PubMed Health⌕ Search

Biomedical subjects

T Voit

Publications and source records attributed to T Voit.

At least 91 records · Page 5Linked to original sources
PubMed1996

Neurosensory hearing loss in secondary adhalinopathy.

We report mild-to-moderate neurosensory hearing loss and severe childhood autosomal recessive muscular dystrophy with adhalin-deficiency in two siblings from a Bulgarian sibship of Turkish origin. Microsatellite analysis excluded linkage to the adhalin gene, mutations of which cause limb girdle muscular dystrophy (LGMD) 2D, but was compatible with linkage to the gene locus of LGMD 2C on chromosome 13q12. Compound heterozygosity of the affected siblings was detected in this chromosomal region. A severe autosomal recessive form of neurosensory deafness has been linked to the same region (locus NSRD1) which is now contained in a 7 Mb YAC contig. Using polymorphic markers and STS PCR primers mapping in this contig, we did not find evidence for major rearrangements in the suspected region. These preliminary findings are not in favor of, but do not completely exclude a contiguous gene syndrome in these cases. Therefore, we consider a potential role of the putative 13q12 gene product and/or adhalin in neurosensory hearing.

Alleles↗
PubMed1996

A cysteine 3340 substitution in the dystroglycan-binding domain of dystrophin associated with Duchenne muscular dystrophy, mental retardation and absence of the ERG b-wave.

We report the first C-terminal missense mutation in a Duchenne muscular dystrophy patient. A G10227A transition of the dystrophin gene was found which resulted in the substitution of a highly conserved cysteine at position 3340 within the second half of the dystroglycan-binding domain. Residual amounts of 427 kDa dystrophin were detected in western blot analysis of the patient's muscle tissue, and immunohistological examination revealed weak traces of dystrophin on all fibers. Sarcolemmal staining intensity of 43 kDa beta-dystroglycan was also reduced. Mental retardation in our patient and absence of the b-wave in his electroretinogram indicate that central nervous functions of dystrophin isoforms also depend on the presence of cysteine 3340.

Binding Sites↗
PubMed1996

Fetal CNS damage after exposure to maternal trauma during pregnancy.

Nine case reports are presented to indicate the possible effects of maternal trauma on surviving fetuses. Previous reports have only addressed fatal consequences. Traumata occurred between gestational weeks 23 and 37. Seven mothers had motor-vehicle accidents (MVA), two had blunt abdominal traumata. Four mothers suffered severe injuries, such as cerebral contusion, fractures or placental abruption leading to emergency Cesarean section. Premature uterine contractions were observed in five mothers and hemorrhage in two. The nine children were born after 30 to 40 weeks of gestation. Seven had normal postpartal vital signs, one required resuscitation and one premature needed assisted ventilation. Clinical symptoms were variable: movement disorders (n = 3), hydrocephalus (n = 2), convulsions (n = 1), cerebral palsy (n = 1), and normal (n = 3). Follow-up ranged from 7 months to 5 years. Neuroimaging revealed periventricular leukomalacia (n = 2), localized vascular infarctions (n = 2), hemorrhage (n = 1), hydrocephalus (n = 2) and global damage (n = 1). The causative role of maternal accidents was extremely likely in one patient, and probable but unproved in the remaining cases.

Accidents, Traffic↗
PubMed1996

Wheat kernel ingestion protects from progression of muscle weakness in mdx mice, an animal model of Duchenne muscular dystrophy.

A simple, reproducible test was used to quantify muscle weakness in mdx mice, an animal model of Duchenne muscular dystrophy. The effect of bedding on wheat kernels and of dietary supplementation of alpha-tocopherol on the progression of muscle weakness was investigated in mdx mice. When measured during the first 200 d of life, mdx mice developed muscle weakness, irrespective of bedding and diet. When kept on wood shavings and fed a conventional rodent diet, mdx mice showed progressive muscle weakness over the consecutive 200 d, and eventually showed a significant weight loss during the next 200-d observation period. Progression of muscle weakness and weight loss were almost completely prevented in mdx mice that were kept on wheat kernel bedding. In contrast, only incomplete maintenance of muscle strength and body weight was observed in mdx mice kept on wood shavings and fed the alpha-tocopherol-supplemented diet. It is concluded from these experiments that a component of wheat kernels other than alpha-tocopherol is essential to prevent the progression of muscle weakness in mdx mice.

Aging↗
PubMed1995

X-linked dilated cardiomyopathy. Novel mutation of the dystrophin gene.

