[Promotion of physical activity for older patients with rheumatism : Characteristics of inflammatory rheumatic diseases against the background of physical activity recommendations]. / Bewegungsförderung für ältere Rheumapatienten : Besonderheiten bei entzündlich rheumatischen Erkrankungen vor dem Hintergrund aktueller Bewegungsempfehlungen.

Due to the wide range of positive effects and the clear evidence of effectiveness, physical activity is one of the most important treatments for inflammatory rheumatic diseases. Because of the frequent overlap of disease and age-related aspects in older patients, the implementation of the German national physical activity recommendations has to be checked and accompanied by physicians. To get the older patients in motion, a patient-centered approach is required that takes the individual health problem(s) and the current context of life into account. This article provides an overview of the activity-related characteristics of older patients with inflammatory rheumatic diseases. Against this background a simple strategy is provided for promoting physical activity during medical consultation, which takes the characteristics of older patients with rheumatism into consideration. In this way, physicians can integrate a targeted, resource and time-saving economic strategy into consultations that is in concordance with the national physical activity recommendations.

Weighting schemes in pooled linkage analysis.

To identify susceptibility gene regions for complex diseases a combined linkage analysis of several genome scans might give additional insights to individual studies. In this article we consider different weighting schemes to combine the score statistics of individual studies to an overall statistic within multipoint nonparametric linkage analysis by GENEHUNTER/ALLEGRO. With the Genetic Analysis Workshop (GAW) 12 asthma data sets the weights are dominated by the large differences in the relevant sample sizes.

Genotype-phenotype analysis in Apert syndrome suggests opposite effects of the two recurrent mutations on syndactyly and outcome of craniofacial surgery.

Apert syndrome is an autosomal dominant condition characterized by craniosynostosis and severe syndactyly, caused by two recurrent mutations in the fibroblast growth factor receptor 2 gene (FGFR2). The genotype-phenotype correlations of 21 patients with Apert syndrome were analysed as to the craniofacial appearance following surgery and the degree of syndactlyly. The craniofacial appearance following craniofacial surgery was better in patients with the P253R mutation, whereas these patients showed a more pronounced severity of the syndactyly.

Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3).

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.

Nonsyndromic X-linked mental retardation: mapping of MRX58 to the pericentromeric region.

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.

Phenotypic expression of the fibroblast growth factor receptor 3 (FGFR3) mutation P250R in a large craniosynostosis family.

The craniosynostosis syndromes are a heterogeneous group of sporadic, autosomal dominant disorders with significant clinical overlap. Recently, we described a large family with autosomal dominant craniosynostosis suggestive of Saethre-Chotzen syndrome, in which linkage to the Saethre-Chotzen syndrome loci on 7p had been excluded. We now report the presence of a mutation in the fibroblast growth factor receptor 3 (FGFR3) in this family. The mutation, P250R, had been previously reported in 10 patients with non-syndromic craniosynostosis. Variable expression of this mutation is evident especially in two additional members of this family, one of whom is severely affected with pancraniosynostosis. The family provides a further example of genetic heterogeneity and variable expression of the craniosynostosis syndromes and broadens the phenotypic spectrum associated with the FGFR3 mutation P250R. In addition, we found a polymorphism (F384L) in the transmembrane domain of FGFR3 which occurs with a frequency of 3% in the Turkish population but is uncommon among Germans.

Detection of 100% of the CFTR mutations in 63 CF families from Tyrol.

We identified 100% of the CFTR gene mutations, including three novel mutations, in 126 unrelated cystic fibrosis chromosomes from Tyrol, Austria. The frequency of the major mutation deltaF508 (74.6%) was not significantly different in Tyrolian CF-patients than in patients from Bavaria (71.0%) and Middle- and Northern Germany (71.9%), but was significantly higher than in patients from Styria (58.1%) or Northern Italy (47.6%). Interestingly, the distribution of the next most frequent mutations, R1162X (8.7%) 2183AA-->G, 2789+5G-->A and G542X (2.4% each), was more similar to the distribution of these mutations among CF-patients from Northern Italy than to those from Styria, Bavaria or Middle- and Northern Germany. Nine further mutations occurred once or twice. One of these, the missense mutation M1101K, is rare worldwide but very frequent in the Hutterite brethren, a small founder population which came from Southern Austria to Northern America. Three other different mutations (deltaL453, 1874insT and 4108delT) were present in single Tyrolian families and have not been described before. The identification of 100% of CFTR gene mutations in a particular CF population demonstrates the power of genetic analysis for the diagnosis and counselling of CF families in this restricted geographical area of Austria. Our study provides evidence for a closer genetic relation between CF patients from Tyrol and those from Bavaria or Middle- and Northern Germany as well as Northern Italy, than between CF patients from the two Austrian states Tyrol and Styria.

Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product.

The Wiskott-Aldrich syndrome protein (WASP) gene was found to be mutated in patients presenting with WAS and in patients showing X-linked thrombocytopenia. Mutation analysis in 19 families of German, Swiss and Turkish descent by single-strand conformation polymorphism and sequencing resulted in the detection of seven novel and 10 known mutations. A striking clustering of missense mutations in the first four exons contrasted with a random distribution of nonsense mutations. More than 85% of all known missense mutations were localized in the amino-terminal stretch of the WASP gene product; this region contained a mutational hot spot at codon 86. No genotype-phenotype correlation emerged after a comparison of the identified mutations with the resulting clinical picture for a classical WAS phenotype. A substitution at codon 86 resulted in an extremely variable expression of the disease in a large Swiss family. An extended homology search revealed a distant relationship of this stretch to the vasodilator-stimulated phosphoprotein (VASP), which is involved in the maintenance of cyto-architecture by interacting with actin-like filaments.

Regional localization of two MRX genes to Xq28 (MRX28) and to Xp11.4-Xp22.12 (MRX33).

Two genes responsible for a nonspecific form of X-linked mental retardation (MRX28 and MRX33) were localized by linkage analysis with 40 highly polymorphic DNA markers situated along the entire the X chromosome. In family 1, the gene could be mapped within a 14-cM interval at Xq28, distal to the recombining marker DXS1113 (MRX28). The maximum LOD score was 2.75, with DXS52 at phi = .0. In family 2, the gene was localized within a 30-cM interval at Xp11.4-22.12 between the recombining markers DXS365 and MAOB, including the DMD gene (MRX33). Maximum LOD scores of 2.82 were obtained with markers DMD-STR49, DMD-DysII, CYBB, and DXS1068.

Geographic distribution and origin of CFTR mutations in Germany.

The geographic distribution and origin of CFTR mutations in Germany was evaluated in 658 three-generation families with cystic fibrosis (CF). Fifty different mutations were detected on 1305 parental CF chromosomes from 22 European countries and overseas. The major mutation. delta F508 was identified on 71.5% of all CF chromosomes, followed by R553X (1.8%), N1303K (1.3%), G542X (1.1%), G551D (0.8%) and R347P (0.8%). According to the grandparents' birthplace, 74% of CF chromosomes had their origin in Germany; the delta F508 percentage was 77%, 75%, 70% and 62% in northern, southern, western and eastern Germany, respectively. Ten or more mutant alleles in the investigated CF gene pool originated from Austria, the Czech Republic, Poland, Russia, Turkey and the Ukraine. This widespread geographic origin of CFTR mutations in today's Germany reflects the many demographic changes and migrations in Central Europe during the 20th century.

Craniosynostosis suggestive of Saethre-Chotzen syndrome: clinical description of a large kindred and exclusion of candidate regions on 7p.

We describe the clinical manifestations of an autosomal dominant form of craniosynostosis in a large family with eight affected relatives. Unilateral or bilateral coronal synostosis, low frontal hair line, strabismus, ptosis, and partial cutaneous syndactyly of fingers and toes are findings suggestive of the diagnosis of Saethre-Chotzen syndrome. The disease locus was excluded from the two adjacent Saethre-Chotzen candidate regions on 7p by linkage analysis with markers D7S664 and D7S507. This indicates heterogeneity of Saethre-Chotzen syndrome with a locus outside the candidate regions on 7p.

An evaluation of FASTMAP with emphasis on fine-mapping.

We present an evaluation of the FASTMAP method with special reference to the issue of fine-mapping, using both 'real-life' and constructed data, and demonstrate some of the shortcomings of the method. Since the advantages of FASTMAP in terms of savings in computer resources compared to LINK-MAP are enormous, further improvements of the FASTMAP method would be highly desirable.

