Biomedical subjects

Manfred Stuhrmann

Publications and source records attributed to Manfred Stuhrmann.

At least 19 recordsLinked to original sources

PubMed2007

Hereditary hemorrhagic telangiectasia. Genetics, pathogenesis, clinical manifestation and management.

Hereditary hemorrhagic telangiectasia HHT, Morbus Osler or Osler-Weber-Rendu syndrome OMIM 187300, is an autosomal dominant disorder characterized by epistaxis, telangiectasia, multi-systemic vascular dysplasia and clinical presentation of wide variation. The pathogenesis involves dilated post-capillary venules or telangiectases in the mucus membrane of various organs as well as larger arteriovenous malformations. Genetic heterogeneity of HHT is confirmed; 2 disease loci, ACVRL1 and ENG genes, have been identified and characterized. The 2 major types of the disease, HHT1 and HHT2, are attributed to mutations in the ENG and ACVRL1 genes. ENG and ACVRL1 genes code for proteins, namely endoglin and activin-receptor-like kinase 1 ALK-1, which are members of the TGF-beta receptor family, are essential for maintaining vascular integrity. Another gene has been implicated in HHT; the HHT3 locus linked to chromosome 5. In the last 2 decades, the genetics, pathogenesis, clinical manifestations and management of HHT have been extensively researched. At this stage, it is deemed appropriate to review the wealth of information accumulated on the topic. Better understanding of the functions of endoglin, ALK-1, and other proteins involved in the pathogenesis of HHT should facilitate better management of patients with this disorder.

Humans↗

PubMed2006

Genetic analysis of candidate genes modifying the age-at-onset in Huntington's disease.

The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington's disease (HD) and determines 42-73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.

Acyltransferases↗

PubMed2006

Origin of the prevalent SFTPB indel g.1549C > GAA (121ins2) mutation causing surfactant protein B (SP-B) deficiency.

The SFTPB gene indel g.1549C > GAA (121ins2) accounts for about 2/3 of the mutant alleles underlying complete surfactant protein B deficiency. It is unclear, however, whether its prevalence is due to recurrent mutation or a founder effect. The underlying mutational mechanism was therefore sought through the analysis of local DNA sequence complexity. A relatively complex two-step process was proposed: the first step involving slipped mispairing mediated by a direct repeat and generating an AGAA micro-insertion, the second step involving hairpin loop resolution resulting in a CA micro-deletion. The possibility of a founder effect was then assessed by typing 8 intragenic SNPs in 17 independent 121ins2 chromosomes from 10 probands, with parental non-121ins2 chromosomes serving as controls. The 121ins2 chromosomes were assigned to three discrete haplotypes, whilst control chromosomes were distributed between 10 of the 11 observed parental haplotypes. The 121ins2 mutation was in strong and significant linkage disequilibrium (LD) with the tightly linked marker g.1580T/C (|D'| = 1; P approximately 0.024), although only moderate LD was found with the rest of the locus (|D'| approximately 0.54; P approximately 0.136). Data on haplotype structure and the locus LD pattern, obtained from 81 independent Western-European chromosomes, were consistent with the three mutation-bearing haplotypes having originated from a common ancestor by recombination. Interestingly, all families harboring the 121ins2 indel had ancestors from a region of Northwestern Europe populated by Frankish/Saxon migration. Taken together, these data are consistent with the view that an indel mutation occurred on a relatively common SFTPB haplotype and now accounts for the majority of (and possibly all) extant 121ins2 chromosomes.

Base Sequence↗

PubMed2005

The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease.

An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.

Age of Onset↗

PubMed2005

Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: support of homozygous lethality.

In a large Saudi Arabian family with hereditary hemorrhagic telangiectasia (HHT), we identified ACVRL1 (ALK1) nonsense mutation Q490X in 40 HHT patients and three healthy children, but neither in 11 individuals with epistaxis, 41 other healthy family members, nor in 50 healthy unrelated Saudi Arabian controls. Sequence analysis of the entire coding region of the ACVRL1 and ENG genes in five of the 11 epistaxic individuals did not reveal any other disease-causing mutation. Epistaxis seems to be a relatively common phenocopy of HHT in the family under study. One couple, both affected by HHT and carriers of Q490X, had 12 pregnancies. Three of them ended in spontaneous abortion, four in early neonatal death, and only five yielded living offspring, all of which had HHT and were Q490X heterozygous. This observation corroborates previous claims that homozygosity for HHT-causing mutations is lethal.

