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Biomedical subjects

G W Padberg

Publications and source records attributed to G W Padberg.

At least 19 recordsLinked to original sources
PubMed2006

No effect of folic acid and methionine supplementation on D4Z4 methylation in patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is associated with a contraction of the D4Z4 allele on chromosome 4qter. There is also marked DNA hypomethylation of the D4Z4 allele. The DNA hypomethylation may have a central role in the pathogenesis of FSHD. Supplemental folic acid can boost DNA methylation. We evaluated the effect of oral folic acid and methionine supplementation on the methylation level of 4qter D4Z4 alleles in peripheral-blood lymphocytes of nine patients affected with FSHD and six healthy controls. Methylation levels did not change, while recommended serum-folate concentrations were reached.

Adolescent↗
PubMed2006

Dysphagia in facioscapulohumeral muscular dystrophy.

Dysphagia is not considered a symptom of facioscapulohumeral muscular dystrophy (FSHD). In this study, the authors found that dysphagia does occur in patients with advanced FSHD showing mild involvement of the jaw and lingual muscles. Dysphagia is seldom life threatening in these patients. The authors conclude that dysphagia should not be considered an exclusion criterion for FSHD.

Adult↗
PubMed2006

Intake of 13C-4 creatine enables simultaneous assessment of creatine and phosphocreatine pools in human skeletal muscle by 13C MR spectroscopy.

The feasibility of a novel method for the noninvasive and local assessment of creatine (Cr) and phosphocreatine (PCr) dynamics in human skeletal muscle based on (13)C magnetic resonance (MR) spectroscopy is presented. A high dose of Cr, labeled at the guanidino C-4 position with (13)C 11% enrichment, was administered orally to a human subject for 5 days. Using a surface coil, (13)C MR spectra of the lower leg were acquired on a 1.5T MR system at regular time intervals during and after Cr supplementation. An almost twofold increase in the intensities of the resolved PCr and Cr (13)C-4 signals was observed during this period. The slow decrease in these signals to normal values after supplementation reflects the slow daily turnover of Cr. The PCr/Cr ratio did not appear to change over the whole measurement period. During exercise of the leg, reversible changes in PCr and Cr signals were observed, reflecting conversion by the Cr kinase reaction.

Carbon Radioisotopes↗
PubMed2006

An unbiased and efficient computerised tomography method to quantify muscle and adipose tissue volume in neuromuscular patients.

The objective was to evaluate the applicability and reliability of an unbiased stereological computerised tomography (CT) method for estimating total human body (HB), skeletal muscle (SM) and adipose tissue (AT) volumes in groups of neuromuscular patients. In 10 neuromuscular patients HB, SM and AT volumes were estimated using systematic sampling on equidistant CT sections throughout the total body axis using a counting grid with systematically ordered intersection points. Each intersection point hitting HB, SM or AT represented a known volume dependent on intersection point distance and sum of section thickness and gap. Random and systematic intra- and interobserver errors for volume estimates were below 0.035. These errors were negligible to the coefficient of variation of the group mean, being 0.190 for HB, 0.323 for SM and 0.471 for AT. Even in the presence of intrafascicular and intramuscular fat in neuromuscular patients, unbiased and reliable quantification of HB, SM and AT is possible.

Adipose Tissue↗
PubMed2005

The neuropathology of hereditary congenital facial palsy vs Möbius syndrome.

OBJECTIVE: To characterize the neuropathology of hereditary congenital facial palsy. METHODS: The authors compared brainstem pathology of three members of one family with autosomal dominant congenital facial palsy to that in three age-matched controls. The neuropathologic findings of the familial patients were compared with those of patients with Möbius syndrome. RESULTS: The authors observed a marked decrease in the number of neurons in the facial motor nucleus with corresponding small facial nerve remnants. In the patients with congenital facial palsy the number of facial motoneurons ranged between 280 and 1,680 as compared to 5,030 and 8,700 for controls. No signs of neuronal degeneration or necrosis with neuronal loss, gliosis, or calcifications were present. There were no other abnormalities of the rhombencephalon and its associated structures. The corticospinal tracts were fully developed. In contrast, Möbius syndrome is part of a more complex congenital anomaly of the posterior fossa with hypoplasia of the entire brainstem, including the traversing long tracts, with signs of neuronal degeneration and other congenital brain abnormalities. CONCLUSION: Neuropathologic findings confirm clinical observations that hereditary congenital facial palsy and Möbius syndrome are two different entities with a different pathogenesis.

