intermediate cag repeats: analysis of the cooperative huntington’s observational research trial...
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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