Martin-Bell phenotype in males with acquired central nervous system lesions. 15 males diagnosed during a systematic etiological study of 274 mentally retarded males

Martin-Bell phenotype in males with acquired central nervous system lesions. 15 males diagnosed during a systematic etiological study of 274 mentally retarded males: After a brief survey of the etiological findings in 274 moderately mentally retarded adult males, we present data on the phenotypic features in the group of 65 patients with a acquired (pre-, peri- or postnatal) cause of their handicap. In 15 of them "Martin-Bell stigmata" were observed i.e. they had 3 or more symptoms as found in fra(X) positive "Martin-Bell" males. These data are a further indication for a disregulation of the cortico-hypothalamico-hypophyseal axis in the fra(X) syndrome.     

Possibility of EEG-diagnosis of heterozygotic Martin-Bell syndrome

A case of fragile-X syndrome (the Martin-Bell syndrome) in two male half-sibs from different marriages of their mother was described. Both patients suffered from mental retardation and had some characters of the Martin-Bell syndrome. Somatically healthy mother was characterized by IQ-101. The EEG study showed similar changes both in mother and her sons. The diagnostic specificity of the method presented was discussed.     

Evidence against close linkage of the loci for fraXq of Martin-Bell syndrome and for factor IX

Summary Linkage between the loci for fraXq of Martin-Bell syndrome and factor IX was studied in nine families exhibiting this syndrome by means of a restriction fragment length polymorphism at the factor IX locus. Computer analysis of the data indicates there to be no evidence for close linkage between the syndrome and the factor IX locus.     

A common fragile site at Xq27: theoretical and practical implications.

The fragile site at Xq27 (FRAXA) is associated with a common form of X-linked mental retardation (Martin-Bell syndrome). It is induced in culture by conditions of thymidylate stress and is generally considered a rare fragile site found only in association with an X-linked form of mental retardation. Using a somatic cell hybrid system, we previously demonstrated that fragile-X expression can be induced by thymidylate stress in normal X chromosomes at low levels (4%-5%). In the present report, significantly higher levels of fragile-X expression (6%-28%) have been induced in lymphocytes or lymphoblasts of all seven control males using high doses of aphidicolin (1.5 microM). Similar high levels of expression (10%-12%) were observed in both of two normal male chimpanzees (Pan troglodytes). These data demonstrate that Xq27 contains a common fragile site (FRAXD) that is ancestral to the divergence of man and the chimpanzee. Presence of a common and a rare fragile site in the same metaphase chromosome band does not prove that they are identical and may, in fact, represent two unrelated fragile sites. However, the possibility exists that the common fragile site at Xq27 may be the substrate for unequal recombination events that produces the rare fragile site associated with Martin-Bell syndrome. In addition, presence of a common fragile site at Xq27 may explain the occasional observation of low-frequency fragile-X expression in normal control individuals. Caution is therefore warranted in the interpretation of low-level fragile-X expression in diagnostic and prenatal diagnostic settings.     

Expression of the autosomal folate-sensitive fragile sites in ten kindreds with Martin-Bell syndrome

The authors analyse the expression of all the folate-sensitive fra sites in a sample of 24 male patients with Martin-Bell syndrome (MBS) and their 12 mothers distributed in 10 kindreds. The cytogenetic results are compared with that of a control group, constituted by 8 unrelated normal subjects. Except for the fra Xq27, there was no autosomal folate-sensitive fra site significantly more expressed in patients with MBS than in the control group. On the basis of the present cytogenetic sample of about 6 500 R-banded mitoses, a list of all the in vitro folate-sensitive fra sites and their relative frequencies is given.     

X-linked mental retardation. I. Martin-Bell syndrome (report of 18 families)

Eighteen families with X-linked mental retardation (MR) with or without macroorchidism, fragile-X positive at Xq27 (Martin-Bell syndrome) have been studied clinically and cytogenetically. All 58 affected males presented variable degrees of MR, fra(X) (q27) of their peripheral lymphocytes, macroorchidism in all adult patients with the exceptions of one with microorchidism as 47,XXY sex chromosome complement and the other with borderline testes, and characteristic facial appearance. The expression of the marker X in the heterozygotes seems to be more related to the mental development rather than the age of the individual. In two families the transmission of the syndrome through unaffected males seems probable.     

