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1.
Clinical manifestations and other aspects of nonspecific X-linked mental retardation are reviewed using data from the literature and information on affected males in 24 new families ascertained in British Columbia. A great degree of variability was apparent in the mental abilities of affected males. Speech defects, other CNS disorders and minor physical changes such as “big” ears or a highly arched palate were not present in many cases. Evidence for the existence of a clinical entity of mental retardation associated with the fragile site at Xq27 or 28 and macro-orchidism is discussed. Genetic phenomena of reduced penetrance in males and of partial expression in females with respect to X-linked recessive genes are examined. Consideration is given to the question of whether this type of mental retardation is due to X-linked recessive or autosomal dominant sex-limited genes. Most ascertained cases of X-linked mental retardation are from families of northern European extraction. Recommendations are made regarding the diagnosis and counseling of X-linked mental retardation cases. 相似文献
2.
Diana S. Herbst Patricia A. Baird Jürgen Herrmann 《American journal of medical genetics. Part A》1982,13(2):197-208
Cases of nonspecific mental retardation (MR) born in British Columbia between 1952 and 1970 ascertained through the British Columbia Health Surveillance Registry were linked by birth registration number to family sibships from computer-linked groupings of birth and marriage records in British Columbia. It was possible to retrieve family information for 97% of the cases by this method. Because of good ascertainment and relatively large sample size, the 1952–1965 birth cohort comprising 2,209 index cases was selected for calculations of overall risks and recurrence risks to sibs categorized by sex, MR level, associated neurological disability, and singleton versus multiple birth. The overall risk of affected individuals among all sibs was 4.4 ± 0.6%, which was about ten times greater than the minimum population incidence of nonspecific MR. The risk among subsequent sibs of the first affected case in a family was 3.7 ± 0.8%. These risks varied depending on sex, MR level, and whether the mental retardation was associated with hydrocephalus, microcephalus, cerebral palsy, or epilepsy. The recurrence risk after two affected individuals was 12 ± 7% – about three times greater than after one affected individual. Even though the frequency of MR is greater among twins than in the overall population, the recurrence risk of nonspecific MR was not significantly different for index cases from either singleton or multiple births. 相似文献
3.
The diagnosis and frequency of X-linked conditions in a cohort of moderately retarded males with affected brothers 总被引:7,自引:0,他引:7
An epidemiological study was carried out on the group of moderately retarded brothers (IQ, 30-55) identified by Turner and Turner [1974]. Of the original 58 sets of brothers, 54 sets (now 17 to 32 years old) were traced; another four sets (missed in the earlier survey) were added. Forty-five of the 58 pairs were diagnosed as having nonspecific X-linked mental retardation (MR) giving an overall frequency of 5.57 moderately retarded males/10,000 male births. In 12 of the 45 families, affected males had the fragile(X) and macroorchidism; six had macroorchidism alone, giving a frequency of 2.8 moderately retarded males with X-linked MR and macroorchidism +/- the fragile(X) per 10,000 males. Corresponding heterozygote frequencies are 7.34 and 3.65/10,000 females respectively. A new subgrouping of nonspecific X-linked mental retardation is described in six families: X-linked MR, macroorchidism without the fragile(X). Three other X-linked conditions were identified: in one family, the Coffin-Lowry syndrome, in another, Duchenne muscular dystrophy, and in two families X-linked MR and muscle atrophy. Half (56%) of the obligatory carriers of fra(X)-MR in this study were dull to mildly retarded. The mildly retarded heterozygotes had a significantly higher percentage of fra(X) expressing lymphocytes as compared to the intellectually normal heterozygotes. When the three types of nonspecific X-linked MR for which population frequencies were calculated were considered together, half of the obligatory carriers (46%) were dull or mildly retarded, thus confirming that this condition is a significant cause of mild intellectual handicap in females. 相似文献
4.
M. Jennings J. G. Hall H. Hoehn Jürgen Herrmann 《American journal of medical genetics. Part A》1980,7(4):417-432
With the exception of macro-orchidism, three families with X-linked mental retardation showed diagnostic concordance of clinical features among the affected males. Since macro-orchidism was a variable feature among the otherwise identically affected males in one family, we question the existence of a separate entity of X-linked mental retardation characterized only by testicular enlargement. The X chromosome marker of Lubs was expressed, under the culture conditions of Sutherland, in lymphocytes of the affected males of two families, one with and the other without megalotestes. Two affected members of the third family, with megalotestes, did not show the marker. Telomeric structural changes similar to the mar(X) (qter) formation were found on certain autosomes, notably, chromosome 6 in some of the affected males, potential and obligate carrier females, and in both related and unrelated normal males. These autosomal markers appear to represent a nonspecific response to either in vivo or in vitro folate deficiency. Caution against premature introduction of this test for prenatal diagnosis, in the face of current ignorance regarding diagnostic specificity, is urged. 相似文献
5.
