ADULT FRAGILE-X SYNDROME - NEUROPSYCHOLOGY, BRAIN ANATOMY, AND METABOLISM

To understand the implications of suboptimal gene expression in fragil e X syndrome [fra(X)], we sought to define the central nervous abnorma lities in fra(X) syndrome to determine if abnormalities in specific br ain regions or networks might explain the cognitive and behavioral abn ormalities in this syndrome. Cranial and ventricular volumes were meas ured with quantitative computed tomography (CT), regional cerebral met abolic rates for glucose (rCMRglc) were measured with [18-F]-2-fluoro- 2-deoxy-D-glucose (18FDG), and patterns of cognition were determined w ith neuropsychological testing in ten healthy, male patients with kary otypically proven fra(X) syndrome (age range 20-30 yr). Controls for t he CT studies were 20 healthy males (age range 21-37 yr), controls for the PET studies were 9 healthy males (age range 22-31 yr), and contro ls for the neuropsychological tests were 10 young adult, male Down syn drome (DS) subjects (age range 22-31 yr). The mean mental age of the f ra(X) syndrome group was 5.3 yr (range 3.5-7.5 yr; Stanford-Binet Inte lligence Scale). Despite comparable levels of mental retardation, the fra(X) subjects showed poorer attention/short term memory in compariso n to the DS group. Further, the fra(X) subjects showed a relative stre ngth in verbal compared to visuospatial attention/short term memory. A s measured with quantitative CT, 8 fra(X) subjects had a significant ( P < 0.05) 12% greater intracranial volume (1,410 +/- 86 cm(3)) as comp ared to controls (1,254 +/- 122 cm(3)). Volumes of the right and left lateral ventricles and the third ventricle did not differ between grou ps. Seven of eight patients had greater right lateral ventricle volume s than left, as opposed to 9 out of 20 controls (P < 0.05). Global gra y matter CMR-glc in nine fra(X) patients was 9.79 +/- 1.28 mg/100 g/mi nute and did not differ from 8.84 +/- 1.31 mg/100 g/minute in the cont rols. R/L asymmetry in metabolism of the superior parietal lobe was si gnificantly higher in the patients than controls. A preliminary princi pal component analysis of metabolic data showed that the fra(X) subjec ts tended to form a separate subgroup that is characterized by relativ e elevation of normalized metabolism in the lenticular nucleus, thalam us, and premotor regions. Further, a discriminant function, that refle cted rCMRglc interactions of the right lenticular and left premotor re gions, distinguished the fra(X) subjects from controls. These regions are part of a major group of functionally and anatomically related bra in regions and appear disturbed as well in autism with which fra(X) ha s distinct behavioral similarities. These results show a cognitive pro file in fra(X) syndrome that is distinct from that of Down syndrome, t hat the larger brains in fragile X syndrome are not accompanied by gen eralized cerebral cortical atrophy or hypoplasia, and that distinctive alterations in resting regional glucose metabolism, measured with 18 FDG and PET, occur in fra(X) syndrome. (C) 1995 Wiley-Liss, Inc.