A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients.

BACKGROUND: The gene encoding fatty acid CoA ligase 4 (FACL4) is mutated in families with non-specific X linked mental retardation (MRX) and is responsible for cognitive impairment in the contiguous gene syndrome ATS-MR (Alport syndrome and mental retardation), mapped to Xq22.3. This finding makes this gene a good candidate for other mental retardation disorders mapping in this region. METHODS: We have screened the FACL4 gene in eight families, two MRX and six syndromic X linked mental retardation (MRXS), mapping in a large interval encompassing Xq22.3. RESULTS: We have found a missense mutation in MRX68. The mutation (c.1001C>T in the brain isoform) cosegregates with the disease and changes a highly conserved proline into a leucine (p.P375L) in the first luciferase domain, which markedly reduces the enzymatic activity. Furthermore, all heterozygous females showed completely skewed X inactivation in blood leucocytes, as happens in all reported females with other FACL4 point mutations or deletions. CONCLUSIONS: Since the FACL4 gene is highly expressed in brain, where it encodes a brain specific isoform, and is located in hippocampal and cerebellar neurones, a role for this gene in cognitive processes can be expected. Here we report the third MRX family with a FACL4 mutation and describe the development of a rapid enzymatic assay on peripheral blood that we propose as a sensitive, robust, and efficient diagnostic tool in mentally retarded males.

Apparently enhanced visual information processing in female fragile X carriers: preliminary findings.

Eighteen normally intelligent adult female fragile X carriers were tested with the "de Sonneville Visual Attention Tasks," a computer-based set of reaction-time experiments, in order to assess different aspects of their attention capacity. The subject group was compared with a group of 48 adults, who were not known to be fragile X carriers. We publish preliminary results of this study. These show that the fragile X carriers have significantly faster reaction times at a substantial number of the tests. This suggests that normally intelligent female fragile X carriers might process simple visual information, such as the targets offered in these reaction time experiments, at a faster rate than control women.

Unusual chromosomal mosaicism in Wolf-Hirschhorn syndrome: del(4)(p16)/der(4)(qter-q31.3::pter-qter).

We report on the unusual cytogenetic findings in a girl with moderate mental retardation and a mosaic karyotype 46,XX,del(4)(p16)/46,XX,der(4)(qter-q31.3::pter-qter). The facial features observed in the child initially did not suggest the diagnosis of Wolf-Hirschhorn syndrome (WHS), but the distinct facial gestalt became obvious at prepubertal age. Fluorescence in situ hybridization (FISH) analysis with different probes that map to 4p and 4q helped to clarify the karyotype. We discuss the mechanism of appearance of this unusual type of mosaicism, which has not been reported before.

Molecular-intelligence correlations in young fragile X males with a mild CGG repeat expansion in the FMR1 gene.

Several mechanisms can explain the occurrence of full-mutation fragile X males with an IQ level above -2 SD below mean, also called "high-functioning fragile X males." Incomplete methylation of the CpG island at the 5' end of the FMR1 gene is one of these mechanisms. The present study describes the physical and behavior phenotypes in 7 fragile X boys with CGG repeat insertions in the FMR1 gene between 600-2,400 base pairs. The degree of methylation at the FMR1-associated CpG island ranges in peripheral blood lymphocytes from 0-95%. Subjects with a low degree of methylation at this site have mild or absent physical characteristics of the fragile X syndrome, while subjects with a high degree of methylation at this site have more severe physical characteristics. In this range of CGG repeat insertion (600-2,400 base pairs), the degree of methylation at the FMR1-associated CpG island is a good predictor of intelligence, while CGG repeat insertion length is not.

New findings in the behavioral profile of young FraX females.

Nine girls, with a 50% risk to be carrier of the FMR-1 gene and who attended normal school and did not have a mentally retarded fraX relative, were selected to exclude influences of external factors. These subjects were submitted to an extensive neurocognitive and psychiatric evaluation before molecular analysis of their FMR-1 status was done to obtain completely unbiased results. The findings of this study suggest that differentiation according to the FMR-1 status may be more significant at the neurocognitive level than at the behavioral level and support the hypothesis that behavioral problems are more influenced by external factors than by the FMR-1 carrier state.