Astrid Golla Imma Rost Kerry Baldwin Jedele Angelika Albert Jan Murken Elke Holinski-Feder 《American journal of medical genetics》2002,107(1):18-25
A nonspecific X-linked mental retardation (MRX) family is reported with four mild to moderately affected males and no intellectual impairment in their obligate carrier mothers. Linkage analysis obtained the same multipoint lod score of 2.08 for two intervals on the X chromosome already reported to be linked to other MRX and syndromic X-linked mental retardation (XLMR) families: one pericentromeric and the other at Xq26. Since the responsible gene is not yet characterized, haplotyping is presently the only means available for carrier and prenatal testing for this form of MRX. Carrier risk estimation using pedigree and haplotype data for five females at risk is presented, and the difficulties of prenatal diagnosis given linkage to two different regions is discussed. 相似文献
6.
Monogenic X-linked mental retardation: is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations 总被引:4,自引:0,他引:4
Mental retardation affects 30 to 50% more males than females, and X-linked mental retardation (XLMR) is thought to account for the major part of this sex bias. Nonsyndromic XLMR is very heterogeneous, with more than 15 genes identified to date, each of them accounting for a very small proportion of nonsyndromic families. The Aristaless X (ARX) gene is an exception since it was found mutated in 11 of 136 such families, with a highly recurrent mutation (dup24) leading to an expansion of a polyalanine tract in the protein. The rather high frequency of dup24 reported in families with clear X-linked MR (6.6%) contrasts with the very low prevalence of this mutation observed in sporadic male MR (0.13%). We conclude that monogenic XLMR has much lower prevalence in male MR (< 10%) than the 23% that would be required to account for a 30% male excess of mental retardation. 相似文献
7.
I A Glass E M White M J Pope L A Pirrit F Cockburn J M Connor 《American journal of medical genetics》1991,38(2-3):240-243
We report on a large 5-generation family with "nonspecific" X-linked mental retardation. Nine living affected males have an IQ between 50 and 70 but have normal stature, facial appearance, and testicular volumes and no other abnormalities. Two obligate carrier females had borderline intellectual abilities and visual-psychomotor difficulties similar to those seen in affected males. Results of chromosome studies, including fragile X, were normal in males and females. Linkage analysis was undertaken, with 19 X-specific chromosomal restriction fragment length polymorphisms (RFLPs), giving a maximal LOD score of 1.60 at a 0.10 recombination fraction for F9, suggesting a localization to distal Xq for the mutant gene in this family. 相似文献
8.
C E Schwartz M May T Huang D Ledbetter G Anderson D F Barker H A Lubs F Arena R E Stevenson 《American journal of medical genetics》1992,43(1-2):467-474
A family in which 6 males have X-linked mental retardation has been studied with polymorphic DNA probes. The males differ from unaffected males only in impaired intellect and in smaller head size. The gene that causes mental retardation in the family appears to be located in band Xq21 on the basis of linkage with 3 markers: DXS250, DXS345 and DXS3 (theta max = 0.00; Zmax = 1.6). A multipoint lod score of 2.36 was obtain with no recombination relative to DXS326 in Xq21. This family is considered to have nonspecific X-linked mental retardation and has been given the designation MRX8. 相似文献
9.
Chabrol B Girard N N'Guyen K Gérard A Carlier M Villard L Philip N 《American journal of medical genetics. Part A》2005,138(4):314-317
Recent reports have demonstrated that mutations in the OPHN1 gene were responsible for a syndromic rather than non-specific mental retardation. Abnormalities of the posterior fossa with cerebellar hypoplasia have been demonstrated in all male patients reported to date. We report here a new family with X-linked mental retardation due to mutation in OPHN1 and present unpublished data about two families previously reported, concerning the facial and psychological phenotype of affected males and carrier females. Our study confirms that cerebellar hypoplasia is a hallmark of this syndrome. In addition, affected males display facial similarities that can help the diagnosis. Most carrier females have mild mental retardation and subtle facial changes. 相似文献
10.
A seven-generation pedigree of apparent X-linked, nonspecific mental retardation is reported. There are 19 known affected males who appear to have received the gene through normal mothers. Retardation, lack of fine motor coordination, hyperactivity and a speech defect are the characteristics of affected individuals studied. 相似文献
11.