Mental retardation in heterozygotes for the fragile-X mutation: evidence in favor of an X inactivation-dependent effect.

The still debated question of whether the expression of mental retardation in heterozygous carriers of the Martin-Bell syndrome is influenced by X inactivation has been investigated in a group of phase-known double heterozygotes for the FRA-X mutant and the G6PD Mediterranean variant. In these individuals, the number of somatic cells (fibroblasts or red cells) with an active FRA-X chromosome could be assessed through the G6PD phenotype at the single-cell level. The data reported indicate a significant inverse correlation between the IQ level (as measured by the Wechsler-Bellevue test) and the percentage of fibroblast cells with an FRA-X active chromosome. In contrast, no significant correlation was found when the IQ level and red cell data were compared, thus suggesting the occurrence of somatic selection against hematopoietic stem cells with an active FRA-X chromosome.     

Mental impairment in Martin-Bell syndrome is probably determined by interaction of several genes: simple explanation of phenotypic differences between unaffected and affected males with the same X chromosome

Summary A family with Martin-Bell syndrome (MBS) is described with transmission of this X-linked trait by a normal male who manifested the fragile site at Xq27. This family shows features apparently typical for all families with a normal male transmitter. The daughters of this male are mentally normal and their fragile site is difficult or impossible to detect but detection of the heterozygous genotype is much easier among the granddaughters. This can be explained by a model assuming that mental deficiency in patients with MBS is determined by several genes, i.e. the X-linked MBS-gene as major gene undergoing X-inactivation and interacting with at least one modifying gene. The model assuming one autosomal modifier segregating independently from the MBS-gene is tested using the results of segregation analysis performed by Sherman et al. (1984, 1985). No significant differences have been found between the predictions of this model and the findings of the segregation analysis. Nearly all of the segregation data are exactly predicted by the model. Possible differences are discussed either to be due to biased data or to require slight modification of the model to get a better fit of the data. The apparent phenotypic differences between a normal carrier grand-father and his affected grandsons as well as between his daughters and his heterozygous granddaughters are also simply explained on the basis of this model. Several modifier loci may exist each of them related to one of the various phenotypic effects of the X-linked major gene (MBS-gene) leading typic effects of the X-linked major gene (MBS-gene) leading to a syndrome that does not include any obligate feature.     

X-linked mental retardation. II. Renpenning syndrome and other types (report of 14 families)

Fourteen families with X-linked mental retardation (XMR) have been studied clinically and cytogenetically. All affected males failed to show a fragile site (FS) on Xq of their peripheral lymphocytes. Five families may be considered examples of Renpenning syndrome while the remaining may be divided in two groups: one of seven (type I) and one of two (type II). The seven families of type I had some physical features of the Martin-Bell syndrome but with normal to large sized testes whence the name of X-linked MR with slight macroorchidism (XMR +/- MO). The two families of type II showed unremarkable facial appearance, mild to moderate degree of MR and a certain microorchidism whence the possible name of X-linked MR with different degree of microorchidism (XMR +/- MiO).     

Linkage study in a large pedigree with Stickler syndrome: exclusion of COL2A1 as the mutant gene

Summary A three generation family with Stickler syndrome is reported. Affected patients exhibited myopia with frequent retinal detachment or glaucoma. Most of them had characteristic facial dysmorphism, the Pierre-Robin sequence being observed in four individuals. Neonatal radiological signs of the Weissenbacher-Zweymüller syndrome were also noticed but early arthopathy was not reported in adults. Restriction fragment length polymorphism studies with the type II collagen gene (COL2A1) showed a recombination event between the disease locus and COL2A1, thus excluding collagen type II as the candidate gene. Although the calculation of the likelihood of genetic heterogeneity versus homogeneity based on 10 families was not statistically significant, we suggest that a second locus is probably involved in this highly variable syndrome.     

