Beverly J. White

X-chromosome effects on female brain: a magnetic resonance imaging study of Turner's syndrome

Many neuropsychiatric disorders differ between the sexes in incidence, symptoms, and age at onset. To investigate the effects of X-chromosome aneuploidy and of sex steroid deficiency during childhood on brain structure and function, we used neuropsychological tests and quantitative magnetic resonance imaging (MRI) to study the brains of eighteen women with Turners syndrome (TS) and nineteen healthy control women of similar age. Nine TS subjects had mosaic 45,X karyotypes, and 9 had non-mosaic 45,X. The TS group had significantly lower scores than the controls for all the Wechsler adult intelligence scale tests, except verbal comprehension and reading level. The greatest difference was in visuospatial construction (mean 90 [SD12] vs 118 [13], p < 0.0001). The TS subjects also had a greater discrepancy than controls between verbal and performance intelligence quotients (9 [8] vs -5 [9], p < 0.001). We found that TS subjects had significantly smaller values than controls in MRI-measured volumes of hippocampus, caudate, lenticular, and thalamic nuclei, and parieto-occipital brain matter, on both sides. Women with mosaic TS had values between the full TS and control groups for cerebral hemisphere and lenticular and thalamic nuclei volume and for verbal ability. Within the mosaic TS group, visuospatial ability was significantly correlated with the percentage of lymphocytes that had the 45,X karyotype. Hippocampal volume and memory test scores were significantly lower in mosaic and non-mosaic 45,X TS subjects than in controls. We postulate that in human beings the X chromosome plays an important part in the development and ageing of grey matter in striatum, diencephalon, and cerebral hemispheres.

Syndrome of Anosmia with Hypogonadotropic Hypogonadism (Kallmann Syndrome) Clinical and Laboratory Studies in 23 Cases

Abstract We have studied 23 patients (14 men, nine women) in 18 kindreds with anosmia and hypogonadotropic hypogonadism. Seven kindreds had more than one affected member, and included five eugonadal persons with anosmia and two eusomic women with hypogonadotropic hypogonadism. Other clinical abnormalities observed included: obesity (in nine), cryptorchidism (six), osteopenia (six), mild neurosensory hearing loss (five), gynecomastia (five), diabetes mellitus (four), cleft lip or palate or both (three), high-arched palate (two), short fourth metacarpal (two), and clinodactyly, camptodactyly, shortened frenulum of the tongue, multiple facial anomalies, right-sided aortic arch, malrotation of the gut, renal diverticulum, and mild red-green color blindness (one each). Normal secondary sex characteristics developed in all 20 patients treated on a long-term basis with chorionic gonadotropin or gonadal steroids. Responses to a single injection of gonadotropin-releasing hormone were heterogeneous. Five men had no luteinizing hormone response, five had a depressed response, and one an exaggerated response; two had no follicle-stimulating hormone response, five responses were depressed, three were normal, and one was ex-aggerated. None of seven women achieved a normal luteinizing hormone response to gonadotropin-releasing hormone; two had depressed follicle-stimulating hormone response, four responses were normal, and one was exaggerated. None of 11 patients tested responded to clomiphene. Two men fathered children. Each of two other men who underwent biopsy of the testes before and after long-term chorionic gonadotropin therapy showed mildly increased spermatogenesis. Little or no maturation beyond primordial follicles was observed in two ovarian biopsy specimens. Fifteen of 17 patients had normal basal prolactin levels and 14 of 16 had normal thyrotropin-releasing hormone-induced prolactin increase, but nine of 15 tested had a decreased or absent response of prolactin to chlorpromazine. Circulating concentrations of thyroid hormones were normal, but four of 17 patients tested had depressed TSH (thyroid-stimulating hormone) responses to thyrotropin-releasing hormone, and one man had an exaggerated response. Three of 12 patients had a depressed cortisol response to insulin-induced hypoglycemia, and two of seven patients had slightly depressed deoxycortisol responses to metyrapone. Growth hormone and vasopressin release in all 14 and all 12 patients, respectively, studied were essentially normal. Patients with anosmia and hypogonadotropic hypogonadism may have hypothalamic defect(s) responsible for the hypogonadotropism and perhaps for certain additional deficiencies of anterior pituitary function found in some. The cause of less frequent phenotypic abnormalities has not been established. In certain pedigrees, the evidence suggests that the major manifestations of the syndrome are inherited as an autosomal recessive trait.