Personality profile in adult female fragile X carriers: assessed with the Minnesota Multiphasic Personality Profile (MMPI).

To assess if the higher incidence of psychiatric morbidity in fragile X carriers is related to a particular pathological personality profile, we obtained a Minnesota Multiphasic Personality Profile from 11 normally intelligent (female) fragile X carriers. The sample mean for the clinical and validity scales all fell within the normal range. Although no pathological profile was found, some unexpected results emerged: low scores for the scales "schizophrenia" and "social introversion" and a so-called faking-good profile on the validity scales. This combination suggests that the subjects might not be aware of some personality characteristics in these areas. Implications for further research are discussed.

Cognitive profile in adult, normal intelligent female fragile X carriers.

Here we present the results of the study of the cognitive profile of 11 adult, normally intelligent female fragile X [fra(X)] carriers. In all individuals 3 types of testing were performed: full scale Wechsler Adult Intelligence Scale, a set of neuropsychological tests and an arithmetic achievement test. All 11 subjects showed an average to above-average intelligence but 10 of 11 performed better on the performance than on the verbal subscale. Neuropsychological tests suggest a dysfunction of the reticulo-thalamic axis with deficiency on tests requiring visual memory and a pronounced deficiency of attention skills combined with an impulsive way of completing tests.

MASA syndrome: delineation of the clinical spectrum at prepubertal age.

Here we describe the clinical and neurological findings in 2 brothers with MASA syndrome and the changes in phenotypic and neurological findings during the prepubertal period. MASA syndrome seems to be an X-linked mental retardation syndrome with progressively appearing manifestations and neurological signs, making clinical diagnosis before age 4 years difficult.

Longitudinal changes in IQ among fragile X females: a preliminary multicenter analysis.

Longitudinal declines in IQ among fragile X [fra(X)] males have been reported previously by several investigators. Remarkably little is known about longitudinal changes in IQ scores among fra(X) females. Previously, one cross-sectional study showed a significant negative correlation between age and IQ scores. However, a recent investigation of girls with fra(X) syndrome noted longitudinal increases in IQ scores in 8 of 11 individuals. Therefore, the purpose of this preliminary multicenter study was to determine: (1) the characteristics of longitudinal changes in IQ among fra(X) females; and (2) whether these changes were comparable to those which have been observed among fra(X) males. IQ test and retest scores for 11 fra(X) females were obtained from 3 centers: Greenwood, South Carolina; Ibaraki, Japan; and Leuven, Belgium. To ensure high reliability, only test-retest scores from the Wechsler and Stanford-Binet tests were used. Age of subjects at initial testing ranged from 5 to 35 years. Mean intertest interval was 4.5 years. In contrast to a report of longitudinal increases, we found 9/11 (82%) subjects demonstrated decreases in IQ scores. Mean decline was 9 points. Females over 18 years of age showed little or no change in IQ scores. Decreases in scores appeared to be related to initial IQ score. Females in the earlier longitudinal report were higher functioning than those in our study, which may account for the observed difference in direction of change; or, change in IQ score may be related to size of the fra(X) mutation.(ABSTRACT TRUNCATED AT 250 WORDS)

Longitudinal changes in cognitive and adaptive behavior in fragile X females: a prospective multicenter analysis.

