Martine Borghgraef

Fragile (X) syndrome: a study of the psychological profile in 23 prepubertal patients

In this study a further analysis of the psychological profile in the prepubertal fragile (X) (fra(X)) male was performed. The results of the psycho‐diagnostic examination of 23 fra(X) boys were compared to a control group of 17 males of the same age with ‘non‐specific’ mental retardation. A number of important quantitative and qualitative differences were observed between the two groups. In the preschool age group the majority of fra(X) boys was mildly mentally retarded. In the school‐age group, however, most boys were moderately to severely mentally retarded. This indication of a decline in intellectual performance with age in the fra(X) syndrome was confirmed by a longitudinal individual follow‐up of seven fra(X) boys in this age group. In contrast to intellectual performance, appearance of the attention deficit disorder (or hyperkinesis), with its attendent overactivity and impulsiveness, decreases with age, and is independent of the intellectual level. Autistic behaviour was more frequently observed in the youngest fra(X) males, and was more pronounced in the moderately mentally retarded. In more than 50% of the boys of preschool age the association of hyperkinesis and autistic features was found. Language and speech development in the fra(X) syndrome is both symptomatic and specific. Beside a severe, global speech retardation, there are some distinct speech characteristics in the young fra(X) males such as rapid speech rhythm, speech impulsiveness and perseverative speech.

Strengths and weaknesses in the cognitive profile of youngsters with Prader-Willi syndrome

In this report we present the results of a study of the intellectual functioning and cognitive profile of 26 Prader‐Willi syndrome (PWS) patients. The mean IQ score was 62.3 (range 39–96). In 13 patients a significant difference between verbal and performance IQ was found. In 10 of them the performance IQ was higher than the verbal. The results of subtest analysis indicate that cognitive strengths are more visible than cognitive weaknesses. Highest scores were noted especially in the performance scale, i.e. Block Design (9 children) and Coding or Mazes (5 children). Analysis of all available data indicates that PWS patients score better on visual motor discrimination skills than on auditory verbal processing skills. These results are promising for intervention programs and education stiategies.

Screening for FMR-1 premutations in 122 older Flemish males presenting with ataxia.

Recently, Hagerman et al described the occurrence of a late-onset neurological disorder in five male carriers of the fragile-X (FMR-1) premutation. The major characteristics of this disorder, designated the Fragile-X Tremor Ataxia Syndrome (FXTAS), are progressive intention tremor, cerebellar ataxia and cognitive decline. Most cases of FXTAS published thus far were ascertained through families with a known fragile-X proband. Since cerebellar ataxia is one of the main cardinal features, we performed FMR-1 premutation screening in 122 male patients, older than 50 years, who were referred to us for testing of the spinocerebellar ataxia (SCA 1, 2, 3, 6, 7) genes and who were found to be negative. In this group of patients, we found five patients with an FMR-1 premutation. In four of them, a definite diagnosis of FXTAS could be made, based on the proposed diagnostic clinical and radiological criteria for FXTAS. In light of these figures, we recommend that FMR-1 analysis should be included in the molecular diagnostic work-up in the group of male ataxia patients older than 50 years.

Seventh international workshop on the fragile X and X-linked mental retardation

The Seventh International Workshop on the Fragile X and X-linked Mental Retardation was held at the University of Tromso in Norway on August 2-5, 1995. Approximately 120 participants from 20 countries attended the Workshop. By special invitation Dr. Felix de la Cruz, who initiated the first international Workshop on fragile X, attended this Workshop. For the first time, the workshop took place in Scandinavia and was hosted by Lisbeth Tranebjaerg and Herbert Lubs. For most participants this Workshop, held at the northernmost university in the world, presented a unique opportunity to visit this exotic place. Between sessions, the participants had a chance to experience 24 hours of daylight, codfishing, and extreme weather situations with excessive amounts of rain as well as spectacular changes in the light and rainbows. The format of the Workshop was a combination of platform presentations and poster presentations. In contrast to previous meetings, the Workshop opened with syndromal and non-syndromal X-linked mental retardation in order to allow time for discussion. 34 refs., 1 fig.

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.

