[Phenotypic screening for X-linked mental retardation: fragile Xq syndrome].
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Adolescent↗
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X-linked mental retardation and the fragile-X syndrome.
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Chromosome Fragility↗
Fragile X syndrome: search for phenotypic manifestations at loci for hypoxanthine phosphoribosyltransferase and glucose-6-phosphate dehydrogenase.
The subjects of this study were individuals with the form of X-linked mental retardation that is associated with the presence of a cytologically variant X chromosome having a secondary constriction or "fragile site" at Xq 27-28 (Fra X). Studies were carried out to test the hypothesis that deletions or modifications at neighboring loci occur as a consequence of events at the fragile site. Skin fibroblasts and peripheral blood lymphocytes from affected males were analyzed with respect to the expression of two X-lined enzymes: glucose-6-phosphate dehydrogenase (G6PD) and hypoxanthine phosphoribosyltransferase (HPRT); loci for these enzymes are known to be located in the region of the fragile site. Although the number of cells resistant to thioguanine (HPRT-deficient) obtained from some cultures from one Fra X male and blood cells of another was greater than expected, the frequency of these cells was not increased in cultures from other Fra X males. Furthermore, our results indicate that the G6PD activity and electrophoretic mobility in Fra X males is similar to that in normal cells, thus providing no evidence for the loss of the long-arm telomere in the fragile X syndrome.
Adult↗
A marker X chromosome associated with nonspecific male mental retardation. The first South African cases.
This report describes the first cases of X-linked mental retardation with a marker X chromosome seen in South Africa, and forms part of an ongoing study. The marker was found in 11 affected males and 1 carrier female in 4 families investigated. The demonstration of the marker X chromosome characterized by a fragile site at the long arm (fra(X) (q27) in association with nonspecific X-linked mental retardation heralds a new era in cytogenetics. The attention of human geneticists everywhere is focused on various aspects of this fascinating phenomenon. It has now become possible to diagnose an apparently common familial cytogenetic condition with a high risk of recurrence and to identify female carriers; perhaps in time we will be able to provide prenatal diagnosis. Because of the familial involvement through X-linked inheritance the syndrome is believed to be more common than trisomy 21. The nature of the association of mental retardation with the marker X chromosome is unknown, but it could be related to close linkage with abnormal gene(s) or due to faulty transcription of the genes beyond the fragile site.
Adult↗
Fragile X mental retardation syndrome: DNA diagnosis and carrier detection in New Zealand families.
AIMS: To establish a DNA-based test for the diagnosis and carrier detection of fragile X syndrome, and to investigate the nature of the mutation and patterns of inheritance in New Zealand families. METHODS: A probe for the FRAXA region was generated by polymerase chain reaction, cloned in a plasmid vector, and its structure was confirmed by DNA sequencing. This probe was used in a Southern blot assay to detect full mutations or premutations associated with fragile X syndrome in DNA from peripheral blood samples submitted to our laboratory for routine testing. RESULTS: We tested 379 individuals from throughout New Zealand. Full mutations were found in 29 males, leading to a fragile X diagnosis, or confirmation of an earlier cytogenetic diagnosis. Premutations were detected in 45 females and 11 males, all of whom are asymptomatic carriers of the disease. CONCLUSIONS: The DNA test is rapid and accurate, in contrast to the cytogenetic test. It allows unequivocal detection of carriers, enabling effective counselling, prenatal testing, and more generalised screening of at-risk populations. Our discovery of one large pedigree with many carriers and no prior history of X-linked mental retardation demonstrates that the DNA test is appropriate even in apparently sporadic cases of mental retardation.
Blotting, Southern↗
Genetic analysis of a kindred with X-linked mental handicap and retinitis pigmentosa.
A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5'-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified.
Adolescent↗
Segregation of FRAXE in a large family: clinical, psychometric, cytogenetic, and molecular data.
During an ongoing study on X-linked mental retardation, we ascertained a large family in which mild mental retardation was cosegregating with a fragile site at Xq27-28. Clinical, psychometric, cytogenetic, and molecular studies were performed. Apart from mild mental retardation, affected males and females did not show a specific clinical phenotype. Psychometric assessment of four representative affected individuals revealed low academic achievements, with verbal and performance IQs of 61-75 and 70-82, respectively. Cytogenetically the fragile site was always present in affected males and was not always present in affected females. With FISH the fragile site was located within the FRAXE region. The expanded GCC repeat of FRAXE was seen in affected males and females either as a discrete band or as a broad smear. No expansion was seen in unaffected males, whereas three unaffected females did have an enlarged GCC repeat. Maternal transmission of FRAXE may lead to expansion or contraction of the GCC repeat length, whereas in all cases of paternal transmission contraction was seen. In striking contrast to the situation in fragile X syndrome, affected males may have affected daughters. In addition, there appears to be no premutation of the FRAXE GCC repeat, since in the family studied here all males lacking the normal allele were found to be affected.
