X linked mental retardation: a clinical guide

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non‐syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non‐syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.     

Linkage mapping of a nonspecific form of X‐linked mental retardation (MRX53) in a large Pakistani family

Nonspecific X‐linked mental retardation is a nonprogressive, genetically heterogeneous condition that affects cognitive function in the absence of other distinctive clinical manifestations. We report here linkage data on a large Pakistani family affected by a form of X‐linked nonspecific mental retardation. X chromosome genotyping of family members and linkage analysis allowed the identification of a new disease locus, MRX53. The defined critical region spans approximately 15 cM between DXS1210 and DXS1047 in Xq22.2–26. A LOD score value of 3.34 at no recombination was obtained with markers DXS1072 and DXS8081. © 2001 Wiley‐Liss, Inc.     

The fragile X chromosome in a large Indian kindred

A large Indian kindred in which the fragile X chromosome is segregating has been investigated in Cape Town. Eight male hemizygotes and four female heterozygotes were mentally retarded. There is suggestive evidence that one deceased male of reportedly normal intelligence may have been a hemizygote. The existence of the fragile X syndrome in a number of different ethnic groups supports the contention that the gene controlling the phenotype and the fragile site are the same, or at least overlap.     

Fragile X syndrome in mildly mentally retarded children in a Northern Swedish county. A prevalence study

In an extensive etiological study of an unselected series of mildly mentally retarded children (MMR) (IQ 50–70) born 1959–1970 in a northern Swedish county, 5 of 110 boys (4.5%) and none of 61 girls had a fragile site on the distal end of the X-chromosome (Fra Xq 28). Consequently fragile X was seen in 2.9% of the total series of 171 children. In a combined series of severe and mild mental retardation, the incidence of the fragile X syndrome was calculated to be 1:3000 in the county of Vasterbotten. Next to trisomy 21 the fragile X syndrome was the most common single identified cause of MMR in boys. A cytogenetic investigation using special cultural conditions and banding techniques should be performed in cases of mental retardation of unclear etiology and in possible female carriers.     

Klinefelter syndrome and two fragile X chromosomes

Two fragile X chromosomes were found in 20% of the cells in a moderately mentally retarded patient with Klinefelter syndrome.     

Tightly linked polymorphic markers for fragile X syndrome and prenatal cytogenetic diagnostic experience

Linkage analysis using the polymorphic loci DXS369, DXS296, DXS297 and DXS306 was carried out on a cohort of 17 families segregating for fragile X syndrome. The observed recombination fractions at: DXS369 (Zmax = 3. 02; theta=0. 06), DXS297 (Zmax= 2. 92; theta = 0.0), DXS296 (Zmax = 3. 82; theta = 0.0), DXA306 (Zmax = 4. 55; theta = 0.05) confirm that these loci are tightly linked to FRAXA. Our experience in the cytogenetic analysis of 58 at risk pregnancies by chorionic villus or fetal blood sample examination documents a false negative rate in obligate carrier male pregnancies for CVS of 11% and for FBS of 3%.     

Two unrelated patients with inversions of the X chromosome and non-specific mental retardation: physical and transcriptional mapping of their common breakpoint region in Xq13.1.

Two unrelated mildly retarded males with inversions of the X chromosome and non-specific mental retardation (MRX) are described. Case 1 has a pericentric inversion 46,Y,inv(X) (p11.1q13.1) and case 2 a paracentric inversion 46,Y,inv(X) (q13.1q28). Both male patients have severe learning difficulties. The same chromosomal abnormalities were found in their mothers who are intellectually normal. Fluorescence in situ hybridisation mapping showed a common area of breakage of each of the inverted chromosomes in Xq13.1 near DXS131 and DXS162. A detailed long range restriction map of the breakpoint region was constructed using YAC, PAC, and cosmid clones. We show that the two inverted chromosomes break within a short 250 kb region. Moreover, a group of ESTs corresponding to an as yet uncharacterised gene was mapped to the same critical interval. We hypothesise that the common inversion breakpoint region of the two cases in Xq13.1 may contain a new MRX gene.     