We report on a family with a severe form of X-linked dilated cardiomyopathy (DCM). Two brothers, the elder requiring heart transplantation, and a maternal cousin presented elevated creatine kinase levels, increased right ventricular diameters and electrocardiographic abnormalities. All complained of exertional cramping myalgia, but none had muscle weakness or a pathological electromyogram. Muscle biopsies of these individuals revealed a mild myopathic picture with atrophic type I and hypertrophic type II fibers. Immunofluorescence using N- and C-terminal antibodies (dys-2, dys-3) against the dystrophin protein showed preserved, but reduced intensity of staining of the sarcolemmal membranes. Using the same two antibodies, Western blot analyses revealed a dystrophin molecule of the expected molecular weight, which was quantitatively reduced by 80%. However, the dys-1 antibody, directed against the mid rod region of the dystrophin protein, did not react with dystrophin both on Western blot and immunofluorescence. Linkage analysis with polymorphic markers of the dystrophin gene revealed an identical haplotype at the 5' region in all affected individuals (two point lod score of 1.93, phi = 0). A deletion of exons 48, 45-53, 2-7 and 1 including the promoter region of the dystrophin gene, as described in rare cases with similar clinical signs could be excluded by multiplex PCR and Southern blot analyses of this DCM family. In addition, a major splice-mutation of dystrophin mRNA was excluded by RT-PCR of skeletal and heart muscle tissue. Therefore, we conclude that a novel mutation in the 5' region of the dystrophin gene phenotypically leads to this severe form of DCM. Extensive analyses of the dystrophin gene, in particular of the sequences coding for the antigenic determinants of the dys-1 antibody in the mid rod region, may identify the molecular cause of this monogenetic form of DCM.

Adult↗
PubMed1995

X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes.

The X-chromosome activity states of 11 manifesting carriers of dystrophinopathies, all with normal karyotypes, were estimated by restriction fragment length polymorphism (RFLP)-methylation analysis with the probes M27 beta (DXS255), p2-19(DXS605) and pSPT/PGK (PGK1) to test the role of skewed X-inactivation ratios as the cause of their affected phenotypes. In eight cases preferential inactivation of the putative X chromosome carrying the normal dystrophin allele in > or = 90% of their peripheral lymphocytes was observed, two cases showed non-apparent deviant ratios (60:40 and 70:30) from the theoretically expected values around the mean of 50% and in one case the three markers employed yielded no information. The analysis of the X-inactivation ratio in six mother-daughter pairs, all non-manifesting Duchenne muscular dystrophy (DMD) carriers, and in the close female relatives of the patients showed: (a) neither of the two X chromosomes was preferentially inactivated with respect to their parental origin; (b) a high concordance among the activation ratios of mothers and daughters, a result difficult to explain just in terms of random X-chromosome inactivation.

Child↗
PubMed1995

Sarcolemmal expression of dystrophin C-terminus but reduced expression of 6q-dystrophin-related protein in two DMD patients with large deletions of the dystrophin gene.

Partial deletions of the dystrophin gene are the predominant genetic lesions in Duchenne (DMD) and Becker (BMD) muscular dystrophies. According to the reading frame hypothesis [1], any deletion disrupting the translational reading frame of the mRNA cannot result in expression of the dystrophin molecule and should lead to severe phenotypes of DMD. In contrast, deletions which maintain the reading frame across the deleted exons may give rise to truncated, semifunctional proteins and milder courses of the disease (i.e. BMD). Among the notable exceptions of this hypothesis are very large "in-frame" deletions by which functionally indispensable domains of the dystrophin molecule have been removed. Here, we report on two DMD patients with large intragenic in-frame deletions. Grossly truncated, but stable dystrophin molecules with preserved C-terminal domains were detected at the sarcolemma on cryosections in both patients. However, dystrophin organization on single-teased muscle fibers revealed disarrangement of the costameric pattern, if compared to normal skeletal muscle fibers. Compared to dystrophin-deficient DMD muscle, expression of chromosome-6-encoded dystrophin-related protein (DRP) was greatly diminished in skeletal muscle of both patients. We show, that loss of more than 50% of dystrophin seems to be deleterious for the protein's function and therefore, the extent of the deletions may have an impact on construction of dystrophin mini genes. Moreover, these findings shed new light on the functional significance of the C-terminal domain of dystrophin. They also suggest a negative correlation between sarcolemmal expression of the dystrophin C-terminus and DRP expression at the sarcolemma.

Blotting, Western↗
PubMed1995

Preserved merosin M-chain (or laminin-alpha 2) expression in skeletal muscle distinguishes Walker-Warburg syndrome from Fukuyama muscular dystrophy and merosin-deficient congenital muscular dystrophy.

