Impaired sequence learning in carriers of the DYT1 dystonia mutation

• Published in: Annals of neurology Vol. 54; no. 1; pp. 102 - 109
• Main Authors: Ghilardi, Maria-Felice, Carbon, Maren, Silvestri, Giulia, Dhawan, Vijay, Tagliati, Michele, Bressman, Susan, Ghez, Claude, Eidelberg, David
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2003; Willey-Liss
• Subjects: Biological and medical sciences; Carrier Proteins - genetics; Cerebellum - blood supply; Cerebellum - diagnostic imaging; Cerebellum - metabolism; Diseases of striated muscles. Neuromuscular diseases; Dystonia - complications; Dystonia - diagnosis; Dystonia - genetics; Female; Functional Laterality - physiology; Glucose - metabolism; Heterozygote; Humans; Learning Disorders - complications; Learning Disorders - diagnosis; Male; Medical sciences; Middle Aged; Molecular Chaperones; Neurology; Point Mutation - genetics; Prefrontal Cortex - blood supply; Prefrontal Cortex - diagnostic imaging; Prefrontal Cortex - metabolism; Psychomotor Performance; Random Allocation; Severity of Illness Index; Tomography, Emission-Computed; Cerebellum; Human; Nervous system diseases; Supplementary motor area; Nucleotide sequence; Prefrontal cortex; Glucose; Metabolism; Cerebral disorder; Involuntary movement; Learning; Striated muscle disease; Central nervous system disease; Premotor cortex; Dystonia; Mutation; Neurological disorder; Extrapyramidal syndrome; Positron; Emission tomography
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.10610

Previous positron emission tomography (PET) studies have shown that nonmanifesting carriers of the DYT1 dystonia mutation express an abnormal pattern of resting glucose metabolism. To determine whether motor behavior is impaired in these subjects, we compared movement and sequence learning in 12 clinically unaffected DYT1 carriers with 12 age‐matched controls. Regional differences in brain function during task performance were assessed with simultaneous H215O/PET. We found that motor performance was similar in the DYT1 and control groups, with no significant differences in movement time and spatial accuracy measured during each of the tasks. In contrast, sequence learning was reduced in gene carriers relative to controls (p < 0.01). PET imaging during motor execution showed increased activation in gene carriers (p < 0.001, uncorrected) in the left premotor cortex and right supplementary motor area, with concomitant reduction in the posterior medial cerebellum. During sequence learning, activation responses in DYT1 carriers were increased in the left ventral prefrontal cortex, and lateral cerebellum. These findings suggest that abnormalities in motor behavior and brain function exist in clinically nonmanifesting DYT1 carriers. Although localized increases in neural activity may enable normal movement execution in these subjects, this mechanism may not compensate for their defect in sequence learning. Ann Neurol 2003;54:102–109