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B Wirth

Publications and source records attributed to B Wirth.

At least 37 records · Page 2Linked to original sources
PubMed1998

Identification of a candidate modifying gene for spinal muscular atrophy by comparative genomics.

Spinal muscular atrophy (SMA) is a common recessive disorder characterized by the loss of lower motor neurons in the spinal cord. The disease has been classified into three types based on age of onset and severity. SMA I-III all map to chromosome 5q13 (refs 2,3), and nearly all patients display deletions or gene conversions of the survival motor neuron (SMN1) gene. Some correlation has been established between SMN protein levels and disease course; nevertheless, the genetic basis for SMA phenotypic variability remains unclear, and it has been postulated that the loss of an additional modifying factor contributes to the severity of type I SMA. Using comparative genomics to screen for such a factor among evolutionarily conserved sequences between mouse and human, we have identified a novel transcript, H4F5, which lies closer to SMN1 than any previously identified gene in the region. A multi-copy microsatellite marker that is deleted in more than 90% of type I SMA chromosomes is embedded in an intron of this gene, indicating that H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.

Amino Acid Sequence↗
PubMed1998

SMN oligomerization defect correlates with spinal muscular atrophy severity.

Spinal muscular atrophy (SMA) is a motor-neuron disorder resulting from anterior-horn-cell death. The autosomal recessive form has a carrier frequency of 1 in 50 and is the most common genetic cause of infant death. SMA is categorized as types I-III, ranging from severe to mild, based upon age of onset and clinical course. Two closely flanking copies of the survival motor neuron (SMN) gene are on chromosome 5q13 (ref. 1). The telomeric SMN (SMN1) copy is homozygously deleted or converted in >95% of SMA patients, while a small number of SMA disease alleles contain missense mutations within the carboxy terminus. We have identified a modular oligomerization domain within exon 6 of SMN1. All previously identified missense mutations map within or immediately adjacent to this domain. Comparison of wild-type to mutant SMN proteins of type I, II and III SMA patients showed a direct correlation between oligomerization and clinical type. Moreover, the most abundant centromeric SMN product, which encodes exons 1-6 but not 7, demonstrated reduced self-association. These findings identify decreased SMN self-association as a biochemical defect in SMA, and imply that disease severity is proportional to the intracellular concentration of oligomerization-competent SMN proteins.

Cyclic AMP Response Element-Binding Protein↗
PubMed1998

Axonal neuropathy and predominance of type II myofibers in infantile spinal muscular atrophy.

Two affected siblings with infantile spinal muscular atrophy (SMA I) presented with generalized muscular hypotonia, which progressed to early death. Quadriceps muscle biopsy did not show the typical neurogenic pattern of spinal muscular atrophy. The histochemical fiber type determination revealed a predominance of type II fibers without type I hypertrophy, an unprecedented finding in spinal muscular atrophy. Sural nerve biopsy exhibited findings typical for axonal neuropathy. In one patient, electrical stimulation of peripheral nerves showed an inexcitability of motor and sensory nerves. Genetic studies revealed homozygous deletions of the telomeric survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene in the affected children. This is the second case report of molecular genetically proven spinal muscular atrophy associated with axonal neuropathy. We conclude atypical findings on muscle biopsy and evidence of axonal neuropathy are compatible with the diagnosis of infantile spinal muscular atrophy.

Adult↗
PubMed1997

Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region.

Three newborn siblings presented with generalized weakness, asphyxia, facial diplegia, and external ophthalmoplegia. Electrophysiological testing showed inexcitability of motor and sensory nerves and myographic signs of denervation. Nerve biopsies and postmortem examination showed loss of myelinated fibers and axonal damage in sensory and mixed nerves. Many spinal motor neurons were chromatolytic although their number was normal. Molecular genetic investigations revealed a homozygous deletion of the survival motor neuron (SMN) gene and a loss of markers Ag1-CA and C212 in the paternal haplotype. These findings are consistent with the diagnosis of an unusually severe type of spinal muscular atrophy. Given the large extent of the deletion, it must be considered that the unusual severe phenotype with involvement of brainstem nuclei and afferent nerves might also be due to changes of yet unknown genes neighboring the SMN gene.