Crimino-biologic study of patients with the XYY syndrome and Klinefelter's syndrome

Summary 12 psychopathic patients with chromosome aberrations found among 480 individuals in two institutions for criminal psychopaths in Denmark have been crimino-biologically investigated. 5 of these individuals have Klinefelter's syndrome, 5 are of the XYY karyotype, 1 is 46,XY/47,XY ?Xq- mosaic, and the remaining one is 46, ?Xp-Y.The mean age at first offence is 18.5 years; 83% are recidivists with the mean number of sentences being 7.0. The criminal acts of 5 patients with the XYY syndrome consist mainly of petty thieving, indecency and arson. The criminal offences of 5 patients with Klinefelter's syndrome is mainly petty thieving, sexual offences and less violent crimes. The relationships between the individual criminal life curve, age at first offence, number of sentences, criminality among siblings, milieu factors, intelligence, and psychiatric diagnosis are discussed.Psychoinfantile personality is pronounced in 5 patients with Klinefelter's syndrome. Schizoid personality was remarkable in 3 patients with the XYY syndrome.

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Zusammenfassung 12 psychopathische Patienten mit Chromosomenaberrationen, die unter 480 Insassen von zwei Anstalten für kriminelle Psychopathen in Dänemark gefunden wurden, wurden kriminalbiologisch untersucht: 5 von ihnen hatten das Klinefelter-Syndrom, 5 zeigten den XYY-Karyotyp, 1 war 46, XY/47,XY,?Xq-Mosaik, der letzte war 46, ?Xp-Y.Das Durchschnittsalter bei dem ersten Vergehen war 18,5 Jahre; 83% wurden rückfällig; die durchschnittliche Zahl der Verurteilungen betrug 7,0. Die Vergehen der 5 Personen mit XYY-Syndrom bestanden vor allem aus geringfügigen Diebereien, Sittlichkeitsvergehen und Brandstiftung. Die Vergehen der 5 Patienten mit Klinefelter-Syndrom setzten sich vor allem zusammen aus geringfügigen Diebereien, sexuellen Vergehen und weniger gewaltsamen Vergehen. Die Beziehungen zwischen den individuellen Lebensläufen bezüglich der Kriminalität, dem Alter beim ersten Vergehen, der Zahl der Verurteilungen, der Kriminalität unter Geschwistern, den Milieufaktoren, der Intelligenz und der psychiatrischen Diagnose werden diskutiert. Bei 5 Patienten mit Klinefelter-Syndrom finden sich deutliche Zeichen einer psychoinfantilen Persönlichkeit. 3 Patienten mit XYY-Syndrom zeigten deutliche schizoide Züge.

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The author dedicates this paper to emeritus Prof. Dr. S. Yoshimasu on his 70th birthday.

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Stipendiat of the Alexander von Humboldt-Stiftung.     

Laurence-Moon-Biedl syndrome in presumably identical twins

Summary A Saudi Arabian family with 3 cases of Laurence-Moon-Biedl syndrome, 2 of whom are presumably identical twins, is presented. Although it is generally accepted that this condition is inherited as an autosomal recessive trait, no conclusive data exist in the literature to support this theory.

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Zusammenfassung Wir präsentieren eine saudiarabische Familie, in der 2 Mitglieder vermutlich eineiige Zwillinge sind. In dieser Familie finden sich 3 Fälle von Laurence-Moon-Biedl-Syndrom. Wenngleich allgemein angenommen wird, daß dieser Zustand als autosomales recessives Merkmal vererbt wird, existieren hierfür keine überzeugenden Daten in der Literatur.

     

Delineation of Cohen syndrome following a large-scale genotype-phenotype screen

Cohen syndrome is an autosomal recessive condition associated with developmental delay, facial dysmorphism, pigmentary retinopathy, and neutropenia. The pleiotropic phenotype, combined with insufficient clinical data, often leads to an erroneous diagnosis and has led to confusion in the literature. Here, we report the results of a comprehensive genotype-phenotype study on the largest cohort of patients with Cohen syndrome assembled to date. We found 22 different COH1 mutations, of which 19 are novel, in probands identified by our diagnostic criteria. In addition, we identified another three novel mutations in patients with incomplete clinical data. By contrast, no COH1 mutations were found in patients with a provisional diagnosis of Cohen syndrome who did not fulfill the diagnostic criteria ("Cohen-like" syndrome). This study provides a molecular confirmation of the clinical phenotype associated with Cohen syndrome and provides a basis for laboratory screening that will be valuable in its diagnosis.     