Albert E. Chudley Joan Knoll John W. Gerrard Lawrence Shepel Ellen McGahey Jo Anderson John M. Opitz 《American journal of medical genetics. Part A》1983,14(4):699-712
Members of eight Saskatchewan families with fragile (X) X-linked mental retardation were studied in an attempt to relate frequency to age and intelligence. The mean IQ of 37 affected men was 35 (range 10–66). The mean IQ of 32 carriers was 88 (range 57–119), and the mean IQ of 13 females who remain at risk for being carriers, have no affected sons, and who failed to demonstrate the fra(X) was 100 (range 78–126). We demonstrated a significant inverse relationship between age and frequency of the fra(X) in carriers and in affected males. However, we demonstrated a more highly significant inverse relationship between frequency of the fra(X) and IQ in carriers but to a lesser extent in affected males. Of 32 carriers, only 3 (9.4%) did not demonstrate the fra(X) after addition of 5-fluoro-2′-deoxyuridine (FUdR) to the folic acid and thymidine-reduced culture medium. From these data we would recommend that chromosome studies in individuals at risk for fra(X) X-linked mental retardation be carried out at the youngest age and that the addition of FUdR to culture medium is useful in carrier identification. It is clear that, in at least the carriers, a lower expression of the fra(X) is highly significantly correlated to higher intelligence. 相似文献
12.
Patricia A. Jacobs Thomas W. Glover Martha Mayer Patricia Fox John W. Gerrard Henry G. Dunn Diana S. Herbst John M. Optiz 《American journal of medical genetics. Part A》1980,7(4):471-489
Seven families with X-linked mental retardation (MR) have been studied clinically and cytogenetically. All affected males in six of the families were found to have a fragile site on Xq in a number of their peripheral lymphocytes. The fragile site was not seen in any of the affected males in the seventh family. The affected males in the six families with the fragile X had a syndrome characterized by a variable degree of MR, macro-orchidism, a characteristic repetitive, jocular speech, normal body proportions, and large jaws and ears. The fragile X chromosome could only be detected in a proportion of female carriers and its frequency in females was found to be correlated with their mental status and to be inversely correlated with their age. 相似文献
13.
J. Fernando Arena Charles Schwartz Lisbeth Ouzts Roger Stevenson Marvin Miller Judith Garza Martha Nance Herbert Lubs 《American journal of medical genetics. Part A》1996,64(1):50-58
We reevaluated a family previously described as having nonspecific X-linked mental retardation (XLMR) by Snyder and Robinson [1969: Clin Pediatr 8:669–674] (MIM 309583). Clinical and DNA studies were conducted on 17 relatives, including 6 males with mild-to-moderate mental retardation, 3 carrier females, and 8 normal males. In contrast to the normal appearance and minimal clinical findings reported 22 years ago, affected males were found to have a characteristic set of clinical findings. These developed gradually over the first 2 decades, and included thin body build with diminished muscle mass, osteoporosis and kyphoscoliosis, slight facial asymmetry with a prominent lower lip, nasal speech, high narrow or cleft palate, and long great toes. Carrier females were clinically normal. Multipoint linkage analysis indicated linkage to markers distal to the 3′ end of DMD (DXS41 and DXS989), with a maximal lod score of 4.7. On the basis of these findings, this entity is redefined as XLMR syndrome. © 1996 Wiley-Liss, Inc. 相似文献
14.
15.
Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor 总被引:3,自引:1,他引:3
Bienvenu T; des Portes V; Saint Martin A; McDonell N; Billuart P; Carrie A; Vinet MC; Couvert P; Toniolo D; Ropers HH; Moraine C; van Bokhoven H; Fryns JP; Kahn A; Beldjord C; Chelly J 《Human molecular genetics》1998,7(8):1311-1315
Non-specific X-linked mental retardation (MRX) is a very common disorder
which affects approximately 1 in 600 males. Despite this high frequency,
little is known about the molecular defects underlying this disorder,
mainly because of the clinical and genetic heterogeneity which is evident
from linkage studies. Recently, a collaborative study using the candidate
gene approach demonstrated the presence of mutations in GDIalpha, a Rab
GDP-dissociation inhibitor encoded by a gene localized in Xq28, associated
with non-specific mental retardation. GDIalpha is mainly a brain-specific
protein that plays a critical role in the recycling of Rab GTPases involved
in membrane vesicular transport. The study presented here was designed to
assess the prevalence of mutations in the GDIalpha in mentally retarded
patients and to discuss the clinical phenotypes observed in affected
individuals. Mutation screening of the whole coding region of the GDIalpha
gene, using a combination of denaturing gradient gel electrophoresis and
direct sequencing, was carried out in 164 patients found negative for
expansions across the FRAXA GCC repeat. In addition to the nonsense
mutation recently reported in MRX48, we have identified a novel missense
mutation in exon 11 of the GDIalpha gene in one familial form of
non-specific mental retardation. In this family (family R), all affected
males show moderate to severe mental retardation, and the X-linked
semidominant inheritance is strongly suggested by the severe phenotypes in
males with respect to mildly affected females or unaffected obligatory
carriers. This study showed that the prevalence of GDIalpha mutations in
non-specific mental retardation could be estimated to be 0.5-1%, and
molecular diagnosis and genetic counselling in some cases of non-specific
mental handicap can now be provided.