Axons↗
PubMed1997

Different entities of proximal spinal muscular atrophy within one family.

The molecular analysis of the survival motor neuron (SMN) gene and several closely flanking polymorphic markers in an atypical pedigree with four patients suffering from spinal muscular atrophy (SMA) over two generations has raised new aspects concerning the etiology and the molecular spectrum of autosomal recessive SMA. Three patients in two generations show homozygous deletions of exons 7 and 8 of the telomeric copy of SMN (telSMN), thus confirming the presence of autosomal recessive SMA, with localisation on chromosome 5q12. The fourth SMA patient with mild neurogenic atrophy (confirmed by muscle biopsy and electromyography) shows no homozygous deletion of telSMN but carries a heterozygous deletion of telSMN, as can be deduced from her two affected homozygously deleted children. No intragenic mutation has been identified in the remaining telSMN. In addition, she shares only one SMA chromosome with her affected brother, is haploidentical with two healthy brothers, and has a 31-year-old healthy son, who has inherited an SMN-deleted paternal chromosome and the SMN non-deleted maternal chromosome. These results suggest that this patient either has a neurogenic atrophy of a different origin or exhibits an unusual heterozygous manifestation of SMA 5q12. Interestingly, the two haploidentical telSMN-deleted affected sibs in the second generation show a strikingly discordant clinical picture indicating that, in addition to telSMN mutations, other factors influence the phenotype of SMA in the reported pedigree.

Adult↗
PubMed1997

Spinal muscular atrophy--clinical and genetic correlations.

A clinical and molecular genetic study of nearly 500 patients with proximal spinal muscular atrophy (SMA) was undertaken. On the basis of defined achieved milestones, survival probabilities in type I (never able to sit), type II (able to sit but not to walk) and the probability of being ambulatory in type III (achieved ability to walk) SMA for a total of 445 patients with SMA are given. Specific deletions of the survival motor neuron (SMN) gene were found in 96% type I, 94% type II and 82% type III in a total of 191 patients, while four SMA type IV patients with an age of onset beyond 30 years were not deleted. The SMN gene obviously plays an important role in the pathogenesis of SMA but there is evidence that the SMN gene is not the SMA gene itself. The demonstration of SMN deletions in healthy siblings of affected persons, the high intrafamilial similarity of the clinical course on the background of a broad clinical spectrum of proximal SMA and the demonstration of different mutations causing different clinical manifestations in single pedigrees indicate that additional genetic factors might be relevant. Linkage studies, as well as the analysis of the SMN gene, recognised that SMA variants (with severe arthogryposis or cerebellar or diaphragmatic involvement) are not linked to chromosome 5q markers.

Chromosome Aberrations↗
PubMed1997

De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.

Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder. We have identified de novo rearrangements in 7 (approximately 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric copy of the survival motor neuron (SMN) gene (telSMN), in two cases accompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, with loss of markers Ag1-CA and C212, which are near the 5' ends of the SMN genes. In one case, an interchromosomal rearrangement involving both the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intrachromosomal deletion or gene conversion. In six of the seven cases, the de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allowed us to estimate for the first time the mutation rate for a recessive disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compares well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. These findings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype analysis in combination with direct SMN-gene deletion testing in SMA families.

Alleles↗
PubMed1997

Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA).

Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor neuron gene (SMN) is a strong candidate for SMA and present in two highly homologous copies (telSMN and cenSMN) within the SMA region (5q11.2-q13.3). More than 90% of SMA patients show homozygous deletions of at least exon 7 of telSMN, whereas absence of cenSMN seems to have no clinical consequences. In 23 non-deleted SMA patients, we searched for intragenic mutations of the SMN genes in exons 1-7 and the promotor region by single strand conformation analysis. We identified two different missense mutations, S2621 and T2741, in exon 6 of telSMN in three independent SMA families, providing further evidence for the telSMN gene as a SMA determining gene. Both mutations, as well as two previously described mutations (Y272C and G279V) are located within a highly conserved interval from codon 258 to codon 279 which seems to be an important functional domain of the telSMN protein. Recently, this region has been shown to contain a tyrosine/glycine-rich motif, which is also present in various RNA binding proteins, suggesting a potential role of SMN in RNA metabolism. Missense mutations might be useful for in vivo and transgenic experiments and further investigations on understanding the function of the telSMN protein.

