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Biomedical subjects

Michael Ludwig

Publications and source records attributed to Michael Ludwig.

At least 19 recordsLinked to original sources
PubMed2006

Distribution of persistent organochlorine contaminants in infertile patients from Tanzania and Germany.

PURPOSE: To test whether environmental pollutants could affect fertility in humans. METHODS: 31 women and 16 men from Tanzania and 21 couples from Germany were included (n = 89). Pesticides and polychlorinated biphenyls were measured in serum, follicular fluid or seminal plasma by gaschromatography and related to sperm quality and pregnancy rates. RESULTS: Higher concentrations of DDT+DDE and dieldrin in Tanzania and higher concentrations of PCBs in Germany and in men were detected. All compounds showed higher concentrations in serum and lowest concentrations in seminal plasma. A lower pregnancy rate in German women with high serum concentrations of DDT+DDE was observed. The toxins had no impact on sperm quality. CONCLUSIONS: The distribution of toxins between agricultural and industrial countries is different. Seminal plasma seems to be inert against chemicals. In patients with high serum concentrations of DDT and DDE pregnancy rates were impaired.

DDT↗
PubMed2006

Hypercalciuria in patients with CLCN5 mutations.

Hypercalciuria is regarded as a characteristic symptom of Dent disease, an X-linked recessive tubulopathy characterized by low molecular weight (LMW) proteinuria, nephrocalcinosis/nephrolithiasis, and progressive renal failure due to mutations in the CLCN5 gene. As the presence of hypercalciuria may affect the decision to consider a CLCN5 mutation in the differential diagnosis, the phenotypic spectrum and the relative frequency of hypercalciuria in patients with CLCN5 mutations was determined. We assessed renal calcium excretion in 34 male patients with proven CLCN5 mutations, who had been referred because of LMW proteinuria and at least one additional symptom of Dent disease. Hypercalciuria was defined as renal calcium excretion exceeding 0.1 mmol/kg per day. Data obtained were compared with all series of CLCN5-positive patients identified by a systematic literature survey. In 7 of our 19 families, at least 1 affected male had normal calcium excretion. Hypercalciuria was observed in 22 of 31 patients tested (71%) compared to 85 of 90 (94.4%) in series from Europe and North America and 74.4% from Japan. LMW proteinuria was present in all CLCN5-positive patients; 25% of the patients in European and North American series, 45% of the Japanese, and 41% in the present series had only two of the four principal symptoms of Dent disease. Therefore, a CLCN5 mutation should be considered irrespective of the presence of hypercalciuria in a patient with LMW proteinuria and one additional symptom of Dent disease.

Adolescent↗
PubMed2006

MTHFR 677 TT genotype in a mother and her child with Down syndrome, atrioventricular canal and exstrophy of the bladder: implications of a mutual genetic risk factor?

Apart from Husmann and Vandersteen [in: Gearhart JP, Matthews R (eds) The Epispadias-Exstrophy Complex. Kluwer, New York, pp 199-206, 1999], we report only the second case of Down syndrome (DS) associated with exstrophy of the bladder (EB). Besides the appearance of DS, the newborn exhibited a complete atrioventricular canal (CAVC) and classical EB, including diastases of the symphysis, an epispadic penis and an open bladder plate. Despite current recommendations, the mother had not supplemented her intake of folic acid during the periconceptional period. In a comparable case, Al-Gazali et al. (Am J Med Genet 103:128-132, 2001) found the homozygous 677T allele of the methylenetetrahydrofolate (MTHFR) gene 677C-->T polymorphism in a mother and her child with DS and cervical meningomyelocele. They found that the mother, who also had not supplemented her folic acid intake, had a secondarily altered folate status with an increased homocysteine level, suggesting that the homozygous TT mutation in the MTHFR gene in both mother and her child had contributed to the presentation of DS and a neural tube defect. The combined clinical findings of the present case and the observations of Al-Gazali et al. led us to investigate the 677C-->T polymorphism in our mother-child pair. Likewise we found that mother and child were homozygous for the mutant 677T allele. Our findings support the suggestion of Al-Gazali et al. that the MTHFR 677TT could be a mutual genetic risk factor for the co-occurrence of trisomy 21 and midline defects, the risk of which may be reduced by periconceptional folic acid supplementation.

Bladder Exstrophy↗
PubMed2006

Congenital partial atresia of the Fallopian tube.

Partial tubal atresia is a rare anomaly of unknown pathogenesis. It can occur unilaterally or bilaterally, mainly including the proximal isthmic portion or the proximal ampullary segment ('mid-portion'), and is especially associated with uterine anomalies. Any more extensive pelvic surgery, including preoperative diagnosis of associated urological anomalies, must be well planned in such patients. Salpingostomy and fimbrial approximation is a realistic option in patients with congenital ampullary atresia who wish to have a child. A MEDLINE search was performed and 18 patients found with partial atresia of different tubal portions. This report describes a further patient and reviews the available literature.

