Neuropsychological manifestations of the genetic mutation for Huntington's disease in presymptomatic individuals.
A triplet repeat (CAG) expansion mutation in the huntingtin gene on chromosome 4 is responsible for Huntington's disease (HD). Presymptomatic genetic testing for this mutation has identified clinically normal persons who are virtually certain to develop this dementing illness if they live a normal lifespan. The present study sought to determine whether these "mutation-positive" persons have impairments in cognitive functioning. Seventy-five mutation-positive persons did not differ from 128 mutation-negative persons on tests selected for their sensitivity to early-stage HD. Interestingly, however, those with the mutation viewed themselves as more likely to develop HD than did those without the mutation. Among mutation-positive subjects, having a longer CAG repeat mutation was likewise not associated with cognitive impairment. However, being closer to estimated disease onset (a product of repeat length and parent's age at onset) was associated with selected cognitive impairments. When viewed in light of previous studies showing atrophy of the caudate nucleus and putamen in mutation-carriers who are close to onset but not those far from onset, these results suggest that subtle changes in brain and behavior may be detected shortly before subjects with the HD mutation develop sufficient signs and symptoms for diagnosis. Conceptual and methodological problems associated with the search for presymptomatic cognitive and behavioral indicators of dementing illness are discussed.
Brandt
Jason
J
Baltimore Huntington's Disease Research Center, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, MD, USA. jbrandt@jhmi.edu
Shpritz
Barnett
B
Codori
Ann Marie
AM
Margolis
Russell
R
Rosenblatt
Adam
A
D000328:Adult; D001479:Basal Ganglia / Q000473:pathology; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D003072:Cognition Disorders / Q000175:diagnosis* / Q000209:etiology; D003342:Corpus Striatum / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009483:Neuropsychological Tests; D009687:Nuclear Proteins / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018911:Trinucleotide Repeats / Q000235:genetics
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins