We extend the theory of maximally even sets to determine the evenness of partitions of the chromatic universe U-c. Interactions measure the average evenness of colour sets (partitioning sets) of U-c. For 2-colour partitions the Clough-Douthett maximal-evenness algorithm determines maximally even partitions. But to measure the evenness of non-maximally even partitions, it is necessary to use computational methods. Moreover, for more than two colour sets there is no simple algorithm that determines maximally even partitions. Again, we rely on computational methods. We also explore collections of partitions and partition-classes (orbits under a dihedral group) and construct tables that order partition-classes according to the evenness of their partitions. We use Bell numbers, Stirling numbers of the second kind, and integer partitions to enumerate relevant combinatorial objects related to our investigation.

Different mutations occurring in the unstable CGG repeat in 5' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed ‘full mutation’ and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term ‘abnormal methylation’ is used here to distinguish the DNA methylation induced by the expanded repeat from the ‘normal methylation’ occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed ‘premutation’ is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing.

Background: Detection of myocardial fibrosis and left ventricular dysfunction in Duchenne muscular dystrophy (DMD) is the corner stone for further therapeutic studies. Little is known about the ability of cardiac magnetic resonance imaging (CMR) to evaluate progression of myocardial fibrosis. Aim of our study was to provide CMR data in a previously genotyped DMD family and to evaluate whether progression of myocardial fibrosis could be visualized.Methods and results: DMD genotypes were available in 14 family members. CMR was performed in 4/5 carrier females, in 2/2 affected males and in one healthy family member with normal genotype. Functional images and late gadolinium enhanced (LGE) images in contiguous short-axis orientation were acquired at baseline and follow-up of 1231 days CMR examination could be repeated in three carrier females, in one affected male and in the healthy subject previously scanned. Mean decrease of left ventricular ejection fraction during the follow-up period was 10.5 +/- 11.0%, mean progression of LGE volume 11.7 +/- 9.5%.Conclusions: Myocardial fibrosis seems to occur prior to global left ventricular dysfunction in DMD diseased males and carrier females. CMR could be used to evaluate progression of myocardial fibrosis and left ventricular function and may thus serve as an important diagnostic tool in the evaluation of therapeutical options in DMD. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

CHARACTERISTICS 1.1 Name of the disease (synonyms)The term fragile X-associated disorders (FXD) refers to a family of conditions all caused by changes in fragile X mental retardation 1 gene (FMR1).Fragile X mental retardation syndrome, fragile X syndrome (FXS), Martin-Bell syndrome Males affected with FXS present with mild-to-severe mental retardation.Dysmorphic features often include large prominent ears, an elongated face, a prominent forehead, macrocephaly and a high arched palate, which is occasionally accompanied by a cleft palate, These dysmorphic features are generally more striking after early childhood.Macroorchidism, while not specific for FXS, is the most consistent finding, present in B90% of boys by the age of 14. Behavioral disturbances including hyperactivity, hyperarousal, anxiety and aggressive outbursts are common.FXS represents the most common monogenic disorder responsible for autism and autism spectrum disorders.2][3] This subgroup of boys presents with the same behavioral and social profile observed in children with idiopathic autism. 3trong gaze avoidance, even when the individual is seeking interaction, represents one of the hallmarks of FXS.In addition, tactile defensiveness and tantrum behaviour when subjected to excessive auditory or visual stimuli suggest a sensory processing disorder.FXS is an X-linked disorder and females usually present with a milder phenotype.Females affected with FXS generally have IQs in the borderline to low normal range (mean IQ: 82).Most females present with learning disabilities, half meeting the criteria for intellectual and developmental disabilities 4 and approximately a quarter being mentally retarded (IQo70). 5ffected females have fewer behavioral problems than males, with shyness and social anxiety being the most commonly seen.Residual FMRP (protein produced by FMR1) levels in females are related to the X activation ratio (AR).Women may produce close to normal levels of FMRP when the normal X chromosome is preferentially activated (high AR), or much lower levels when the normal X chromosome is preferentially inactivated.

Background 153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was confirmed by three independent laboratories using different PCR primers: while some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees. Conclusions The authors find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practice when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.

We screened 217 patients from Germany ( n = 213), Austria ( n = 2) and Switzerland ( n = 2) with a positive family history for amyotrophic lateral sclerosis (ALS) for mutations in the copper/zinc superoxide dismutase (SOD1) gene. We found that 13% of the families tested carried mutations. By analyzing inheritance, we detected a clear-cut co-segregation in 5 of the 28 families; however, in two families with an established mutation, co-segregation was absent. In Germany, the R115G mutation is comparatively frequent and exhibits a specific aggressive phenotype. The L144F mutation, which is the most prevalent mutation in the Balkan countries, and the D90A mutation which is the most frequent SOD1 mutation globally, seem to be the second most common disease-causing mutations in Germany.

Das 20. Jahrhundert kann als Zeitalter der modernen Diktaturen bezeichnet werden, mithin als eine Epoche der diktatorischen Systeme, die vorgaben, sich auf die Unterstützung der Bevölkerungsmehrheit berufen zu können. Der breite Rückhalt, den Diktatoren in der Bevölkerung finden, macht es Menschen, die sich nicht auf diktatorische Systeme einlassen wollen, oftmals so schwer, sich Diktaturen zu widersetzen. Und dieser Rückhalt kann auch erklären, weshalb es nach dem Sturz des Diktators oftmals so schwer ist, den Gegnern seiner Herrschaft den verdienten Respekt zu zollen, aus ihrer Verhaltensweise eine neue Grundlage politischer Moral abzuleiten und möglicherweise einen erweiterten freiheitlich-demokratischen Wertekanon zu entwickeln. Welche Impulse kann die Thematisierung des Widerstands gegen den Nationalsozialismus der Demokratiedidaktik geben?

Proximal myotonic myopathy (DM2, PROMM) has not been reported in patients younger than 18 years, and apparent lack of congenital and childhood forms is thought to be one of the distinctive clinical characteristics of this trait. We now describe a 2-year-old boy, the youngest member of a family with a history for myotonia in 2 generations. The patient's 35-year-old mother was diagnosed with DM2 of late juvenile onset. She developed aggravating myotonic symptoms during pregnancy. Remarkably few intrauterine child movements were noticed. After birth the child showed general muscular hypotonia with delayed statomotoric development (sitting and crawling at 13 months, first lifting into standing position at 18 months). Muscle reflexes were normal. In the CL3N58 region of ZNF9, DM2-typical unstable expanded CCTG arrays of about 14.5 kb (about 2,500 repeats) were detected both in the mother and the patient by Southern blotting. Expansion of the DM1-specific DMPK CTG repeat was excluded.

A 42 year-old female carrier of Duchenne muscular dystrophy (DMD) was referred with suspected subacute myocarditis and non-sustained ventricular tachycardia. Echochardiography and cardiac catheterization revealed severely reduced left ventricular function (LVF). Coronary artery disease was excluded. Cardiac magnetic resonance imaging showed transmural, intramural and subepicardial late gadolinium enhancement. Myocardial biopsy excluded viral infection and showed severe myopathic changes with abnormal expression of dystrophin and utrophin. Moleculargenetic analysis of the DMD gene revealed frameshift duplication of exon 2. The patient received conventional heart failure therapy, implantable cardioverter/defibrillator-implantation and prednisolone to attenuate cardiac degradation. 6 months later she had improved clinically though LVF was still severely reduced.