Adolescent↗
X-linked alpha-thalassemia/mental retardation syndrome. Linkage analysis in a new family further supports localization in proximal Xq.
Linkage analysis was performed in a three generation family with three males affected by the recently delineated X-linked form of alpha-thalassemia/mental retardation syndrome (ATR-X). Results are in agreement with the linkage study reported by Gibbons et al in 1992 and further confirm that the ATR-X gene is located in proximal Xq. Positive LOD scores were obtained for several markers situated in the pericentromeric region. A maximum LOD score of 2.09 at a recombination fraction of 0 was obtained for DXS453 located at the boundary q12-q13.1. The nearest flanking loci demonstrating recombination with the disease locus were AR at Xq11.2-q12 on the centromeric side and DXS72 at Xq21.1 on the telomeric side. Consequently the authors were able to reduce the previously defined candidate region for the gene location. Their results are compatible with a distal boundary at Xq21.1 instead of q21.31.
Chromosome Mapping↗
[X-linked mental retardation: variations in the fragile X mutations and genetic counseling].
The fragile X syndrome is one of the most common forms of genetic mental retardation and is caused by elongation of a small target DNA fragment containing a repeat of the trinucleotide CGG located in a 5' exon of the FMR-1 gene on the X chromosome. The genetic mutations were classified as two main types, premutation and full mutation, according to the size of the elongation. Because clinical findings are varied in patients with the fragile X syndrome, diagnosis of the disease is very difficult when based only on clinical symptoms. Molecular findings in three families with the fragile X syndrome showed that individuals with the full mutation were moderately mentally retarded, but individuals with the premutation had normal intelligence. The intellectual quotient levels in the families related to the sizes of the mutation which were unstable from generation to generation. These findings suggested that molecular studies in patients with mental retardation are very usefull to diagnose the fragile X syndrome, and that genetic counseling should be carried out based on the DNA analyses of the FMR-1 gene in the family members.
Adolescent↗
Agenesis of the corpus callosum associated with MASA syndrome.
MASA syndrome includes mental retardation, adducted thumbs, shuffling gait and aphasia or speech delay. MASA syndrome, X-linked hydrocephalus and X-linked spastic paraplegia have been linked to the same markers on Xq28 and perhaps represent variation in the clinical expression of the same gene or manifestations of different mutant alleles. The present family includes five males in two generations with borderline to mild mental retardation (5/5), speech delay (5/5), spastic paraplegia (5/5), adducted thumbs (2/5) and marked hydrocephalus (1/5). Of these males, four were evaluated by MRI or CT scan and all four were determined to have partial to complete agenesis of the corpus callosum (ACC). DNA studies confirm linkage to Xq28 probe St14 (DXS52) with a lod score of 2.86 and no recombination. It is not known if X-linked ACC is linked to the same Xq28 region.
Abnormalities, Multiple↗
X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism.
We have identified a large Dutch kindred with a new form of X-linked nondysmorphic mild mental retardation. All affected males in this family show very characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Other types of impulsive behavior include arson, attempted rape, and exhibitionism. Attempted suicide has been reported in a single case. The locus for this disorder could be assigned to the Xp11-21 interval between DXS7 and DXS77 by linkage analysis using markers spanning the X chromosome. A maximal multipoint lod score of 3.69 was obtained at the monoamine oxidase type A (MAOA) locus in Xp11.23-11.4. Results of 24-h urine analysis in three affected males indicated a marked disturbance of monoamine metabolism. These data are compatible with a primary defect in the structural gene for MAOA and/or monoamine oxidase type B (MAOB). Normal platelet MAOB activity suggests that the unusual behavior pattern in this family may be caused by isolated MAOA deficiency.
Adult↗
Linkage mapping of a severe X-linked mental retardation syndrome.
A four-generation Swedish family with a new type of X-linked mental retardation syndrome was recently reported by Gustavson et al. The complex syndrome includes microcephaly, severe mental retardation, optical atrophy with decreased vision or blindness, severe hearing defect, characteristic facial features, spasticity, seizures, and restricted joint motility. The patients die during infancy or early in childhood. Twenty-one family members, including two affected males, were available for study. Linkage analysis was conducted in the family by using 11 RFLP markers and 10 VNTR markers spread along the X chromosome. A hypervariable short tandem repeat of DXS294 at Xq26 showed a peak two-point lod score of 3.35 at zero recombination fraction. Calculations using the same markers revealed a multipoint peak lod score of 3.65 at DXS294. Crossover events with the centromeric marker DXS424 and the telomeric marker DXS297 delimit a probable region for the gene localization. It is noteworthy that hte disease loci of two other syndromes with overlapping clinical manifestations recently were shown by Turner et al. and Pettigrew et al. to be linked to markers at Xq26.