Activin Receptors, Type II↗

PubMed2005

Increased seroprevalence of human herpes virus-8 in renal transplant recipients in Saudi Arabia.

BACKGROUND: Human herpes virus-8 (HHV-8) is a herpes virus that is always associated with Kaposi's sarcoma. Previous studies suggested a high rate of Kaposi's sarcoma in renal transplant patients in Saudi Arabia. The aim of this study was to investigate the prevalence of HHV-8 in Saudi renal transplant recipients and healthy controls. METHODS: An immunofluorescence technique was used to detect antibodies to the latent nuclear antigen (LANA) of HHV-8 in renal transplant patients, members of a family affected with Kaposi sarcoma, as well as healthy controls. RESULTS: A significantly higher HHV-8 seroprevalence was detected in renal transplant recipients from Saudi Arabia (27 out of 150; 18%) and in members of a family affected with Kaposi sarcoma (seven out of 10; 70%) relative to the seroprevalence in healthy controls (10 out of 577; 1.7%). Seropositivity for HHV-8 in these transplant patients was not significantly influenced by: the existence of relatives with kidney failure, the donors' country of origin, the recipients' home region within Saudi Arabia, the haemodialysis centre, the time that elapsed since the renal transplantation operation and the immunosuppressive regimen used. CONCLUSION: The present results provide some explanation for the previously noted high incidence of Kaposi's sarcoma in Saudi transplant patients.

Adolescent↗

PubMed2005

Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations.

Hereditary hemorrhagic telangiectasia (HHT), or Osler-Rendu-Weber syndrome, is a heterogeneous inherited disorder characterized by multi-systemic vascular dysplasia and wide variation in its phenotypic expression. Hepatic manifestation is seen in about 8 to 30 % of the patients. The molecular basis for liver involvement is unknown. We screened the two known HHT disease loci, the ALK1 (ACVRL1) and ENG genes, for mutations in a clinically well-characterized group of HHT patients with or without liver involvement. Mutations in the ALK1 gene were detected in eight out of 10 HHT patients with hepatic manifestation. Among nine HHT patients without liver involvement, four had mutations in the ALK1, and three in the ENG genes, respectively. In one patient with hepatic manifestation a mutation was detected in both the ALK1 and ENG genes. No mutation could be detected in two patients with liver involvement and, likewise, in two patients without hepatic manifestation. In this study, we have identified five novel ALK1 and one ENG disease-causing mutations. We conclude that hepatic manifestation in HHT patients is associated with mutations in the ALK1 gene, but rarely with ENG mutations.

Activin Receptors, Type II↗

PubMed2005

Genotype-based screening for hereditary haemochromatosis. I: Technical performance, costs and clinical relevance of a German pilot study.

In 2001, we initiated a pilot study on DNA-based screening of hereditary haemochromatosis (HH) in Germany. A total of 5882 insurants of the German sickness fund Kaufmannische Krankenkasse-KKH requested information on this project, and 3961 of these individuals provided blood samples for testing of the HFE mutation C282Y. Of these, 3930 samples were successfully tested with two independent test methods, and the results were communicated to the referring doctors. In all, 67 of the tested individuals were homozygous for C282Y. Partially, this high rate (1.7%) can be explained by the fact that 42.6% of the homozygotes already knew their clinical diagnosis HH before sending the blood sample. Iron accumulation with further signs or symptoms of HH was present in eight of 34 newly diagnosed C282Y homozygous individuals. Two major aspects of our study were the analytic validity and the direct laboratory costs of different test methods. Of 7860 tests performed, 7841 (99.6%) gave correct results. The overall error rate was 0.24% (95% CI: 0.15-0.38%). The analytic specificity of the tests methods with respect to the detection of homozygosity for C282Y was 100% (7726 of 7726 nonhomozygous test challenges, 95% CI: 99.95-100%), while the analytic sensitivity was 97% (130 of 134 homozygous test challenges, 95% CI: 92.5-99.2%). The direct costs ranged from 11.20-16.35 \[euro] per test method. We conclude that the test methods for C282Y are robust, highly sensitive and specific, and that a DNA-based HH-screening program can be performed at reasonable laboratory costs.