Familial Alzheimer's disease in two kindreds of the same geographic and ethnic origin ☆: A clinical and genetic study

Alzheimers disease (AD) occurred in 37 individuals from two kindreds of Jewish ancestry with a mode of transmission suggesting an autosomal dominant genetic trait. Both kindreds originated from Byelorussia and spoke the Lithuanian dialect of Yiddish. In one of the two families one case of pathologically confirmed AD occurred with clinical and neuropathological signs of Parkinsons disease. In the other family one case of amyotrophic lateral sclerosis and one case of Downs syndrome occurred, both without clinical or pathological signs of AD. In the single kindred tested, a study of the chromosome 6 markers HLA, Bf and GLO failed to reveal a correlation between the transmission of AD and the segregation of these markers. The association of increased aneuploidy of peripheral blood chromosomes with AD was not confirmed in either of these families. Genetic differences between the familial and the sporadic form of AD are discussed.

Trisomy 19 in the laboratory mouse

Weights of viable trisomic mouse fetuses and placentas were compared with those of normal littermates between 12½ and 19½ days’ gestation. Mean trisomic fetal and placental weights were below normal w

Gonadotropin suppression for the treatment of karyotypically normal spontaneous premature ovarian failure: a controlled trial*

OBJECTIVE To determine if gonadotropin suppression improves ovarian follicle function or ovulation rates in patients with karyotypically normal spontaneous premature ovarian failure. DESIGN Prospective, double-blind, placebo-controlled, crossover trial. SETTING Tertiary care research institution. INTERVENTIONS Two intervention phases lasting 4 months each: one placebo phase, and one treatment phase during which each patient received daily subcutaneous injections of 300 micrograms of the gonadotropin-releasing hormone agonist (GnRH-a) deslorelin. During both phases, patients took a standardized estrogen (E) replacement regimen. PATIENTS, PARTICIPANTS Twenty-six patients with karyotypically normal spontaneous premature ovarian failure ranging in age from 18 to 39 years. MAIN OUTCOME MEASURES We measured serum estradiol (E2) and progesterone (P) levels weekly during the 2 months after each intervention. We defined a serum E2 greater than 50 pg/mL (184 pmol/L) as evidence for ovarian follicle function and a serum P greater than 3.0 ng/mL (9.5 nmol/L) as evidence for ovulation. RESULTS The GnRH-a therapy did not significantly enhance recovery of ovarian follicle function or the chance of ovulation. The power to detect a 40% and a 33% ovulation success rate with therapy was 0.95 and 0.83, respectively. We found evidence for ovarian follicle function in 11 of 23 women (48%), and 4 women (17%) ovulated. CONCLUSIONS Patients with karyotypically normal spontaneous premature ovarian failure treated with E replacement did not benefit from the additional gonadotropin suppression achieved with GnRH-a. Because these patients have a significant possibility of spontaneous remission, attempts to induce ovulation should be limited to controlled trials designed to determine safety and effectiveness.

Cytogenetic studies of males with schizophrenia. Screening for the fragile X chromosome and other chromosomal abnormalities.

Genetic factors appear to play a role in the etiology of schizophrenia, although no specific genetic mechanism has yet been identified. As a preliminary measure in the search for the chromosomal location of a gene or genes relevant to this illness, cytogenetic screening of populations of patients might provide clues for further in depth molecular studies. Additionally, since the X chromosome has been implicated as a possible site, specific examinations aimed at identifying abnormalities in this chromosome including the presence of the fragile X site, could also be important. The following report reviews the previous literature on chromosomal aberrations in schizophrenia and presents data from a new survey of 46 unrelated male patients with schizophrenia. No chromosomal aberrations or folate-sensitive fragile sites were found in samples from these patients.