Adult↗
PubMed2006

Novel OCRL1 mutations in patients with the phenotype of Dent disease.

BACKGROUND: Dent disease is an X-linked tubulopathy frequently caused by mutations affecting the voltage-gated chloride channel and chloride/proton antiporter ClC-5. A recent study showed that defects in OCRL1, encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ocrl) and usually found mutated in patients with Lowe syndrome, also can provoke a Dent-like phenotype (Dent 2 disease). METHODS: We investigated 20 CLCN5-negative males from 17 families with a phenotype resembling Dent disease for defects in OCRL1. RESULTS: In our complete series of 35 families with a phenotype of Dent disease, a mutation in the OCRL1 gene was detected in 6 kindreds. All were novel frameshift (Q70RfsX88 and T121NfsX122, detected twice) or missense mutations (I257T and R476W). None of our patients had cognitive or behavioral impairment or cataracts, 2 classic hallmarks of Lowe syndrome. All patients had mild increases in lactate dehydrogenase and/or creatine kinase levels, which rarely is observed in CLCN5-positive patients, but frequently found in patients with Lowe syndrome. To explain the phenotypic heterogeneity caused by OCRL1 mutations, we performed extensive data-bank mining and extended reverse-transcriptase polymerase chain reaction analysis, which provided no evidence for yet unknown (tissue-specific) alternative OCRL1 transcripts. CONCLUSION: Mutations in the OCRL1 gene are found in approximately 23% of kindreds with a Dent phenotype. Defective protein sorting/targeting of Ocrl might be the reason for mildly elevated creatine kinase and lactate dehydrogenase serum concentrations in these patients and a clue to suspect Dent disease unrelated to CLCN5 mutations. It remains to be elucidated why the various OCRL1 mutations found in patients with Dent 2 disease do not cause cataracts.

Chloride Channels↗
PubMed2006

Bladder exstrophy-epispadias complex: Investigation of suppressor of variegation, enhancer of zeste and Trithorax (SET) as a candidate gene in a large cohort of patients.

OBJECTIVE: The bladder exstrophy-epispadias complex (BEEC) describes a rare anterior midline defect with variable expression involving the infra-umbilical abdominal wall, including the pelvis, urinary tract and external genitalia. It is assumed that the underlying cause of BEEC is a multifactorial mode of inheritance; however, its aetiology remains unknown. Only a few BEEC patients with distinctive cytogenetic features such as numeric or structural chromosomal abnormalities have been reported. The observation of translocations concerning the region of chromosome 9q32-q34.1 in two patients implies that this region bears a candidate gene which, during early blastogenesis, governs the development of this primary field. In this context, we considered the suppressor of variegation, enhancer of zeste and Trithorax (SET) gene, located at chromosome 9q34, to be a good candidate, as the protein encoded is involved in the regulation of cell proliferation and differentiation. Moreover, SET expression was detected in embryonic kidney. MATERIAL AND METHODS: A total of 33 patients affected with BEEC were analysed for mutations in the SET gene. RESULTS: SET analysis did not reveal either a mutation or the presence of four single-nucleotide polymorphisms (dbSNP124) already described in the database. CONCLUSIONS: The data obtained in this study most likely exclude the SET gene as a possible genetic cause of BEEC. Hence, other genes in this region may contribute to the development of this midline defect.

Bladder Exstrophy↗
PubMed2006

Variant of the CHEK2 gene as a prognostic marker in glioblastoma multiforme.

OBJECTIVE: Germline mutations of the CHEK2 tumor suppressor gene have been found in families with the Li-Fraumeni syndrome (LFS). Patients with LFS experience a variety of cancers, including malignant astrocytomas. We investigated a potential role for a CHEK2 gene polymorphism in glioblastomas. METHODS: A genetic polymorphism of the CHEK2 gene (CHEK2 SNP rs2017309 A/T) was genotyped in a series of glioblastoma patients (n = 213) and population controls (n = 192). Subsets of tumors were analyzed for loss of heterozygosity 22q(n = 66), loss of heterozygosity CHEK2 (n = 53), CHEK2 expression (n = 21), and CHEK2 coding sequence alterations (n = 18). CHEK2 SNP rs2017309 genotyping findings and traditional clinicopathological parameters were correlated with the patients' prognoses. RESULTS: No association between the CHEK2 SNP and glioblastoma formation was observed. No CHEK2 coding sequence aberrations or tumors completely lacking CHEK2 protein were identified. However, the presence of the CHEK2 rs2017309 A allele was significantly associated with an adverse prognosis (P = 0.034), particularly among patients undergoing postoperative chemotherapy and radiotherapy (n = 28, median survival 10.5 versus 15.5 mo, P = 0.008). We could confirm the patients' age, Karnofsky Performance Scale score, and postoperative radiotherapy and chemotherapy (all P < 0.0001, log-rank test) as decisive prognostic factors. CONCLUSION: Our data suggest that a CHEK2 gene polymorphism might correlate with the prognosis of glioblastoma patients. These findings may point to an as yet unrecognized role for the CHEK2 gene in glioblastomas.