Manifestation of the fragile site Xq27 in fibroblasts

Summary Fibroblasts from a heterozygous carrier for the Martin-Bell syndrome, who manifests the fragile site Xq27, were cloned to separate the population carrying the primary defect on the active X chromosome from the population with this defect on the inactive X. Clones with this defect on the active X manifest the fra(X)(q27) whereas clones from the other population are fra(X)-negative (Steinbach et al. 1983b). In this project, the replication status of the X chromosome manifesting the fra(X)(q27) was studied in seven clones with this defect on the active X.The results obtained on the clones were very similar to the results obtained from uncloned fibroblasts and lymphocytes. In the clones the fragile site was found manifested on the early replicating X in 73 cells and on the late replicating X in four cells.Since the defect is located on the active X chromosome of these cells the manifestation of the fragile site on the late replicating X suggests that the defect and the fragile site cannot be identical. It is concluded that there is no obligate synteny of this defect and the manifested fragile site.     

Bericht über vier Trisomien 18 und ein Trisomie-18-Mosaik

Zusammenfassung Die Autoren berichten über vier Trisomien 18 und ein Trisomie-18-Mosaik. Die fünf Patienten waren weiblich. In der Familienanamnese waren keine Hinweise für die Verursachung der Trisomien erkennbar. Klinisch-pathologisch zeigen die patienten alle typischen Merkmale der Trisomie; auch der Mosaikfall (92% trisome Zellen im Blut) unterscheidet sich in seinen Merkmalen nicht von dem üblichen Bild. Einige seltenere, Mißbildungen sind beobachtet worden (Spaltbildung des Oberkiefers — 2 Fälle —; Syndaktylie an einer Hand — 1 Fall —; Oesophagotracheal-Fistel —1 Fall).Cytogenetische Daten und Hautleistenbefunde werden beschrieben.

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Detailed clinical and cytological information on four trisomy 18 cases and one trisomy 18 mosaic is given. All patients were females. Within the families, no additional cases were detected. The patients, including the mosaic case (92% trisomic cells in the blood-culture), showed all the typical features of the syndrome. Some anomalies were observed which apparently are rather rare features of the syndrome (hare-lip and cleft-palate — 2 cases —; syndactyly of one hand — 1 case —; tracheoesophageal fistula — 1 case).Cytological and dermatoglyphic findings are described.

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Mit 5 Textabbildungen

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Mit Unterstützung, durch das Bundesministerium, für Wissenschaftliche, Forschung.

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Wesentliche Teile der vorliegenden Arbeit werden von Fräulein Renate Schröter als Dissertation der Medizinischen Fakultät der Universität Freiburg i. Br. vorgelegt.     

Fryns syndrome: another example of non-lethal outcome with severe mental handicap.

In this report we present clinical data of a patient with Fryns syndrome who survived the neonatal period. Two sibs died intra-uterine. The syndrome is characterized by craniofacial dysmorphism, diaphragmatic hernia and distal limb hypoplasia. Lethality in most cases is caused by the diaphragmatic hernia with concomitant lung hypoplasia. In patients with Fryns syndrome presenting without the diaphragmatic defect and lung-hypoplasia, survival beyond the neonatal period is possible; mental retardation is present in all four patients described so far. This report illustrates, once more, the great intrafamilial variation of the syndrome and emphasises its important consequences for genetic counseling and prenatal diagnosis.     

Screening for FMR1 and FMR2 mutations in 222 individuals from Spanish special schools: identification of a case of FRAXE-associated mental retardation

Fragile X syndrome is the most common inherited form of familial mental retardation. It results from a (CGG) _n trinucleotide expansion in the FMR1 gene leading to the typical Martin-Bell phenotype. Clinical features vary depending on age and sex. Expansion of a (CCG) _n repeat in the FMR2 gene corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and lacks a consistent phenotype. Analysis of repeat expansions in these two genes allows the molecular diagnosis of these different entities. We report here the screening of the FRAXA and FRAXE mutations in 222 unrelated mentally retarded individuals attending Spanish special schools. PCR and/or Southern blotting methods were used. We detected full mutations in the FMR1 gene in 11 boys (4.9%) and 1 boy (0.5%) with a CCG repeat expansion in the FMR2 gene. The latter shows mild mental retardation with psychotic behaviour and no remarkable physical traits. Molecular studies revealed a mosaicism for methylation in the FMR2 gene. This case supports the observation that expansions greater than 100 repeats can be partially methylated and cause the phenotype. Received: 11 February 1997 / Accepted: 9 June 1997     