AuszugWie gehen postdiktatorische Gesellschaften mit den Folgen diktatorischer Politik um, und welche Ziele verfolgen sie mit den Versuchen, die Vergangenheit aufzuarbeiten? Die Beantwortung dieser Fragen fällt je nach Erfahrung und politischem Standort unterschiedlich aus und spiegelt immer die Wertentscheidungen der Fragenden und der Antwortenden. Nicht einmal einigen können sich die Zeitgenossen auf die großen Linien der Interpretation. Deshalb erregen sie sich immer wieder über scheinbare Details der Vergangenheitsdeutungen, die nicht selten chiffrenartig auf Ereignisse und Personen, Konstellationen und Gefühle bezogen werden. Diese Erregung verstellt den Blick auf Handlungsspielräume, auf Funktionen und Grenzen der Auseinandersetzung mit der Vergangenheit. Und in besonderer Weise betrifft dies die Bewertung eines der wichtigsten Instrumente der Abarbeitung an der Vergangenheit: das Strafrecht.

More than 200 syndromic and nonsyndromic disorders associated with X-linked mental retardation are known, and the gene responsible for the condition has been identified in many cases. The phenotypic effects of known MRX genes, and their obvious overrepresentation on the X chromosome, suggest that they played an important role during human speciation. Keywords: X-linked mental retardation; signal transduction; cytoskeleton organization; synaptic plasticity; human speciation

Fragile X mental retardation syndrome is caused by the absence of functional FMR protein (FMRP), encoded by the fragile X mental retardation gene, FMR1 [for review see Hagerman, 1998; Imbert et al., 1998]. This gene contains a repeat sequence of C, G, and G nucleotide bases (CGG triplet repeat) in the 50 untranslated region [Verkerk et al., 1991]. The repeat varies in length from one person to another, ordinarily falling within a ‘‘normal’’ range (5–58 trinucleotides). In most individuals who have fragile X syndrome, the repeat is expanded to several hundreds of CGGs (>220). This large expansion is called a ‘‘full mutation.’’ In this situation, the gene usually becomes heavily modified by DNA methylation and is shut down. The fully mutated FMR1 gene of affected children is always received from a carrier mother. She may carry a full mutation by herself, but mostly the length of her CGG repeat is between the normal and the full mutation range (59–200 CGGs, premutation). Many female premutation carriers receive the gene from their father. In this case, the father is a transmitting male passing a premutation to all his daughters, but none of his sons who inherit the Y chromosome. According to the experiences from thousands of families and molecular studies, males never pass a full mutation to their daughters. Carriers of a premutation do not typically have symptoms of fragile X syndrome, but the premutated CGG repeat is ‘‘unstable,’’ in that it is prone to further expansion when passed from a mother to her children. A full mutation male may also have children, but he has only premutations in his sperm [Reyniers et al., 1993]. In a recent study, Zeesman et al. [2004] reported a case of a severely affected autistic girl who was diagnosed to carry a mutated FMR1 allele received from her father, a high functioning fragile X male and a methylation mosaic. He had only premutation alleles in his sperm. Several other family members, including another obligate carrier and individuals without a mutated FMR1 allele, had some degree of unexplained behavioral problem and/or intellectual deficit. The proband was interpreted to be the first case of paternal transmission of fragile X syndrome, thereby challenging the central dogma that the fragile X full mutation does never occur upon paternal transmission. However, we totally disagree with this interpretation. According to the molecular data reported, the proband actually is a carrier of a large mitotically unstable premutation. She has no excess of cells with theFMR1alleles of both X-chromosomes being methylated (i.e., transcriptionally silenced). So it is extremely doubtful that she has fragile X syndrome. (1) On the EcoRI/BssHII Southern blot, the results of the proband were grossly misinterpreted. The BssHII site is located in theFMR1 promoter and includes a CpG dinucleotide that is always methylated on the inactive X. In normal females and in female premutation carriers, 50% of all FMR1 alleles (both alleles taken together) are methylated, while the other 50% are unmethylated. This is so because of the fundamental biological fact that each somatic cell carries one active and one inactive X chromosome. In fragile X full mutation females, in addition to the normal methylation associated with X inactivation, the full mutation alleles typically become aberrantly methylated regardless if carried on the inactive or active X chromosome. In the proband, who came to attention because of her severe phenotype, the percentage of cells carrying the normal allele on the active X chromosome was reported to be 32% (0.32) meaning that 68% (0.68) of her cells carry the normal allele on the inactive X (BssHII sites methylated), and that 68% of the cells carry the mutated allele on the active X (i.e., have the BssHII sites unmethylated), while 32% of the mutated alleles are on the inactive X (methylated BssHII sites). So the percentage of methylation of the mutated allele should be at least 32%, and should be even higher if the mutated allele became aberrantly methylated on the active X (as is typically the case for the fully expanded disease alleles). However, contradicting the biology of the female embryo, methylation (i.e., inactivation) of the mutated allele was reported to be only 23% (!). Even an error of measurement as high as 28% (9/32) would still not suggest an excess of methylation as would be typical for full mutation females. Southern analysis gave no evidence that the proband has fragile X syndrome. (2) The proband’s mutation pattern seen on the EcoRI/ BssHII blot is typical for a female carrying a premutation allele with a CGG number at the upper limit of the premutation size range (200–220). Such a large CGG repeat has been shown to be mitotically unstable if unmethylated [Wöhrle et al., 1998, 2001], but to be mitotically stable in a methylated state [Wöhrle et al., 1993, 2001; Steinbach et al., 1998]. The reported size range of 160–260 (average at 210) for the unmethylated expanded allele clearly resulted from its unstable behavior. A size of 340 CGGs was reported for alleles with methylated (i.e., mitotically stable) expansions. The EcoRI/HindIII digested lambda DNA is no appropriate size marker on this blot due to lack of fragments between 5.1 and 21.2 kb. So the measurement of 340 CGGs (i.e., 5.82 kb) most probably is an overestimation resulting from mathematically illegitimate extrapolation. We are quite sure that this band represents a premutated allele being methylated simply because it is carried on the inactive X. (3) Unmethylated premutation alleles in transmitting males as well as expansions in the premutation and in the full mutation size range have been reported in intellectually normal males, and, despite elevation of the mRNA level, were found associated with significant reduction of FMRP [Tassone et al., 1999; Salat et al., 2000; Tassone et al., 2000]. With present knowledge, the idea that reduced FMRP and/or a toxic gain of function effect from elevatedFMR1mRNA levels might *Correspondence to: Peter Steinbach, Department of Human Genetics, University of Ulm, Parkstrasse 11, 89073 Ulm, Germany. E-mail: peter.steinbach@medizin.uni-ulm.de