Adolescent↗
PubMed1997

Proximal and distal spinal muscular atrophy in one family: molecular genetic studies provide further evidence for the non-allelic origin of both diseases.

We present the results of clinical and molecular genetic investigations of a family in which the father suffers from distal spinal muscular atrophy and the younger son is affected by infantile autosomal recessive SMA type I. The molecular analysis of the SMN gene showed homozygous deletions of telSMN exons 7 and 8 in the son only. This was probably the result of a new mutation in the paternal haplotype, since the affected boy did not inherit one copy of the marker Ag1-CA. These results indicate that distal and proximal SMA in this family are not caused by the same gene on chromosome 5q.

Adult↗
PubMed1997

Ureteral stenting using a combined antegrade/retrograde procedure. A technique for difficult cases.

Ureteral stenting is a procedure of daily routine. There are however cases in which cystoscopic placement of a stent fails despite various technical aids. Percutaneous nephrostomy is usually performed in those patients. In some cases however it is no reasonable alternative. For these special cases we used a combined antegrade/retrograde technique consisting in antegrade guide wire insertion followed by retrograde ureteral stenting. In 8 of 12 cases it was finally possible to insert a ureteral stent with this method. To our mind this technique should be applied when other attempts of stenting have failed and percutaneous nephrostomy is no reasonable alternative.

Cystoscopes↗
PubMed1996

Frequent DNA variant in exon 2a of the survival motor neuron gene (SMN): a further possibility for distinguishing the two copies of the gene.

An intragenic single-strand conformation polymorphism (SSCP) variant in exon 2a of the survival motor neuron gene (SMN) has been identified. The SSCP band shift is caused by a silent mutation (AGC-->AGT) at codon 28, which is the first codon of exon 2a. Five exchanges of base pairs at the 3'-end of the gene have been described that allow the two copies of SMN (telSMN and cenSMN) to be distinguished, whereas no DNA variant has been found at the 5'-end. The new DNA variant belongs to cenSMN and may be important for the assignment of point mutations to one of the two copies of SMN in spinal muscular atrophy (SMA) patients. The frequency of this variant is lower in SMA patients (10%) than in controls (24%).

Base Sequence↗
PubMed1996

p53 expression, proliferation marker Ki-S5, DNA content and serum PSA: possible biopotential markers in human prostatic cancer.

OBJECTIVES: The biology of prostate cancer is poorly understood. Despite established prognostic criteria, a confident prediction of the clinical outcome is not always possible. Therefore, additional and more precise information is highly desirable. In the present study, we compared potential biologic markers with the laboratory, clinical, and histopathologic parameters of prostate-specific antigen (PSA) level, tumor stage, and tumor grade. METHODS: Paraffin-embedded material from 62 radical prostatectomies for prostate carcinoma was examined immunohistochemically using monoclonal antibody Ki-S5 to determine the tumor growth fraction and antibody DO-1 to assess p53 protein overexpression. Deoxyribonucleic acid-ploidy was analyzed by flow and image cytometry. Preoperative PSA levels were assessed by standard method. The tumors were categorized according to the Gleason grading system and staged postsurgery after the TNM classification. RESULTS: The p53 expression, proliferation rate (Ki-S5), and rate of aneuploidy correlated closely with stage (P < 0.05) and Gleason score (P < 0.01). However, divergences were occasionally observed. The ploidy status correlated closely with proliferative activity and p53 expression. Conversely, no correlation was seen between these parameters and serum PSA content, the latter being significantly associated with the tumor stage alone. CONCLUSIONS: The results characterize proliferation marker Ki-S5, p53 expression, and ploidy status as tumor biopotential markers, whereas PSA provides diagnostic information. Use of these investigative methods promises to provide additional information relevant in prognosis and therapy selection. Nonetheless, their precise prognostic value will have to be established in further studies.