Evidence that circulating 6keto prostaglandin E1 causes the platelet defect of Bartter's syndrome

Bartter's syndrome is associated with activation of prostaglandin metabolism. In the present study we provide several lines of evidence that a circulating metabolite of prostacyclin, 6ketoPGE1 is responsible for a defect in platelet function present in patients with Bartter's syndrome. In platelet aggregometry studies, plasma from patients contained platelet inhibitory activity which was fully neutralized by coincubation with antibody directed against 6ketoPGE1. Fractionation of lipophilic extracts of plasma by high pressure liquid chromatography yielded a platelet inhibitory fraction which comigrated with authentic 6ketoPGE1 and was neutralized by anti 6ketoPGE1 antibody. Lastly, direct measure of the plasma concentration of 6ketoPGE1 by specific radioimmunoassay indicates a 2-fold increase in patients with Bartter's syndrome (133 +/- 9.1 vs 60.7 +/- 12.3 picograms/ml; p less than 025). These studies provide firm evidence that the platelet dysfunction present in patients with Bartter's syndrome is attributable to an increase in the plasma concentration of 6ketoPGE1. In addition, these data provide further evidence in support of the centrality of activation of prostaglandin metabolism in the pathophysiology of Bartter's syndrome.     

Parental age in retinoblastoma

Summary In a review of information on 444 patients with sporadic retinoblastoma, a correlation with increased fathers'age was demonstrated and no correlation with was found in the unilateral form. These data favor the hypothesis that the bilateral form is caused by a germinal mutation and the unilateral form is due to somatic mutations.

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Zusammenfassung In einer Übersicht über 444 Patienten mit sporadischem Retinoblastom wurde eine Erhöhung des väterlichen Alters demonstriert. Bei den einseitigen Fällen wurde eine solche Erhöhung jedoch nicht gefunden. Die Daten sprechen dafür, daß die doppelseitige Form durch Keimzell-Mutation verursacht ist, während die einseitige form auf somatische Mutationen zurückgeht.

     

Cytogenetic,clinical and genealogical analyses in a series of gonadal dysgenesis patients and their families

Summary 46 individuals, ascertained due to gonadal dysgenesis symptoms, were studied. 16 of them were 45, X and showed characteristics of Turner's syndrome. 15 proved to be chromosome mosaics and presented Turner's syndrome (12 cases), mixed gonadal dysgenesis (2) and gonadoblastoma (1). There were also 2 cases of pure gonadal dysgenesis and 13 patients with normal karyotypes. The clinical and genealogical data obtained from these individuals and their families were compared with 26 other series reported in the literature. Common malformations besides those related to sexual development are: short stature, abnormal nails, low implantation of hair, pigmented naevi, shield chest, short neck and cubitus valgus. Persons with 45,X karyotypes generally presented a more severe clinical picture than mosaics. The prevalence of twins is higher than expected among the patients' sibs in the cases reported here and in 3 of the 5 other series for which data are available.

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Zusammenfassung 46 Personen mit Symptomen der Gonadendysgenesie wurden untersucht. 16 von ihnen waren 45,XO und zeigten Symptome des Turner-Syndroms. 15 erwiesen sich als Chromosomenmosaiken; 12 von ihnen zeigten ebenfalls das Turner-Syndrom, 2 zeigten eine gemischte Gonadendysgenesie, während 1 Patient ein Gonadoblastom aufwies. Außerdem wurden 2 Fälle von einer Gonadendysgenesie und 13 Patienten mit normalem Karyotyp beobachtet. Die klinischen und genealogischen Daten von diesen Patienten und ihren Familien wurden mit denen aus 26 Literaturserien verglichen. Außer den Störungen der sexuellen Entwicklung sind die folgenden Mißbildungen häufig: Kleinwuchs, abnorme Nägel, niedrige Haargrenze, Pigmentnaevi, schildförmiger Torax, kurzer Hals, Cubitus valgus. Im allgemeinen zeigen Personen mit 45,XO-Karyotypen ein schwereres klinisches Bild als Mosaiken. Unter den Geschwistern der Patienten finden sich Zwillinge häufiger als erwartet; das gilt auch für 3 der 5 anderen Serien, für die Daten verfügbar sind.

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Née Suñé.