The merosin M-chain (or laminin-alpha 2) is one of three subunits of laminin-2 which is highly expressed in striated muscle and peripheral nerve. Complete lack of laminin-alpha 2 expression in skeletal muscle is the hallmark of one form of congenital muscular dystrophy which is characterized by dysmyelination of the central nervous system (CNS), links to chromosome 6q2 and is common among Caucasians. Laminin-alpha 2 expression was also found to be significantly reduced in Fukuyama congenital muscular dystrophy which links to chromosome 9q3. We report consistently preserved laminin-2 expression, including laminin-alpha 2, as detected by immunofluorescence in skeletal muscle from five patients with Walker-Warburg syndrome which is characterized by congenital muscular dystrophy and, in addition, type II lissencephaly or pachygyria, defective CNS myelination, and ocular dysgenesis. These findings show that in spite of partial phenotypic overlap between Fukuyama CMD and Walker-Warburg syndrome the two disorders are nosologically separate disease entities. They also exclude that Walker-Warburg syndrome is allelic to the common form of congenital muscular dystrophy with laminin-alpha 2 deficiency.

Antibodies↗
PubMed1995

Clinical results of early orthopaedic management in Duchenne muscular dystrophy.

Although the primary defect of Duchenne muscular dystrophy has been found, there is no causal treatment to alter the natural course of this disease. Based on the recommendations by Glorion and Rideau with early treatment of contractures of the hips and the lower limbs we performed a modified release of the spina muscles, resection of tensor fasciae latae muscle and a lengthening of the tendo calcaneus in 32 patients. The mean age of DMD patients at time of operation was 6.1 years. The mean follow-up was 3.4 years. All children underwent mobilisation the day after surgery. Complete correction of all contractures was immediately achieved after operation and kept in all but two cases up to the follow-up examination after 3.4 years. No loss of ambulation was observed. Our results demonstrate that early selective surgery in DMD patients just at or better before the onset of contractures without performing an additional aponeurectomy of the iliotibial band and percutaneous tenotomy of the hamstrings according to the original Glorion-Rideau technique safely prevents severe contractures and thereby delays the progression of scoliosis.

Child↗
PubMed1995

Autosomal dominant familial spastic paraplegia: reduction of the FSP1 candidate region on chromosome 14q to 7 cM and locus heterogeneity.

Three large pedigrees of German descent with autosomal dominant "pure" familial spastic paraplegia (FSP) were characterized clinically and genetically. Haplotype and linkage analyses, with microsatellites covering the FSP region on chromosome 14q (locus FSP1), were performed. In pedigree W, we found a haplotype that cosegregates with the disease and observed three crossing-over events, reducing the FSP1 candidate region to 7 cM; in addition, the observation of apparent anticipation in this family suggests a trinucleotide repeat expansion as the mutation. In pedigrees D and S, the gene locus could be excluded from the whole FSP1 region, confirming the locus heterogeneity of autosomal dominant FSP.

Alleles↗
PubMed1994

Hyperintense lesions of the globus pallidus on MRI in children with chronic liver disease.

UNLABELLED: In three children with chronic liver disease of different aetiology without obvious hepatic encephalopathy, bilateral and symmetrical hyperintensity of the globus pallidus in T1-weighted images was found on cranial MRI. Reversibility was shown in one child with autoimmune hepatitis after normalisation of liver function tests under immunosuppressive therapy. CONCLUSION: As central nervous system involvement in liver disease is only partially understood, brain imaging by MRI offers a potential additional tool to further elucidate the incidence and time course of previously undetected brain alterations.

Adolescent↗
PubMed1994

Coisogenic all-plus-one immunization: a model for identifying missing proteins in null-mutant conditions. Antibodies to dystrophin in mdx mouse after transplantation of muscle from normal coisogenic donor.

Specific antibody response against an alien protein is one of the basic immunologic mechanisms in immunecompetent organisms. They can be used as a first step in various approaches leading to the identification of proteins or even an antigen-encoding gene. Accordingly, we wanted to find out whether a null-mutant immunecompetent organism would produce specific antibodies against the missing gene product. We chose the mouse mutant mdx (X-linked muscular dystrophy) which represents a null-mutant condition for the gene product of the Duchenne muscular dystrophy (DMD) gene, dystrophin. When dystrophin-deficient mdx mice received dystrophin-containing muscle grafts from coisogenic normal mice, high titres of antibodies specific for dystrophin were detected in the transplanted animals' sera. Because dystrophin-containing muscle grafts were not rejected but have properly regenerated even in the presence of high titre antibodies against dystrophin, these findings have important bearings on all therapeutical strategies based on dystrophin supplementation. Using the mdx mouse as null-mutant model we showed that there was no immune tolerance for the missing protein but specific antibodies were produced when the organism came in contact with this protein. This simple approach may serve as a shortcut for identifying missing proteins presumably not only in neuromuscular disorders but in a wide range of diseases where null-mutant animal models and corresponding coisogenic inbred strains exist.

Animals↗