Bei ihren Bewerbungen beachten Chemiker den Chemiehandel kaum. Das gilt sowohl für Berufsanfänger als auch für berufserfahrene Chemiker und Chemikerinnen. Dabei sucht die Branche qualifizierte Hochschulabsolventen und bietet interessante Arbeitsfelder und Karrierechancen.

The X chromosomal mental retardation genes have attained high interest in the past. A rough classification distinguishes syndromal mental retardation (MRXS) and nonsyndromal mental retardation (MRX) conditions. The latter are suggested to be responsible for human specific development of cognitive abilities. These genes have been shown to be engaged in chromatin remodelling or in intracellular signalling. During this analysis, we have compared the expression pattern in the mouse of four genes from the latter class of MRX genes: Ophn1, Arhgef6 (also called αPix), Pak3, and Gdi1. Ophn1, Pak3, and Gdi1 show a specific neuronal expression pattern with a certain overlap that allows to assign these signalling molecules to the same functional context. We noticed the highest expression of these genes in the dentate gyrus and cornu ammonis of the hippocampus, in structures engaged in learning and memory. A completely different expression pattern was observed for Arhgef6. In the CNS, it is expressed in ventricular zones, where neuronal progenitor cells are located. But Arhgef6 expression is also found in other non-neural tissues. Our analysis provides evidence that these signalling molecules are involved in different spatio-temporal expression domains of common signalling cascades and that for most tissues considerable functional redundancy of Rho-mediated signalling pathways exists.