Exclusion of malignant hyperthermia susceptibility (MHS) from a putative MHS2 locus on chromosome 17q and of the alpha 1, beta 1, and gamma subunits of the dihydropyridine receptor calcium channel as candidates for the molecular defect.

Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disease with autosomal dominant inheritance triggered by exposure to commonly used inhalational anaesthetics or depolarising muscle relaxants. A MHS locus has been identified on human chromosome 19q12-q13.2 and the gene for the skeletal muscle calcium release channel of sarcoplasmic reticulum (ryanodine receptor) (RYR1) is considered a candidate for the molecular defect. However, MH has been shown to be genetically heterogeneous, and in the ensuing search for other MHS genes, a locus on chromosome 17q has been proposed, and the gene for the adult muscle sodium channel (SCN4A) was suggested as a candidate. We performed linkage studies using polymorphic microsatellite markers for subunits of the skeletal muscle dihydropyridine (DHP) receptor, CACNL1A3 mapped to chromosome 1q, as well as C-ACNLB1 and CACNLG, the latter two localised on chromosome 17q11.2-q24 in proximity to the proposed MHS2 and the SCN4A loci, and we also included markers for the loci D17S250, D17S579, NM23 (NME1), GH1, and SCN4A from that region. Our results exclude the alpha 1, beta 1 and gamma subunit of the DHP receptor as well as the SCN4A locus from that region. Our results exclude the alpha 1, beta 1, and gamma subunit of the DHP receptor as well as the SCN4A locus as candidates for the molecular defect in MHS for these pedigrees where also the RYR1 on chromosome 19q13.1 has been excluded. A multipoint analysis excludes the disease from the entire 84 cM interval containing the proposed MHS locus on chromosome 17q.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for genetic heterogeneity of malignant hyperthermia susceptibility.

A locus for malignant hyperthermia susceptibility (MHS) has been localized on chromosome 19q12-13.2, while at the same time the gene encoding the skeletal muscle ryanodine receptor (RYR1) also has been mapped to this region and has been found to be tightly linked to MHS. RYR1 was consequently postulated as the candidate for the molecular defect causing MHS, and a point mutation in the gene has now been identified and is thought to be the cause of MH in at least some MHS patients. Here we report the results of a linkage study done with 19q12-13.2 markers, including the RYR1 cDNA, in two Bavarian families with MHS. In one of the families, three unambiguous recombination events between MHS and the RYR1 locus were found. In the second family only one informative meiosis was seen with RYR1. However, segregation analysis with markers for D19S75, D19S28, D19S47, CYP2A, BCL3, and APOC2 shows that the crossovers in the first family involve the entire haplotype defined by these markers flanking RYR1 and, furthermore, reveals multiple crossovers between these haplotypes and MHS in the second family. In these families, pairwise and multipoint lod scores below -2 exclude MHS from an interval spanning more than 26 cM and comprising the RYR1 and the previously described MHS locus. Our findings thus strongly suggest genetic heterogeneity of the MHS trait and prompt the search for another MHS locus.

Definitive localization of X-linked Kallman syndrome (hypogonadotropic hypogonadism and anosmia) to Xp22.3: close linkage to the hypervariable repeat sequence CRI-S232.

Kallmann syndrome is a genetically heterogeneous disease characterized by hypogonadotropic hypogonadism and anosmia. Six families in which the disorder followed an X-linked inheritance were investigated by linkage analysis. Diagnostic criteria were uniformly applied and included tests for hypogonadotropic hypogonadism and anosmia. Close linkage was found by using the hypervariable repeated sequence CRI-S232 (DXS278) previously mapped to Xp22.3. At a maximum lod score of 6.5, the recombination fraction was calculated as .03. Of 30 fully informative meioses, one recombination between the disease locus and the loci recognized by probe CRI-S232 was observed. When an independent approach is used, these results confirm the X-linked Kallmann syndrome assignment previously made by deletion mapping, and allow definitive localization of the syndrome assignment previously made by deletion mapping, and allow definitive localization of the syndrome to the Xp22.3 region. This opens the way to carrier detection and to the identification of a gene responsible for this disorder.