Regional cerebral glucose metabolism is normal in young adults with Down syndrome

Regional CMRglc (rCMRglc) values were measured with [18F]2-fluoro-2-deoxy-d-glucose (18FDG) and positron emission tomography (PET), using a Scanditronix PC-1024-7B scanner, in 14 healthy, noninstitutionalized subjects with trisomy 21 (Down syndrome; DS) (mean age 30.0 years, range 25–38 years) and in 13 sex-matched, healthy volunteers (mean age 29.5 years, range 22–38 years). In the DS group, mean mental age on the Peabody Picture Vocabulary Test was 7.8 years and dementia was not present. Resting rCMRglc was determined with eyes covered and ears occluded in a quiet, darkened room. Global gray CMRglc equaled 8.76 ± 0.76 mg/100 g/min (mean ± SD) in the DS group as compared with 8.74 ± 1.19 mg/100 g/min in the control group (p > 0.05). Gray matter regional measurements also did not differ between groups. The ratio of rCMRglc to global CMRglc, calculated to reduce the variance associated with absolute rCMRglc, and right/left ratios did not show any consistent differences. These results show that healthy young DS adults do not have alterations in regional or global brain glucose metabolism, as measured with 18FDG and PET, prior to an age at which the neuropathological changes in Alzheimer disease are reported to occur.

Trisomy for the smallest autosome of the mouse and identification of the T1Wh translocation chromosome.

Quinacrine-mustard staining and Giemsa-banding identified the large chromosome of the T1Wh translocations as No. 5; the small autosome of the translocation had previously been found to be No. 19. Others have demonstrated that translocation T163H involved autosomes 9 and 19; these findings were confirmed in our study. Meiotic studies of (T1Wh × T163H) F1 hybrids showed a chain quadrivalent at metaphase I, confirming that both translocations shared in common only chromosome 19. Metaphase II analysis of F1 hybrids demonstrated frequent nondisjunction of the T1Wh and T163H translocation chromosomes, and 12 % of 75 F2 offspring from 16 F1 crosses were trisomic for chromosome 19. Trisomics had three translocation chromosomes and a chromosome number of 38. All newborn trisomics were smaller than their normal littermates and died during the first day of life. The only specific malformation found so far has been cleft palate.

Quantitative CT analysis of brain morphometry in adult Down's syndrome at different ages.

Quantitative CT demonstrated that healthy adults with Downs syndrome (DS) have smaller brains and smaller intracranial volumes than controls. Normalized volumes of CSF, ventricles, and brain parenchyma did not differ in patients and controls. Both DS subjects and controls showed similar significant age-related increments in volumes of CSF and ventricles. Of seven older DS subjects, one was demented, whereas the group as a whole showed reductions in cognitive test scores as compared with younger DS subjects. The results demonstrate cognitive decline in older DS subjects, but no brain atrophy other than that expected with aging.

Decline in cerebral glucose utilisation and cognitive function with aging in Down's syndrome.

The cerebral metabolic rate for glucose (CMRglc) was measured with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in 14 healthy subjects with Downs syndrome, 19 to 33 years old, and in six healthy Downs syndrome subjects over 35 years, two of whom were demented. Dementia was diagnosed from a history of mental deterioration, disorientation and hallucinations. All Downs syndrome subjects were trisomy 21 karyotype. CMRglc also was examined in 15 healthy men aged 20-35 years and in 20 healthy men aged 45-64 years. All subjects were at rest with eyes covered and ears plugged. Mean hemispheric CMRglc in the older Downs syndrome subjects was significantly less, by 23%, than in the young Downs syndrome group; statistically significant decreases in regional metabolism (rCMRglc) also were present in all lobar regions. Comparison of the younger control group with the older control group showed no difference in CMRglc or any rCMRglc (p greater than 0.05). Assessment of language, visuospatial ability, attention and memory showed significant reductions in test scores of the old as compared with the young Downs syndrome subjects. These results show that significant age differences in CMRglc and rCMRglc occur in Downs syndrome but not in healthy controls, and that, although only some older Downs syndrome subjects are demented, significant age reductions in neuropsychologic variables occur in all of them.