Abnormalities, Multiple↗
Mental status of females with an FMR1 gene full mutation.
The cloning of the FMR1 gene enables molecular diagnosis in patients and in carriers (male and female) of this X-linked mental retardation disorder. Unlike most X-linked disorders, a considerable proportion of the female carriers of a full mutation of the FMR1 gene is affected. In this study, the intelligence quotients (IQs) were ascertained by the Wechsler Adult Intelligence Scale in 33 adult females with a full mutation, with 28 first-degree adult female relatives (mainly sisters) without a full mutation as controls. Seventy-one percent of the females with a full mutation had IQ scores below 85. In paired analysis, no significant correlation could be detected between the IQs of the females with a full mutation and those of their first-degree female relatives, reflecting a dominant effect of the FMR1 gene full mutation in the mental development of females. Considering females with a full mutation only, we observed a significant relation between the proportion of normal FMR1 alleles on the active X chromosome and IQ. We present a model to explain this relationship.
Adult↗
A gene for dominant nonspecific X-linked mental retardation is located in Xq28.
A large family (MRX48) with a nonspecific X-linked mental retardation condition is described. An X-linked semidominant inheritance is suggested by the segregation in three generations of a moderate to severe mental retardation in seven males and by a milder intellectual impairment in two females, without any specific clinical, radiological, or biological feature. Two-point linkage analysis demonstrated significant linkage between the disorder and several markers in Xq28 (maximum LOD score [Zmax] = 2.71 at recombination fraction [theta] = 0); multipoint linkage analyses confirmed the significant linkage with a Zmax of 3.3 at theta = 0, at DXS1684. A recombination event observed with the flanking marker DXS8011 delineates a locus between this marker and the telomere. The approximate length of this locus is 8-9 cM, corresponding to 5.5-6 Mb. In an attempt to explain the variable intellectual impairment in females, we examined X-chromosome inactivation in all females of the family. Inactivation patterns in lymphocytes were random or moderately skewed, and no correlation between the phenotypic status and a specific inactivation pattern was observed. The interval of assignment noted in this family overlaps with five MRX loci previously reported in Xq28.
Adult↗
[Undifferentiated X-linked oligophrenias].
In the course of investigation of 262 families with non-differentiated forms of oligophrenias it is established that in 48 families (18.3%) mental deficiency in sibs is caused by pathological mutations in the X-chromosome. Besides, it is not excluded that in certain inbred families oligophrenia in female persons is also, due to mutations linked with X-chromosome. This is supported by the dependence established between the frequency of the cases of oligophrenia among female persons and the inbreeding coefficient for the X-linked loci. The possibility of manifestation of the recessive genes of oligophrenia linked with X-chromosomes in heterozygous state is discussed.
Female↗
A gene for FG syndrome maps in the Xq12-q21.31 region.
FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at theta = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, theta = 0, alpha = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region.
Abnormalities, Multiple↗
Regional localization of two genes for nonspecific X-linked mental retardation to Xp22.3-p22.2 (MRX49) and Xp11.3-p11.21 (MRX50).
Two families with nonspecific X-linked mental retardation (XLMR) are presented. In the first family, MRX49, 5 male patients in 2 generations showed mild to moderate mental retardation. Two-point linkage analysis with 28 polymorphic markers, dispersed over the X-chromosome, yielded a maximal LOD score of 2.107 with markers DXS7107 and DXS8051 at theta = 0.0, localizing the MRX49 gene at Xp22.3-p22.2, between Xpter and marker DXS8022. Multipoint linkage analysis showed negative LOD values over all other regions of the chromosome. In the second family, MRX50, 4 males in 2 generations showed moderate mental retardation. Pairwise linkage analysis with 28 polymorphic markers yielded a LOD score of 2.056 with markers DXS8054, DXS1055, and DXS1204, all at theta = 0.0. Flanking markers were DXS8012 and DXS991, situating the MRX50 gene at Xp11.3-Xp11.21, in the pericentromeric part of the short arm of the X chromosome.
Adolescent↗
A gene for non-specific X-linked mental retardation (MRX55) is located in Xp11.
A new family with a non-specific X-linked mental retardation (MRX55) is described. An X-linked recessive inheritance is suggested by the segregation from two healthy transmitting females of moderate mental retardation in three males, without any specific clinical, radiological or biological features. Two point linkage analysis demonstrated significant linkage between the disorder and several markers in Xp11 (Zmax = 2.11, theta = 0); multipoint linkage analyses confirmed the significant linkage with a maximum lod score (Z = 2.11 at theta = 0, at DXS8012). Recombination events observed with the flanking markers DXS1068 and DXS1275 delineate a 34 centimorgan interval in the pericentromeric region. The interval of assignment pointed out in this family overlaps with several MRX loci previously reported in Xp11 which are reviewed here in.
Chromosome Mapping↗