Adult↗

PubMed2005

Genotype-based screening for hereditary hemochromatosis: II. Attitudes toward genetic testing and psychosocial impact--a report from a German pilot study.

In collaboration with the German Sickness Fund (Kaufmännische Krankenkasse-KKH), we conducted a pilot study on DNA-based population screening of hereditary hemochromatosis (HH) in Germany. The health insurance organization KKH briefly informed their members about the possibility to participate voluntarily in this pilot project. A total of 5882 KKH members contacted us and received detailed information on the aim of the project and clinical and genetic aspects of HH. Of these individuals, 3961 requested HFE genotyping. After genotype results had been communicated to the participants' general practitioner, we sent a self-administered questionnaire to all homozygous (n = 67) and heterozygous (n = 485) as well as 448 wild-type study participants (sigma = 1000) to assess the psychosocial impact of HFE genotyping. In addition, questionnaires were sent to 8000 randomly selected members of the KKH to investigate their attitude toward genetic testing. Six hundred thirty-one (63.1%) of the test participants and 2141 (26.8%) of the randomly chosen KKH members responded. A total of 59.1% of the members would generally accept predictive genetic testing and 3.7% objected to such tests in principle. Individuals with higher educational status accepted predictive testing significantly more often than individuals with less education. Of the tested individuals, 69.9% thought that participation in the pilot study was probably beneficial for them and 1% (5 heterozygotes and 1 wild-type) thought that it was probably harmful. Of the participants, 94.6% judged their decision to have participated in the pilot study as right and 0.3% (2 heterozygotes) as probably wrong. Only very few of the tested individuals underwent pretest (1 case) or posttest (11 cases) genetic counseling. We conclude that genotype- based screening for HH is generally accepted and was perceived as beneficial. Negative psychosocial consequences are rare and could presumably have been prevented by delivering appropriate pretest and posttest information.

Attitude↗

PubMed2005

Genetic predisposition for a compromised immune system after multiple trauma.

Severe trauma induces sustained changes of the immune response, which are thought to be related to secondary organ dysfunction. Despite a similar injury severity, the extent of the inflammatory response may vary between polytraumatized patients. It is unclear whether inflammatory variability is associated with genetic variations. In this prospective cohort study, patients were included when the following criteria were fulfilled: Injury Severity Score >16, age 18 to 60 years, and a survival >48 h after injury. Four different polymorphisms (TNF-Nco1, IL-1-Taq1, IL-6-174G/C, and IL-8-251A/T) were determined. Patients were separated according to the severity of the systemic inflammatory response syndrome (SIRS; ACCP/SCCM criteria: >2 criteria at 2 consecutive days or at 3 days of the observation period: group +SIRS; <or=2 criteria: group -SIRS). Ninety-seven severely injured patients were included (-SIRS, 56 patients; +SIRS, 41 patients). A significantly higher incidence of the IL-6-174G allele and the IL-6-174G homozygous genotype in +SIRS patients was observed. The IL-6-174G/C polymorphism was associated with the severity of posttraumatic SIRS. This data points toward a genetic predisposition regarding an enhanced inflammatory response after polytrauma that may be associated with adverse outcome.

Adolescent↗

PubMed2004

Tourette syndrome is not caused by mutations in the central cannabinoid receptor (CNR1) gene.