Adults with Williams-Beuren syndrome : evaluation of the medical, psychological and behavioral aspects

In order to evaluate the medical, psychological and behavioral aspects of Williams‐Beuren syndrome in adulthood, data were collected on 11 patients aged 17 to 66 years. The medical data did not confirm previous reports of significant morbidity. All adults were found to have a moderate or severe degree of mental handicap. They showed the same psychological profile as found in children: good verbal abilities, poor motor abilities, problems with sequencing and with performance tasks. The adults we evaluated showed little disturbing behavior in comparison to other mentally retarded subjects. They achieved a good level of autonomy. The majority lived at home with one or both parents and attended a day centre.

Phenotypic checklist to screen for fragile X syndrome in people with mental retardation.

The development of a phenotypic checklist for identifying people with fragile X syndrome is described. The checklist was designed to identify people with developmental disabilities of unknown causes for molecular genetic testing for fragile X syndrome. The list consists of 28 items (7 on physical characteristics and 21 on behavioral features). Validation data were collected for 110 boys and men with fragile X syndrome and for 79 members of a control group, matched for CA, level of cognitive development, and social (mal)adaptation. On the basis of checklist results, those boys who are likely to be diagnosed as having fragile X syndrome can be identified. The screening list can be considered to be a consistent, reliable, and valid instrument.

A distinct neurocognitive phenotype in female fragile-X premutation carriers assessed with visual attention tasks.

Premature ovarian failure (POF) and underlying hormonal changes are recognized as a distinct phenotype in female fragile‐X premutation carriers. Neurocognitive deficits, in particular mental retardation, are associated with the full mutation in males and females. In female full mutation carriers this neurocognitive phenotype is expressed more mildly than in males. Research on whether the fragile‐X premutation is associated with a particular neurocognitive phenotype or not has been equivocal. By means of the Sonneville Visual Attentions Tasks (SVAT) computer‐based battery of neurocognitive tasks, we assessed reaction time on different tasks in three groups of subjects: female premutation carriers, female full mutation carriers, and female control subjects. The results show that a fraction of the female premutation carriers perform poorly on several selective attention tasks, but not on other tasks. Their neurocognitive profile is different from that of control subjects and of the majority of female premutation carriers. It may also be different from the phenotype of female full mutation carriers, though in that respect this study remains inconclusive. These findings support earlier findings that the fragile‐X premutation may affect neurocognitive functioning, in particular aspects of attention.

The female and the fragile X syndrome : data on clinical and psychological findings in 7 fra(X) carriers

In this report we present precise data on the clinical, intellectual and behavioural findings in 7 young fra(X) positive girls. The two most common and most important findings are an overgrowth syndrome present from birth on and common behavioural features like severe attentional problems and extreme shyness and anxiety. These symptoms seem to constitute the major criteria for fra(X) screening in prepubertal girls. The findings in previous studies are compared with the present observations.

Inv(X)(p21.1;q22.1) in a man with mental retardation, short stature, general muscle wasting, and facial dysmorphism: clinical study and mutation analysis of the NXF5 gene.

We describe a 59‐year‐old male (patient A059) with moderate to severe mental retardation (MR) and a pericentric inversion of the X‐chromosome: inv(X)(p21.1;q22.1). He had short stature, pectus excavatum, general muscle wasting, and facial dysmorphism. Until now, no other patients with similar clinical features have been described in the literature. Molecular analysis of both breakpoints led to the identification of a novel “Nuclear RNA export factor” (NXF) gene cluster on Xq22.1. Within this cluster, the NXF5 gene was interrupted with subsequent loss of gene expression. Hence, mutation analysis of the NXF5 and its neighboring homologue, the NXF2 gene was performed in 45 men with various forms of syndromic X‐linked MR (XLMR) and in 70 patients with nonspecific XLMR. In the NXF5 gene four nucleotide changes: one intronic, two silent, and one missense (K23E), were identified. In the NXF2 gene two changes (one intronic and one silent) were found. Although none of these changes were causative mutations, we propose that NXF5 is a good candidate gene for this syndromic form of XLMR, given the suspected role of NXF proteins is within mRNA export/transport in neurons. Therefore, mutation screening of the NXF gene family in phenotypically identical patients is recommended.