Linkage analysis in Spanish families with nonspecific X‐linked mental retardation: Significant linkage at Xq13–q21

Mental retardation (MR) is a genetically heterogeneous, clinically variable condition. Many cases of MR are linked to the X chromosome. The aim of this study was to identify candidate loci for nonspecific MR in Spanish samples. We selected seven families with nonspecific MR and a pattern of inheritance compatible with an X‐linked disorder and a group of 26 sib pairs of mentally retarded individuals. We performed linkage analysis with a panel of 15 markers evenly distributed along the X chromosome. The study showed linkage to marker DXS8076, located in Xq21.1, by the lod score method (z = 2.11 at θ = 0.155) and the nonparametric extended relative pair analysis method (χ² = 5.32; P < 0.03). Genetic heterogeneity was found, with an estimated 75% of the families linked at recombination fraction θ = 0.10 to the DXS8076 locus (χ² = 9.51; P < 0.009). Xq13–q21 is one of the critical regions for X‐linked MR previously reported, and our study supports the idea that this region may contain a locus for MR in Spanish patients. © 2001 Wiley‐Liss, Inc.     

Fragile site X chromosomes and X-linked mental retardation in severely retarded boys in a northern Swedish county. A prevalence study

In an unselected series of 96 severely mentally retarded boys (IQ < 50) born 1959–70 in a northern Swedish county, six had a fragile site on the distal end of the X chromosome (FraXq 28). The prevalence of the fragile X syndrome in severely retarded boys was 6 %. Next to trisomy 21, this fragile X syndrome appears to be the most common single cause of severe mental retardation in boys.     

Marker X syndrome in an oriental family with probable transmission by a normal male

We report an oriental family with sex-linked mental retardation, macroorchidism, and a marker or fragile site on the X chromosome–mar(X)(q28). The three affected males resemble clinically most previously reported affected Caucasians. The marker was present in four females 40–70 years old, including one with normal intelligence. Transmission of the disorder appears to have taken place through a clinically normal male to his grandson.     

X chromosome inactivation and X-linked mental retardation

The expression of X-linked genes in females heterozygous for X-linked defects can be modulated by epigenetic control mechanisms that constitute the X chromosome inactivation pathway. At least four different effects have been found to influence, in females, the phenotypic expression of genes responsible for X-linked mental retardation (XLMR). First, non-random X inactivation, due either to stochastic or genetic factors, can result in tissues in which one cell type (for example, that in which the X chromosome carrying a mutant XLMR gene is active) dominates, instead of the normal mosaic cell population expected as a result of random X inactivation. Second, skewed inactivation of the normal X in individuals carrying a deletion of part of the X chromosome has been documented in a number of mentally retarded females. Third, functional disomy of X-linked genes that are expressed inappropriately due to the absence of X inactivation has been found in mentally retarded females with structurally abnormal X chromosomes that do not contain the X inactivation center. And fourth, dose-dependent overexpression of X-linked genes that normally “escape” X inactivation may account for the mental and developmental delay associated with increasing numbers of otherwise inactive X chromosomes in individuals with X chromosome aneuploidy. © 1996 Wiley-Liss, Inc.     

Hereditary motor and sensory neuropathy with deafness,mental retardation,and absence of sensory large myelinated fibers: Confirmation of a new entity

We describe two brothers, 11 and 13 years old, respectively, with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation. Electrophysiological studies showed marked reduction of motor and sensory conduction velocity and absence of sensory action potentials. Sural nerve biopsy, performed in both patients, showed absence of large myelinated fibers with normal density of small myelinated fibers without axonal degeneration. Signs of demyelination were found only in the younger patient. We suggest that motorsensory neuropathy associated with deafness and mental retardation with absence of large myelinated fibers on sural nerve biopsy represents a distinct clinicopathological entity, which is transmitted in families probably as an autosomal recessive trait. Am. J. Med. Genet. 75:309–313, 1998. © 1998 Wiley-Liss, Inc.     

X linked mental retardation and infantile spasms in a family: new clinical data and linkage to Xp11.4-Xp22.11

In order to describe the neurological abnormalities and to identify the gene localisation, we re-evaluated a previously reported family with X linked mental retardation (XLMR). Reliable data were obtained for six of the seven affected males, of whom two had had infantile spasms. Profound MR (IQ<20) was found in one and mild MR (IQ 50-70) in five males. No dysmorphic features, except for macrocephaly in one male, were found. Neurological abnormalities included varying degrees of spinocerebellar involvement. Neuroimaging studies showed abnormalities, such as cerebellar atrophy or corpus callosum hypoplasia or both, in three of the six males. Several affected and unaffected subjects suffered from hyperhidrosis, which appeared to segregate independently as an autosomal dominant trait. Genetic linkage analysis localised the XLMR disease gene to Xp11.4-Xp22.11 with a maximum multipoint lod score of 3.57, overlapping the candidate region recently found in two Belgian XLMR-infantile spasm families. Compared to the Belgian patients, the majority of the affected males in this report had a considerably milder phenotype.     