Aged↗
PubMed1996

Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings.

With the evidence of deletions in the region responsible for autosomal recessive spinal muscular atrophy (SMA) on chromosome 5, it is now possible to further clarify the clinical and diagnostic findings in proximal SMA. Homozygous deletions of the survival motor neuron (SMN) gene can be detected in about 95% of patients with early onset SMA. In a series of more than 200 patients, we tested 31 patients with atypical features of SMA who fulfilled at least one exclusion criterion according to the diagnostic criteria of the International SMA Consortium for the presence of SMN gene deletions. The patients were subdivided into two groups: 1. Seven index patients being not deleted for the SMN gene who belonged to a well-defined SMA plus variant that has already been shown to be unlinked with chromosome 5q markers: diaphragmatic SMA, SMA plus olivopontocerebellar hypoplasia, SMA with congenital arthrogryposis and bone fractures. 2. Twenty-four patients with clinical signs of SMA and neurogenic findings in EMG/muscle biopsy who had unusual features or other organ involvement. In order to structure this heterogeneous group, each patient was assigned to a subgroup according to the leading atypical feature. In 5 out of 8 unrelated patients with a history of preterm birth and/or perinatal asphyxia leading to a picture of severe SMA in combination with respiratory distress and/or cerebral palsy, no deletion of the SMN gene could be detected. There were five unrelated patients with extended central nervous system involvement (cerebral atrophy, EEG abnormalities, pyramidal tract signs, evidence of cerebellar involvement). Most of these patients (4/5) proved to belong to SMA 5q on the basis of SMN gene deletion findings. The same applied to a group of three patients with classical SMA in association with congenital malformations (mainly heart defect). A fourth group of three patients was characterized mainly by an unusual improvement of the condition; in these patients no SMN gene deletions were present. In three index patients a more complex syndrome of the CNS and other organs was suggested, but the detection of SMN gene deletions in two of them made a coincidence of features more likely. In addition, SMN gene deletions were found in two patients with evidence of congenital fibre type dysproportion in one and extremely raised CK activity ( > 10fold) in the other. While the confirmation of SMN gene deletions is very useful in cases with diagnostic doubts, caution is required when offering prenatal prediction with regard to SMA 5q in families with atypical features. There is strong evidence that there are clinical entities resembling SMA which most likely have another pathogenetic background.

Arthrogryposis↗
PubMed1996

Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease.

Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor-neuron gene (SMN), a strong candidate for SMA, is present in two highly homologous copies (telSMN and cenSMN) within the SMA region. Only five nucleotide differences within the region between intron 6 and exon 8 distinguish these homologues. Independent of the severity of the disease, 90%-98% of all SMA patients carry homozygous deletions in telSMN, affecting either exon 7 or both exons 7 and 8. We present the molecular analysis of 42 SMA patients who carry homozygous deletions of telSMN exon 7 but not of exon 8. The question arises whether in these cases the telSMN is truncated upstream of exon 8 or whether hybrid SMN genes exist that are composed of centromeric and telomeric sequences. By a simple PCR-based assay we demonstrate that in each case the remaining telSMN exon 8 is part of a hybrid SMN gene. Sequencing of cloned hybrid SMN genes from seven patients, as well as direct sequencing and single-strand conformation analysis of all patients, revealed the same composition in all but two patients: the base-pair differences in introns 6 and 7 and exon 7 are of centromeric origin whereas exon 8 is of telomeric origin. Nonetheless, haplotype analysis with polymorphic multicopy markers, Ag1-CA and C212, localized at the 5' end of the SMN genes suggests different mechanisms of occurrence, unequal rearrangements, and gene conversion involving both copies of the SMN genes. In approximately half of all patients, we identified a consensus haplotype, suggesting a common origin. Interestingly, we identified a putative recombination hot spot represented by recombination-stimulating elements (TGGGG and TGAGGT) in exon 8 that is homologous to the human deletion-hot spot consensus sequence in the immunoglobulin switch region, the alpha-globin cluster, and the polymerase alpha arrest sites. This may explain why independent hybrid SMN genes show identical sequences.

Biomarkers↗