean (SD)

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) NS 6.94 (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)

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) NS 26.43 (14.88) <.0001

UHDRS Symbol digit modalities test 47.3 (10.91) 45.65 (9.79) NS 30.11 (15.28) <.0001

UHDRS Stroop color naming 74.6 (15.32) 72.27 (12.58) NS 52.05 (20.86) <.0001

UHDRS Stroop word reading 95.7 (18.36) 89.96 (16.67) 0.0187 67.39 (26.10) <.0001

UHDRS Stroop interference 43.4 (13.35) 41.79 (11.59) NS 30.43 (14.74) <.0001

Mean (SD)

Comparison of Individual UHDRS Motor Items between Normal and Intermediate Groups

Comparison of Individual UHDRS Behavioral Items between Normal and Intermediate Groups

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 [%] 1.4 6.0 0.0486 6.4 1.0000

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)

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.

Acknowledgements

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

Beck