Biomarkers↗
PubMed2006

Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system.

OBJECT: Important central nervous system (CNS) manifestations in patients with hereditary hemorrhagic telangiectasia (HHT) include arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Hereditary hemorrhagic telangiectasia is caused by germline mutations of two genes: ENG (HHT Type 1) and ACVRL1 (HHT Type 2). The ENG gene variations have been associated with the formation of intracranial aneurysms. The authors studied whether sequence variations in ACVRL1 or ENG are associated with the development of clinically sporadic arteriovenous dysplasias and aneurysms of the CNS. METHODS: The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5' end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis. One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme-based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers. The authors identified a statistically significant association between the IVS3 -35A/T polymorphism in intron 3 of the ACVRL1 gene and the development of AVMs and DAVFs (p = 0.004; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.19-2.51; after adjustments for age and sex), but not aneurysms (crude OR 0.82; 95% CI 0.55-1.18). CONCLUSIONS: The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs.

Activin Receptors, Type II↗
PubMed2005

R561C missense mutation in the SMARCAL1 gene associated with mild Schimke immuno-osseous dysplasia.

Autosomal-recessive Schimke immuno-osseous dysplasia (SIOD) characterized by spondyloepiphyseal dysplasia, focal-segmental glomerulosclerosis (FSGS), T-cell immunodeficiency and facial dysmorphism is caused by defects in the SMARCAL1 gene. The gene product is involved in the transcriptional regulation of other genes. A 12-year-old boy of consanginous Turkish descent developed disproportionate short stature from spondyloepiphyseal dysplasia at the age of 6 and nephrotic syndrome at the age of 10 years. Renal biopsy revealed FSGS, the kidney function was normal, T-lymphocytes were diminished without infectious complications, and he has had no cerebral ischemia. Analysis of the patient's SMARCAL1 gene revealed a novel homozygous C1798T transition leading to a R561C substitution. The parents and two healthy sisters were found to be heterozygous. A younger brother, who is also homozygous for the mutation, is clinically asymptomatic and has no proteinuria at the age of 18 months. Still, his CD4 cells are diminished. For SMARCAL1 mutations a clear genotype-phenotype correlation has been reported: severe SIOD with in utero or early-childhood onset leading to end-stage renal disease within a few years is caused by nonsense, frame shift or splice mutations. Many patients die from infections and cerebrovascular insults during childhood. Mild SIOD manifests later and progresses more slowly without infectious or cerebral vascular complications--the underlying defect being missense mutations in all three patients reported so far. The novel R561C missense mutation in our patient with mild SIOD is additional evidence for the genotype-phenotype correlation reported for SMARCAL1 mutations.

Amino Acid Motifs↗
PubMed2005

Is there an association between septate uterus and endometriosis?

BACKGROUND: The question of whether Müllerian anomalies are significantly more often combined with endometriosis is a controversially discussed problem. Some publications described this association in patients with obstructive but not non-obstructive Müllerian anomalies or controls without Müllerian anomalies. The aim of this study was to evaluate the incidence of endometriosis in patients with a septate uterus as a non-obstructive form of Müllerian anomalies. METHODS: In a retrospective study, we evaluated 120 patients (29.4 +/- 4.7 years; mean +/- SD) with a septate uterus. The control group consisted of 486 consecutive infertile patients (30.8 +/- 6.3 years) with a normal hysteroscopy and laparoscopy. RESULTS: The incidence of dysmenorrhoea was comparable in both groups, but the incidence of endometriosis was significantly higher in patients with a septate uterus (25.8 versus 15.2%, P = 0.006). CONCLUSION: Our results suggest a higher incidence of endometriosis in patients with a septate uterus. If it can be confirmed by others, the initial finding of a septate uterus in infertile patients should be followed by a combined hysteroscopy and laparoscopy.

Adult↗
PubMed2005

Intraamniotic ethacridine lactate instillation versus vaginal PGE1 in second trimester termination of pregnancy.

