A profile of cognitive deficit in females from fragile X families.

Fragile X, a recently discovered X-linked syndrome, is usually associated with mental retardation in affected males. Less consistent findings have been described for females. neuropsychological evaluation of seven nonretarded females from fragile X families suggested a characteristic profile: on Wechsler IQ tests, a positive Verbal-Performance score difference and lower subtest scaled scores on Arithmetic, Digit Span, Block Design, and Object Assembly; on the Wide Range Achievement Test, a lower score on Arithmetic than on Reading or Spelling; and on the Benton Visual Retention Test, defective recall. These results suggest the existence of X-linked learning disability in females.

Longer brainstem auditory evoked response latencies of individuals with fragile X syndrome related to sedation.

Brainstem auditory evoked response latencies were studies in 75 males (13 with fragile X syndrome, 18 with mental retardation due to other causes, and 44 with no disability). Latency values were obtained for each ear for the positive deflections of waves I (P1), III (P3), and V (P5). Some individuals with mental retardation required sedation. Contrary to previous report, latencies obtained for individuals with fragile X did not differ from those obtained for persons without mental retardation. Persons receiving sedation, whether or not their retardation was due to fragile X, had longer latencies for wave P5 than persons who did not receive sedation. This effect of sedation may also explain the previously reported increased latencies for persons with fragile X.

The Fra(X) syndrome: neurological, electrophysiological, and neuropathological abnormalities.

We have evaluated 62 fragile X syndrome [fra(X)] individuals (55 males and 7 females) with different degrees of developmental disabilities that were clinically non-progressive and non-focal in character. The mean age for the 55 males was 23.1 years +/- 14.3 SD with a range of 2-70: for the 7 females, the mean age was 15.7 years +/- 3.5 SD with a range of 10-20 years. Mental retardation (MR) was found in 53 males (8/53 [15.1%] mild, 26/53 [49.1%] moderate, 14/53 [26.4%] severe, and 5/53 [9.4%] profound). Learning disabilities were found in 2/55 (3.6%) of males. One of the 7 females had mild and one had moderate MR: the other 5 were learning disabled. Autistic stigmata were present in 10/62 (16%) of the patients. Only 14/62 (23%) had a history of seizures, all of which were controlled with anticonvulsants. In 36/62 cases, an electroencephalogram (EEG) was performed. We compared these data with that of others. Brain stem auditory evoked response (BAER) was performed in 12 cases. Abnormalities were found in only 5/12. Neuroimaging and computerized cranial transaxial tomography (CT scan) were performed on 21/62 (34%) of the patients. Only 8 of these 21 (38%) studies were abnormal. One patient died; neuropathological studies showed mild brain atrophy, with light microscopic and ultrastructural abnormalities. Rapid Golgi dendritic spine patterns showed that the proximal apical segments were abnormally developed. Very thin, long tortuous spines with prominent terminal heads and irregular dilatations were present. Marked reductions in the length of the synapses, as determined on EPTA-postfixed tissue where noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Mode of inheritance influences behavioral expression and molecular control of cognitive deficits in female carriers of the fragile X syndrome.

The effect of mode of inheritance on expression of fragile X syndrome [fra(X)] was investigated in nonretarded female carriers. Examination included cognitive and molecular measures. A priori predictions about cognitive impairment and size of an unstable region of DNA containing a CGG repeat on the X chromosome were tested in age and education matched heterozygotes grouped according to parental inheritance. Nine carriers with a maternal fra(X) chromosome, 11 carriers with a paternal fra(X) chromosome and 15 control mothers of children with non X-linked developmental disabilities were tested. Inheritance was established through DNA linkage analysis. Cognitive skills were assessed using the Wechsler Adult Intelligence Scale-Revised and the Benton Visual Retention Test. Molecular status was assessed by Southern blot analysis of genomic DNA digested with Eco RI and Eag I, and probed with StB 12.3. Results supported the inheritance models' predictions. Heterozygotes who inherited the fra(X) from their fathers appeared to be a homogeneous group. They were indistinguishable from controls on cognitive measures and all had genomic insertions of less than 500 base pairs. In contrast, heterozygotes who inherited the fra(X) chromosome from their mothers appeared to be made up of 2 sub-populations. They were as a group deficient in measures of attention and visual memory, but not other measures, with scores of some women consistently below the other subjects. Further, they had some members with greater than 500 base pair inserts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult fragile X syndrome: neuropsychology, brain anatomy, and metabolism.