Tourette syndrome (TS) is a complex inherited disorder of unknown aetiology, characterized by multiple motor and vocal tics. Involvement of the central cannabinoid (CB1) system is suggested because of therapeutic effects of marijuana (Cannabis sativa L.) consumption and Delta(9)-tetrahydrocannabinol (-THC) treatment in TS patients. The central cannabinoid receptor (CNR1) gene encoding the CNR1 was considered as a candidate gene for TS and systematically screened by single-strand conformation polymorphism (SSCP) analysis and sequencing. Compared with the published CNR1 sequence, three single base substitutions were identified: 1326T --> A, 1359G --> A, 1419 + 1G --> C. The change at position 1359 is a common polymorphism (1359 G/A) without allelic association with TS. 1326T --> A was present in only one TS patient and is a silent mutation which does not change codon 442 (valine). 1419 + 1G --> C affects the first nucleotide immediately following the coding sequence. It was first detected in three of 40 TS patients and none of 81 healthy controls. This statistically significant association with TS (P = 0.034) could not be confirmed in two subsequent cohorts of 56 TS patients (one heterozygous for 1419 + 1G --> C) and 55 controls and 64 patients and 66 controls (one heterozygous for 1419 + 1G --> C), respectively. Transcript analysis of lymphocyte RNA from 5 1419 + 1G --> C carriers revealed no systematic influence on the expression level of the mutated allele. In addition, segregation analysis of 1419 + 1G --> C in affected families gave evidence that 1419 + 1G --> C does not play a causal role in the aetiology of TS. We conclude that genetic variations of the CNR1 gene are not a plausible explanation for the clinically observed relation between the cannabinoid system and TS.

Base Sequence↗

PubMed2004

[123I]AM281 single-photon emission computed tomography imaging of central cannabinoid CB1 receptors before and after Delta9-tetrahydrocannabinol therapy and whole-body scanning for assessment of radiation dose in tourette patients.

BACKGROUND: The cannabinoid CB1 receptor agonist Delta9-THC has been suggested for treatment of Tourette syndrome (TS). Based on animal studies, the CB1 antagonist [123I]AM281 (N-(Morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-[123I]iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide) has been proposed for single photon emission computed tomography (SPECT) in humans. Our aims were to 1) evaluate specific binding of [123I]AM281 to CB1 receptors in TS patients and 2) assess radiation exposure associated with the use of AM281 labeled with 123I for SPECT and 124I for positron emission tomography. METHODS: We employed [123I]AM281 in six TS patients before and after Delta9-THC treatment. Dynamic SPECT, plasma measurements (including metabolite analysis with thin layer chromatography), and whole-body imaging were performed. Regions of interest derived from magnetic resonance images were used to extract from SPECT uptake in an area with high CB1 density (lentiform nuclei) and reference regions. Specific over nonspecific partition coefficients V3" were calculated. Whole-body images were carried out for dosimetric analysis. Data obtained with [123I]AM281 were used to predict doses from [124I]AM281. RESULTS: Mean V3" ranged from .19 to .31 and did not change significantly after Delta9-THC treatment. Nevertheless, in the only patient with a marked clinical response, V3" clearly declined. Thin layer chromatography revealed biexponential kinetics of tracer metabolism; about 60% remained nonmetabolized after 3 hours. Effective doses of .011 mSv/MBq for [123I]AM281 and .34 for [124I]AM281 were computed. CONCLUSIONS: This study suggests that specific binding of [123I]AM281 to CB1 receptors can be detected in patients using SPECT. Radiation exposure with [123I]AM281 is low; that with [124I]AM281 is higher but acceptable for single investigations.

Adult↗

PubMed2004

Lack of mutations in the epsilon-sarcoglycan gene in patients with different subtypes of primary dystonias.

Primary dystonias represent a clinically and genetically heterogeneous group of movement disorders. Mutations in the epsilon-sarcoglycan (SGCE) gene have been found recently to cause myoclonus-dystonia (MD). Considerable clinical variation of SGCE mutation carriers leads to the hypothesis that mutations in the SGCE gene might also be relevant for other subtypes of dystonias. To determine the contribution of mutations in the SGCE gene in patients with different subtypes of dystonias, we analyzed the coding sequence of the SGCE gene in a group of 296 patients with a clinical phenotype of primary dystonia and in 2 patients with a clinical phenotype of myoclonus-dystonia. Patients with mutations in the DYT1 gene were excluded. We could not detect a mutation in the SGCE gene in any of the 298 patients. Our results suggest that mutations in the SGCE gene cannot be held responsible for other subtypes of primary dystonia.