A cryptic full mutation in a male with a classical fragile X phenotype

Fragile X syndrome (FRX) is the most common inherited cause of mental retardation affecting approximately 1/4000 males and half as many females. Mosaicism has been reported in 12-41% of male cases. We present a 47-year-old male with the typical FRX phenotype referred for an evaluation of mental retardation and a psychiatric disorder. Analysis of the FMR-1 CGG repeat size was performed on peripheral blood by PCR and Southern blot analysis. The proband was shown to carry a premutation allele of 58 CGG repeats. Because of the compelling clinical phenotype, further testing was performed on DNA extracted from skin fibroblasts, which yielded a 500 CGG repeat allele. Mosaic cases of FRX have been reported but rarely without detectable mosaicism in peripheral blood. Therefore, this case is atypical because of the striking differences in the results obtained for the two different cell types. We concur with others that testing of ectodermally derived tissues may provide improved diagnosis and perhaps better insight into the overall prognosis of the affected individual. This case demonstrates the need to consider further study on other tissues when there is a strong clinical suspicion of FRX.     

The fragile X syndrome: A study of 83 families

The present report summarizes the experience on the mar(X) syndrome in a total of 157 male patients (44 prepubertal and 113 postpubertal) ascertained through 83 index patients from 83 families under investigation.
1. In one third of the families pedigree data were consistent with X-linked recessive inheritance. In the further two thirds of the families the presenting symptom was familial mental retardation with a mentally retarded mother, or mental subnormality with hyperkinetic behaviour in the male patient.
2. No more than 60% of the adult males presented the typical clinical triad (mental retardation -long face - megalotestes). The most characteristic finding in the mar(X) boy is the psychological profile with severe hyperkinetism, hypersensitivity, handbiting and autistic features in some of them.
3. In 4 of the 27 large mar(X) pedigrees strong evidence was present of a possible transmission of the mar(X) through normal males.
4. The high incidence of mental subnormality in the female offspring of heterozygote carriers, and the relationship between mental status, phenotype, age and expression of the mar(X) in different culture conditions is discussed.     

Familial X-linked mental retardation and fragile X chromosomes in two Swedish families

X-linked mental retardation (MR) associated with a fragile X chromosome was found in two Swedish families. The fragile X chromosome was demonstrated in 5/5 boys with mental retardation. Clinical data on four of these boys are presented. In one of the families, the mental retardation was associated with macro-orchidism, large hands and large, folded ears. In the other family, macro-orchidism was not seen, possibly because the boys were younger. Fragile site X chromosomes were also seen in three obligate carriers. A summary of earlier published cases of X-linked MR associated with the fragile X chromosome is given.     

45,X/46,X, + r(X) can have a distinct phenotype different from Ullrich-Turner syndrome

We present a patient with 45,X/46,X, + r(X) mosaicism and lack of inactivation of either the normal or the ring X in the 46,X, + r(X) cells. The patient has mental retardation, syndactyly, minor facial anomalies, and a congenital heart defect. Although most patients with 45,X/46,X, + r(X) have the Ullrich-Turner syndrome, 2 previously described patients with this karyotype also had a distinct phenotype consisting of severe mental retardation, syndactyly, and abnormal face. The unusually severe phenotype in these patients was thought to be due to lack of X-inactivation of the ring X chromosome. The findings in our patient support this hypothesis.     

A new autosomal dominant craniofacial deafness syndrome

A Jewish family is reported in which the proband and her father had congenital hearing loss and unusual facies consisting of facial asymmetry, temporal alopecia with frontal bossing, a broad nasal root and small nasal alae. In addition, both were born with a short frenulum of the tongue. We believe these findings represent a new autosomal dominant deafness syndrome with distinct craniofacial features.     

Folic acid therapy in the fragile X syndrome

Two brothers with fra(X) positive X-linked mental retardation (XLMR) were treated with folic acid. Initially a double blind cross-over design was employed followed by a long-term high dose trial. A decrease in the frequency of fra(X) positive cells was observed when low folic acid culture medium was used but not when an FUdR induction system was employed. Selected behavioral characteristics improved in both while receiving folic acid. Decreased hyperactivity, greater attention span, increased motor coordination, increased quantity and quality of speech were noted. Improvement in Leiter mental age and regression after cessation of treatment was seen in one subject but not in the other. Further controlled trials with larger numbers of subjects using high doses of folic acid over longer periods of time are needed to assess the possible benefits of this experimental form of treatment.