To understand the implications of suboptimal gene expression in fragile X syndrome -fra(X)-, we sought to define the central nervous abnormalities in fra(X) syndrome to determine if abnormalities in specific brain regions or networks might explain the cognitive and behavioral abnormalities in this syndrome. Cranial and ventricular volumes were measured with quantitative computed tomography (CT), regional cerebral metabolic rates for glucose (rCMRglc) were measured with [18-F]-2-fluoro-2-deoxy-D-glucose (18FDG), and patterns of cognition were determined with neuropsychological testing in ten healthy, male patients with karyotypically proven fra(X) syndrome (age range 20-30 yr). Controls for the 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 controls for the neuropsychological tests were 10 young adult, male Down syndrome (DS) subjects (age range 22-31 yr). The mean mental age of the fra(X) syndrome group was 5.3 yr (range 3.5-7.5 yr; Stanford-Binet Intelligence Scale). Despite comparable levels of mental retardation, the fra(X) subjects showed poorer attention/short term memory in comparison to the DS group. Further, the fra(X) subjects showed a relative strength in verbal compared to visuospatial attention/short term memory. As measured with quantitative CT, 8 fra(X) subjects had a significant (P < 0.05) 12% greater intracranial volume (1,410 +/- 86 cm3) as compared to controls (1,254 +/- 122 cm3). Volumes of the right and left lateral ventricles and the third ventricle did not differ between groups. Seven of eight patients had greater right lateral ventricle volumes than left, as opposed to 9 out of 20 controls (P < 0.05). Global gray matter CMR-glc in nine fra(X) patients was 9.79 +/- 1.28 mg/100 g/minute and did not differ from 8.84 +/- 1.31 mg/100 g/minute in the controls. R/L asymmetry in metabolism of the superior parietal lobe was significantly higher in the patients than controls. A preliminary principal component analysis of metabolic data showed that the fra(X) subjects tended to form a separate subgroup that is characterized by relative elevation of normalized metabolism in the lenticular nucleus, thalamus, and premotor regions. Further, a discriminant function, that reflected rCMRglc interactions of the right lenticular and left premotor regions, distinguished the fra(X) subjects from controls. These regions are part of a major group of functionally and anatomically related brain regions and appear disturbed as well in autism with which fra(X) has distinct behavioral similarities. These results show a cognitive profile in fra(X) syndrome that is distinct from that of Down syndrome, that the larger brains in fragile X syndrome are not accompanied by generalized 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.

Aberrant lateralization of brainstem auditory evoked responses by individuals with Down syndrome.

Brainstem auditory evoked response latencies were studied in 80 males (13 with Down syndrome, 23 with developmental disability due to other causes, and 44 with no disability). Latencies for waves P3 and P5 were shorter for the Down syndrome than for the other groups, though at P5, as compared to latencies for the nondisabled group, the difference was not significant. The pattern of left versus right ear responses in the Down syndrome group differed from those of the other groups. This finding was related to research noting decreased lateralization of and decreased ability at receptive and expressive language among people with Down syndrome. Some individuals required sedation. A lateralized effect of sedation was noted.

Cognitive and molecular aspects of fragile X.

The relationships among parental origin of the fragile X gene, gene structure, and specific cognitive deficits were evaluated in nonretarded adult female fragile X carriers to determine whether: (1) origin influences gene structure and cognitive function, (2) mild cognitive impairments are associated with altered gene structure, and (3) specific cognitive domains are affected. Results indicated that 56% of women with maternally inherited, but none with paternally inherited, fragile X showed large genomic structural alterations and selective deficits on measures of visual attention. Thus, molecular status of the fragile X gene appears to be linked to parental origin and may selectively affect specific cognitive skills.

Genetics and expression of the fragile X syndrome.

The discovery of the Fragile X (fra(X] syndrome represents a major advance in our understanding of mild mental retardation. This X-linked syndrome is the most common hereditary form of mental retardation. Recent estimates find that approximately 1/981 males and 1/677 females carry the fra(X) chromosome. The majority of affected males are moderate to severely retarded, but about 20% are mildly retarded and about 5% are borderline. Approximately 20% of males who inherit the fra(X) chromosome are termed non-penetrant; they do not express it cytogenetically and are of normal intellect. About 1/3 of carrier females show mental impairment and about 10% are mildly retarded. We have found evidence for genetic heterogeneity based on linkage analysis to flanking DNA probes. Some large families show tight linkage between fra(X) and the flanking probe F9, while others show loose linkage. Preliminary findings indicate the linkage heterogeneity may also be related to cognition: affected males in tightly linked families tended to be mildly retarded.

Fragile X syndrome: associated neurological abnormalities and developmental disabilities.

The fragile X syndrome is a frequent cause of developmental disabilities. It is associated primarily with nonprogressive X-linked mental retardation. The neurodevelopmental abnormalities of 25 males and 3 females are described. Mental retardation was mild in 4, moderate in 11, severe in 6, and profound in 2 patients, while 4 patients had only learning disabilities. The presence or absence of a developmental disability could not be determined in the youngest (8 months). Seven patients had had infantile autism and 7 had epilepsy. Generally no major focal neurological abnormalities were observed but most of the patients exhibited minor signs. The severity of developmental disabilities in our patients varied between and within families and between genders. All adult males had macroorchidism. Unusual facial features were present in 13 males but none were seen in the females. Familial occurrences were found in 18 cases (64%); 10 cases (36%) were sporadic. Overall, males were more severely affected than females. Diagnostic tests including computed tomographic scans, electroencephalograms, and evoked potentials did not disclose any specific abnormalities.