In prospective studies of young, fragile X [fra(X)] males with the full mutation, cognitive abilities (IQ scores) and adaptive behavior levels (DQ scores) declined in most subjects tested. Little is known about longitudinal changes in IQ and DQ scores in young fra(X) females, although one earlier retrospective study showed declines in IQ scores in 8 of 11 subjects. To examine fra(X) females prospectively, we tested and retested 13 females with the full mutation, age 4 to 15 years. Nine were tested and retested in North America, and four were evaluated at the Catholic University in Leuven, Belgium. Cognitive abilities of North American females were measured using the Stanford-Binet 4th Edition. Adaptive behavior levels were ascertained from the Vineland Adaptive Behavior Scales. For Belgians, test-retest scores from the Wechsler Intelligence Scales for Children-Revised were used. Subjects were subsequently separated into two age cohorts: those tested initially before age 7 years and those tested initially after age 7 years. Compared with young males with the full mutation and of the same age, females expectedly display a wider range of IQ scores. Test-retest IQ scores showed statistically significant decreases (P < 0.03). Analysis of individual test-retest scores indicate that declines in eight females were statistically significant. Adaptive behavior scores were available only for North American females. Five of nine (55%) showed significant declines in DQ. Like young males with the full mutation, all females with the full mutation attained higher adaptive behavior levels than cognitive scores, i.e., DQ > IQ.

Hallermann-Streiff syndrome: clinical and psychological findings in children. Nosologic overlap with oculodentodigital dysplasia?

We describe 3 young children with Hallermann-Streiff syndrome, 2 with typical manifestations and 1 with the facial changes without the eye abnormalities but with a cleft palate and with complete syndactyly of fingers IV and V. The latter case represents overlap of the Hallermann-Streiff syndrome and oculodentodigital dysplasia. "Dwarfism" as a possible clinical risk marker of mental retardation is discussed. As cause, a mendelian autosomal dominant mutation seems most probable.

Relationship between age and IQ among fragile X males: a multicenter study.

Longitudinal decline in IQ among fragile X males was reported recently. However, there are problems in retesting IQ that may affect scores. Two such factors are intertest time interval and score obtained on the first test. To determine the generality of IQ score changes, we examined 101 fragile X males from 6 centers. To ensure high test-retest reliability, only results from Stanford-Binet and Wechsler tests were used. Thus there were retest scores from 60 subjects. Test-retest reliability between first and last scores was very good (r = 0.85) and comparable to those seen in nonfragile X mentally retarded individuals. Also computed were z-scores of differences in IQ scores. The z-score differences were distributed about a mean at 1 SD below the expected zero value. Eighteen subjects showed statistically significant decreases in IQ, 6 showed statistically significant increases, while 5 showed the same scores. Z-score differences were not correlated with type of residence or elapsed intertest interval, but were negatively correlated with first score obtained, indicating a regression-to-the-mean effect. Using a multiple regression analysis, we found first score obtained, age tested, and age retested significant predictors of score differences, accounting for 19% of the total variance. These results suggest that factors previously identified as affecting retest scores have a smaller effect than originally thought. It is suspected that decline in IQ is associated with dynamic neurological processes and needs to be investigated further.

Longitudinal changes in IQ among fragile X males: clinical evidence of more than one mutation?

Longitudinal changes in IQ among mentally retarded (MR) fragile X [fra(x)] males have been reported previously. While age is associated with decline in IQ, not all males are so affected. This suggests that there may be more than one subtype of affected fra(X) male. Therefore, we examined the distribution of standardized difference scores (Zdiff) in IQ to determine if subjects were from an admixture of at least 2 populations. Cluster analysis of Zdiff scores was used to partition subjects into 2 groups. Goodness-of-fit tests indicated that scores were more likely to come from an admixture. Discriminant functions (DF) were calculated to determine predictive validity of Zdiff scores. To eliminate the effect of skewing, a power transform was applied to Zdiff scores and DFs recomputed. Zdiff and transformed scores provided similar results. The mean and variance for one group showed no differences in test-retest scores as would be expected from examining any population while the mean for the second group indicated significant decline in IQ nearly 4 standard errors below the first test score. These results suggest that there may be clinical evidence for 2 types of fra(X) mutation: One which causes MR but is static, and a second mutation which causes MR but is dynamic and contributes to an apparent longitudinal decline in cognitive function.

Mosaic tetrasomy 8p in two patients: clinical data and review of the literature.