OBJECTIVE: To report on our experience with intraamniotic injection of ethacridine lactate (EL) for second trimester termination of pregnancy (TOP) and to compare its effectiveness with vaginal PGE1 in this setting. STUDY DESIGN: (a) Retrospective analysis of 54 intraamniotic EL-induced TOP. (b) Matched pair analysis of 50 second trimester TOP, using intraamniotic EL in group A (n=25) and vaginal PGE1 suppositories in group B (n=25). MAIN OUTCOME MEASURES: success rate, induction-delivery interval, analgesic use, drop in maternal hemoglobin, complications. RESULTS: (a) TOP with EL alone was successful in 50 cases (93%). Mean duration from instillation to delivery was 40.5 h (range 14-58, S.D.: +/-9.0). Mean analgesic need was low. Mean drop in hemoglobin was low (1.0 g/dl, S.D.: +/-1.1). (b) The matched pair analysis revealed a significantly shorter induction-delivery interval in the vaginal PGE1 group (mean 26.9 h, range 8-80, S.D.: +/-16.8 versus 41.0 h, range 24-55, S.D.: +/-7.3, p<.05). There were no significant differences in analgesic use or drop in hemoglobin. In both groups one case of post partum hemorrhage occurred. CONCLUSION: Intraamniotic instillation of ethacridine lactate in second trimester TOP is safe, cheap and successful in the vast majority of cases. Disadvantages are the longer induction-delivery interval compared to modern prostaglandins and the invasive mode of application. However, by the use of EL the side effects of repeated prostaglandin application can be avoided as well as multiple vaginal examinations. Furthermore, the time of delivery can be predicted in a narrower interval.

Abortifacient Agents↗
PubMed2005

Assisted reproduction: the epigenetic perspective.

Developmental pathways in humans and other organisms are buffered against changes in genotype and environment. Therefore, it should not come as a surprise that most of the children conceived by assisted reproduction technology (ART) are healthy, although ART bypasses a lot of biological filters and subjects the gametes and the early embryo to environmental stress. If, however, the buffer breaks down, the development of certain tissues or organs may follow abnormal trajectories. We argue that both normal and abnormal development in children conceived by ART can be explained by epigenetic mechanisms, which control the establishment and maintenance of gene expression patterns in the placenta and fetus. Imprinted genes are of special importance in this respect. There is increasing evidence that genetic factors in infertile couples as well as environmental factors (hormones and culture media) can have adverse effects on epigenetic processes controlling implantation, placentation, organ formation and fetal growth. In addition, loss of epigenetic control may expose hidden genetic variation.

Birth Weight↗
PubMed2005

Functional evaluation of Dent's disease-causing mutations: implications for ClC-5 channel trafficking and internalization.

ClC-5 is a member of the ClC family of voltage-gated chloride channels. Loss-of-function mutations of its corresponding gene (CLCN5) cause Dent's disease, an X-linked kidney disorder, characterized by low-molecular weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis, and progressive renal failure. Here, we examined the effect of different mutations on function and cellular trafficking of the recombinant protein. Mutant CLCN5 cDNAs were generated by site directed mutagenesis for two premature stop codon variants (R347X and M517IfsX528), and several missense mutations (C221R, L324R, G462 V, and R516 W). We also tested L521R (instead of L521RfsX526 observed) and mutants G506E and R648X (previously reported by others). After heterologous expression in Xenopus oocytes, ClC-5 channel activity and surface expression were determined by two-electrode voltage-clamp analysis and ClC-5 surface ELISA, respectively. Except for the R516 W and R648X variants, none of the mutated proteins induced functional chloride currents or reached the plasma membrane. This is readily understandable for the truncation mutations. Yet, the tested missense mutations are distributed over different transmembrane regions, implying that correct channel structure and orientation in the membrane is not only a prerequisite for proper ClC-5 function but also for Golgi exit. Interestingly, the R648X mutant although functionally compromised, displayed a significant increase in surface expression. This finding might be explained by the deletion of a ClC-5 carboxy-terminal PY-like internalization signal, which in turn impairs channel removal from the membrane. Our observations further imply that recruitment of ClC-5 to alternative routes (plasma membrane or early endosomes) in the trans-Golgi network is mediated via different signal sequences.

Animals↗
PubMed2005

A novel epithelial sodium channel beta-subunit mutation associated with hypertensive Liddle syndrome.

Low-renin hypertension responsive to amiloride-thiazide therapy in a 4-year-old Afro-Haitian girl suggested Liddle syndrome. Urine steroid profiling substantiated the diagnosis and DNA analysis of the epithelial sodium channel (ENaC) revealed a novel heterozygous beta ENaC mutation in the patient and in her hypertensive father. Liddle syndrome should be considered as a cause of hypertension in young children particularly with suppressed renin activity.

Amiloride↗