相似文献
16.
Mental retardation (MR) is a group of heterogeneous clinical conditions. There are more than 900 genetic disorders associated with MR and it affects around 3% of the general population. MR can be subdivided into syndromic, if it is characterized by consistent and distinctive clinical findings, and nonspecific, if mental retardation is the only primary symptom among affected individuals. Many MR conditions described are syndromic, fragile X syndrome being the most common clinical entity among them. In the past years, knowledge of the molecular basis of mental retardation has increased remarkably. Eight genes involved in nonspecific X-linked MR have been identified so far, including FMR2, OPHN1, GDI1, PAK3, IL1RAPL, TM4SF2, VCX-A, and ARHGEF6. Two other genes also located on the X chromosome have been involved both in syndromic and in MRX forms (RSK2 and XNP/ATR-X). New insights into the pathogenesis of mental retardation are being provided by the discovery of these genes involved in different cellular signaling pathways in the central nervous system although many others remain to be identified. 相似文献
17.
18.
New X-linked mental retardation disorder with Dandy-Walker malformation, basal ganglia disease, and seizures 总被引:5,自引:0,他引:5
We report on a 4 generation family of individuals with an X-linked form of mental retardation involving 9 affected males and 5 obligate carrier females. Key manifestations include severe mental retardation, early hypotonia with progression to spasticity and contractures, choreoathetosis, seizures, presence of a long, narrow face with coarse features, cystic enlargement of the fourth ventricle with cerebellar hypoplasia (Dandy-Walker malformation), and iron accumulation in the basal ganglia with neuroaxonal dystrophy similar to Hallervorden-Spatz disease. Of the 5 known heterozygotes, 3 are dull intellectually, and one of the 3 developed a "presenile dementia." At autopsy she had iron deposition and neuroaxonal dystrophy in the basal ganglia and atrophy of the cerebral cortex. Although the clinical findings among relatives are variable, we conclude that this is a distinct, previously unrecognized X-linked mental retardation syndrome. 相似文献
19.
A survey of the mentally retarded children with an IQ between 30 and 55 born in a 10-year period (1955-64) and now of school age was carried out in New South Wales. The number of propositi who had a similarly affected sib of the same sex was ascertained; 58 boys had a similarly affected brother(s) and 22 girls had a similarly affected sister(s). It is suggested that the excess of affected brothers represents X-linked forms of mental retardation. An estimate of prevalence rate was calculated from the brother pair excess and was found to be 0·74/1000 males. The calculated incidence of X-linked forms of mental retardation appeared to account for most of the male excess found in the survey and suggests that 1 in every 5 of the mentally retarded boys in the IQ range in this survey may be retarded on the basis of genes on the X chromosome. 相似文献
20.
E Holinski-Feder S Chahrockh-Zadeh O Rittinger K B Jedele M Gasteiger C Lenski J Murken A Golla 《American journal of medical genetics》1999,86(2):102-106
An Austrian family with nonsyndromic X-linked mental retardation (MRX) is reported in which the obligatory carrier females are normal, and 5 affected males have mild to moderate mental retardation. Linkage analysis indicated an X pericentromeric localization, with flanking markers DXS989 and DXS1111 and a maximum multipoint LOD score of 2.09 (straight theta = 0) for the 7 cosegregating markers DXS1243, CybB, MAOB, DXS988, ALAS2, DXS991, and AR. MRX58 thus mapped within a 50-cM interval between Xp11.3 and Xq13.1 and overlapped with 23 other MRX families already described. This pericentromeric clustering of MRX families suggests allelism, with a minimum of 2 X-linked mental retardation (XLMR) genes in this region. 相似文献