We report on 2 girls with mosaic tetrasomy 8p. Patient 1 showed the extra iso 8p chromosome in 20% of cultured lymphocytes and 18% of cultured fibroblasts [46,XX/47,XX,+i(8p)]. She presented with growth retardation, mild facial alterations, and motor developmental delay. Patient 2 presented with developmental delay, hypotonia, and slight facial alterations; she had the extra iso 8p chromosome in 94% of cultured peripheral lymphocytes. The patients are compared to the 6 previously reported cases. In our experience, the presently reported patients clinically resemble children with inv dup(8)(p21-p22) and patients with mosaic trisomy 8.

Temperament in Williams syndrome.

In this study we evaluated the temperament characteristics of a group of 13 subjects with Williams-Beuren syndrome (WBS) and compared the results to the findings in a control group of 13 individuals with the same degree of mental retardation of different etiology. On the different subscales of the Dutch adaptation of the Parent Temperament Questionnaire no statistically significant differences between the WBS and the control group were noted. An easier temperament was noted in the control group, and we also found greater intensity, less persistence and lower treshold in WBS subjects. The present findings indicate that the "specific" behavioural phenotype in WBS patients is apparently more related to mental retardation itself than to the underlying genetic defect. Further studies on a large group of WBS patients and mentally retarded control group are needed to confirm these findings.

The 48,XXYY syndrome. Follow-up data on clinical characteristics and psychological findings in 4 patients.

In this study we report the physical and psychological findings in 4 males with 48,XXYY syndrome. They were diagnosed at the ages of 4, 6, 18 and 25 years respectively. The major indication for chromosomal analysis in these four slightly mentally retarded males was not their clinical appearance but the presence of behavioral problems with personality disturbances i.e. psychotic reactions, loss of structure, violent and impulsive reactions. These data are compared with previous findings in the literature.

Fragile X boys: evolution of the mental age in childhood. Preliminary data on 10 prepubertal boys.

In this report we present data on the longitudinal evolution of the mental versus the chronological age in 10 fragile X boys diagnosed before the age of 6 years and compare these findings to the longitudinal evolution in children with Down syndrome (6 patients) and Williams syndrome (4 patients). The present findings suggest that the evolution of the velocity of development is more decreased in fra(x) boys compared to the two other groups.

Psychological profile and behavioural characteristics in 12 patients with Prader-Willi syndrome.

In the present study medical, psychological and behavioural aspects in 12 patients with Prader-Willi syndrome (PWS), aged between 13 months and 28 years are presented. In half of the patients the diagnosis of PWS was made before the age of one year. The contribution of cytogenetic investigations with the detection of a 15q11 deletion in half of the PWS patients is discussed. In the evaluation of the intellectual performances IQ levels were spread between 45 and 95 with a mean IQ of 54. A specific behavioral profile in all patients with characteristic fluctuations with age was observed. Rapid changes in behaviour increased with age and after puberty, mostly related with withholding of food. The present study reinforces the importance of early diagnosis in the PWS with adequate and intelligible information towards the parents. It may prevent the dramatic obesity which leads to severe physical problems and psychological burdens in PWS adolescents and adults.

Ring chromosome 15: follow-up data on physical and psychological development.

In this report, we summarize the clinical and psychological follow-up data over a period of 6 to 9 years of three girls with ring chromosome 15. Ring chromosome 15 in these children was associated with marked symmetrical growth retardation without obvious dysmorphism, slight mental retardation in two patients and borderline intelligence in the third. In all three performantial IQ was better developed than attention and concentration and severe verbal disability, present in the first years of life, disappeared almost completely after the age of 6 years. The present data suggest that, despite their severe growth failure, social integration and functioning may be satisfactory in r(15) patients.

Terminal deletion of long arm of chromosome 4: patient report and literature review.

We report on a girl with a terminal deletion (46,XX,del(4)(q33-->ter). She presented with developmental delay and slight facial dysmorphism. The clinical features are compared with the patients in the literature and a review of the psychologic data is given.