Adult↗

PubMed2004

Mutation at the SCA17 locus is not a common cause of primary dystonia.

Spinocerebellar ataxia type 17 (SCA17) is a dominant progressive neurodegenerative disorder, caused by a triplet repeat expansion within the TATA-binding protein. As well as ataxia and dementia, Parkinsonism and dystonia are common in SCA17. In some pedigrees focal dystonia in the absence of ataxia has been described as a main clinical feature. To evaluate the relevance of SCA17 mutations for primary dystonia, we examined the TBP repeat expansion in a series of 288 patients with different subtypes of primary torsion dystonia. We did not find any repeat sizes in the pathogenic range. We conclude that the SCA17 repeat expansion is not a common cause of familial and sporadic dystonia.

Adult↗

PubMed2004

Naxos disease in an Arab family is not caused by the Pk2157del2 mutation. Evidence for exclusion of the plakoglobin gene.

OBJECTIVE: Naxos disease is a rare hereditary disorder characterized by palmoplantar keratoderma, woolly hair and cardiomyopathy. This study aims to determine whether Naxos disease in a Saudi Arab family is caused by the Pk2157del2 mutation that was identified in Greek families from Naxos Island where the disease had originally been described. METHODS: This study was undertaken at King Fahad Hospital of the University, Al-Khobar, and the Medical University of Hannover, in the spring of 2003. Naxos disease has been encountered in a 2-year-old girl and her 30-year-old aunt of a Saudi Arab family. Deoxyribonucleic acid samples of this family were analyzed by polymerase chain-reaction (PCR) amplification of the respective region of the plakoglobin gene, and direct nucleotide sequencing of the PCR-products. Segregation analysis was performed employing the newly detected IVS11+22G/A polymorphism. RESULTS: Molecular genetic analysis of the DNA sample of the child diagnosed with Naxos disease showed absence of the Pk2157del2 mutation. In addition, the segregation analysis revealed heterozygosity for IVS11+22G/A in the affected girl. CONCLUSION: Absence of the Pk2157del2 frameshift in the affected child proved that Naxos disease in this Saudi Arab family is not caused by the same mutation that was identified in the Greek families. Furthermore, heterozygosity for the IVS11+22G/A polymorphism provided evidence for exclusion of the plakoglobin gene in this consanguineous family.

Adult↗

PubMed2003

Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.

An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in approximately 10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P<.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7, P<.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.

Base Sequence↗

PubMed2003

Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.

Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.

Adolescent↗

PubMed2003

Frequency and phenotypic variability of the GAG deletion of the DYT1 gene in an unselected group of patients with dystonia.

BACKGROUND: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures. A 3-base pair (GAG) deletion in the DYT1 gene is held responsible for most cases of early-onset primary generalized dystonia in the Ashkenazi Jewish population as well as in non-Jewish patients. OBJECTIVES: To investigate the prevalence of the GAG deletion in the DYT1 gene and the phenotypic variability in the general population by testing patients with different subtypes of dystonia from 4 different movement disorder outpatient clinics in Germany. METHODS: Two hundred fifty-six patients were tested for the GAG deletion mutation in the DYT1 gene by means of published primers and polymerase chain reaction amplification to determine GAG deletion status. RESULTS: Six of the 256 patients did carry the GAG-deletion in the DYT1 gene. However, only 2 of the 6 mutation carriers presented with what is thought to represent classic features of early-onset primary generalized dystonia. The DYT1 mutation was also detected in 2 patients with multifocal dystonia, 1 of them presenting with involvement of cranial and cervical muscles, and in 2 patients with writer's cramp of both hands with only slight progression. Our findings demonstrate that the mutation may be associated with not only generalized but also segmental and multifocal forms of dystonia. CONCLUSIONS: Our data underline the wide range of phenotypic variability of the DYT1 mutation. A priori prediction of the mutation carrier status in dystonic patients and genetic counseling of affected families with respect to the clinical manifestation may prove difficult.

Base Pairing↗