Fragile X syndrome is a triplet repeat disorder caused by expansions of a CGG repeat in the fragile X mental retardation gene (FMR1) to more than 220 triplets (full mutation) that usually coincide with hypermethylation and transcriptional silencing. The disease phenotype results from deficiency or loss of FMR1 protein (FMRP) and occurs in both sexes. The underlying full mutations arise exclusively on transmission from a mother who carries a premutation allele (60-200 CGGs). While the absolute requirement of female transmission could result from different mechanisms, current evidence favours selection or contraction processes acting at gametogenesis of pre- and full mutation males. To address these questions experimentally, we used a model system of cultured fibroblasts from a male who presented heterogeneous unmethylated expansions in the pre- and full mutation size range. On continual cell proliferation to 30 doublings we re-examined the behaviour of the expanded repeats on Southern blots and also determined the expression of theFMR1 gene by FMRP immunocytochemistry, western analysis, and RT-PCR. With increasing population doublings, expansion patterns changed and showed accumulation of shorter alleles. The FMRP levels were below normal but increased continuously while the cells that were immunoreactive for FMRP accumulated. The level ofFMR1 mRNA was raised with even higher levels of mRNA measured at higher passages. Current results support the theory of a selection advantage of FMRP positive over FMRP deficient cells. During extensive proliferation of spermatogonia in fragile X males, this selection mechanism would eventually replace all full mutations by shorter alleles allowing more efficient FMRP translation. At the proliferation of oogonia of carrier females, the same mechanism would, in theory, favour transmission of any expandedFMR1 allele on inactive X chromosomes.

American Journal of Medical GeneticsVolume 84, Issue 3 p. 226-228 Letter to the Editor Mitotic behavior of expanded CGG repeats studied on cultured cells: Further evidence for methylation-mediated triplet repeat stability in fragile X syndrome Dieter Gläser, Dieter Gläser Department of Medical Genetics, University of Ulm, Ulm, GermanySearch for more papers by this authorDoris Wöhrle, Doris Wöhrle Department of Medical Genetics, University of Ulm, Ulm, GermanySearch for more papers by this authorUlrike Salat, Ulrike Salat Department of Medical Genetics, University of Ulm, Ulm, GermanySearch for more papers by this authorWalther Vogel, Walther Vogel Department of Medical Genetics, University of Ulm, Ulm, GermanySearch for more papers by this authorPeter Steinbach, Corresponding Author Peter Steinbach peter.steinbach@medizin.uni-ulm.de Department of Medical Genetics, University of Ulm, Ulm, GermanyAbteilung Medizinische Genetik, Universitätsklinikum, Parkstr. 11, 89073 Ulm, GermanySearch for more papers by this authorJürgen Mücke, Jürgen Mücke Department of Human Genetics, University of Homburg, Homburg (Saar), GermanySearch for more papers by this author Dieter Gläser, Dieter Gläser Department of Medical Genetics, University of Ulm, Ulm, GermanySearch for more papers by this authorDoris Wöhrle, Doris Wöhrle Department of Medical Genetics, University of Ulm, Ulm, GermanySearch for more papers by this authorUlrike Salat, Ulrike Salat Department of Medical Genetics, University of Ulm, Ulm, GermanySearch for more papers by this authorWalther Vogel, Walther Vogel Department of Medical Genetics, University of Ulm, Ulm, GermanySearch for more papers by this authorPeter Steinbach, Corresponding Author Peter Steinbach peter.steinbach@medizin.uni-ulm.de Department of Medical Genetics, University of Ulm, Ulm, GermanyAbteilung Medizinische Genetik, Universitätsklinikum, Parkstr. 11, 89073 Ulm, GermanySearch for more papers by this authorJürgen Mücke, Jürgen Mücke Department of Human Genetics, University of Homburg, Homburg (Saar), GermanySearch for more papers by this author First published: 29 April 1999 https://doi.org/10.1002/(SICI)1096-8628(19990528)84:3<226::AID-AJMG12>3.0.CO;2-4Citations: 17AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume84, Issue3Special Issue: X-Linked Mental Retardation, Part II28 May 1999Pages 226-228 RelatedInformation