Abnormalities, Multiple↗
PubMed2005

Cognitive evaluation in adult patients with Möbius syndrome.

OBJECTIVE: To establish the occurrence of mental retardation in a group of patients with Möbius syndrome and subsequently, if mental retardation is absent, to screen major aspects of memory and attention, in order to assess possible pervasive dysfunction in these cognitive domains which might be responsible for the current view that mental retardation occurs frequently in Möbius syndrome. METHODS: In a group of 12 Dutch Möbius patients, intellectual performance, memory function and attention were assessed using a number of standardized neuropsychological tests. RESULTS: The mean general intellectual performance did not differ significantly from that of the Dutch population. Screening of selective attention and memory did not provide indications of pervasive dysfunctions in these domains. CONCLUSION: The rate of occurrence of mental retardation in our group of Möbius patients did not differ from that in the normal Dutch population. Furthermore, there was no evidence of attention and memory dysfunction in our group of Möbius patients.

Adolescent↗
PubMed2005

Experienced fatigue in facioscapulohumeral dystrophy, myotonic dystrophy, and HMSN-I.

OBJECTIVE: To assess the prevalence of severe fatigue and its relation to functional impairment in daily life in patients with relatively common types of neuromuscular disorders. METHODS: 598 patients with a neuromuscular disease were studied (139 with facioscapulohumeral dystrophy, 322 with adult onset myotonic dystrophy, and 137 with hereditary motor and sensory neuropathy type I). Fatigue severity was assessed with Checklist Individual Strength (CIS-fatigue). Functional impairments in daily life were measured with the short form 36 item health questionnaire (SF-36). RESULTS: The three different neuromuscular patient groups were of similar age and sex. Severe experienced fatigue was reported by 61-74% of the patients. Severely fatigued patients had more problems with physical functioning, social functioning, mental health, bodily pain, and general health perception. There were some differences between the three disorders in the effects of fatigue. CONCLUSIONS: Severe fatigue is reported by the majority of patients with relatively common types of neuromuscular disorders. Because experienced fatigue severity is associated with the severity of various functional impairments in daily life, it is a clinically and socially relevant problem in this group of patients.

Activities of Daily Living↗
PubMed2004

Strength training and albuterol in facioscapulohumeral muscular dystrophy.

BACKGROUND: In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of strength training and albuterol on muscle strength and volume in FSHD. METHODS: Sixty-five patients were randomized to strength training of elbow flexors and ankle dorsiflexors or non-training. After 26 weeks albuterol (sustained-release, 8 mg BID) was added in a randomized, double-blind, placebo-controlled design. Primary outcome was maximum voluntary isometric strength (MVIC) at 52 weeks. Secondary outcomes comprised dynamic strength and muscle volume. RESULTS: Training and albuterol were well tolerated. Training of elbow flexors did not result in a significant effect on MVIC, but dynamic strength improved significantly. Elbow flexor MVIC strength increased significantly in albuterol vs placebo treated patients. Ankle dorsiflexor strength decreased in all groups. Eleven out of twelve non-trained muscles in the albuterol group showed a positive effect on MVIC compared to the placebo group (p < 0.05 in seven muscle groups). Muscle volume decreased in the placebo-treated, and increased in the albuterol-treated patients. No synergistic or antagonistic effects were observed between training and albuterol. CONCLUSIONS: In FSHD strength training and albuterol appear safe interventions with limited positive effect on muscle strength and volume. Consequences of prolonged use are presently unclear, which precludes routine prescription.

Adrenergic beta-Agonists↗
PubMed2004

Ventilatory support in facioscapulohumeral muscular dystrophy.

Respiratory insufficiency due to respiratory muscle weakness is a common complication of many neuromuscular diseases. The prevalence of respiratory failure in facioscapulohumeral muscular dystrophy (FSHD) is unknown. The authors identified 10 FSHD patients on nocturnal ventilatory support at home, representing approximately 1% of the Dutch FSHD population. Severe muscle disease, wheelchair dependency, and kyphoscoliosis appeared to be risk factors for respiratory failure.

Adult↗
PubMed2004

Genomewide scan identifies susceptibility locus for dyslexia on Xq27 in an extended Dutch family.

CONTEXT: Dyslexia is a common disorder with a strong genetic component, but despite significant research effort, the aetiology is still largely unknown. OBJECTIVE: To identify loci contributing to dyslexia risk. METHODS: This was a genomewide linkage analysis in a single large family. Dutch families with at least two first degree relatives suffering from dyslexia participated in the study. Participants were recruited through an advertisement campaign in papers and magazines. The main outcome measure was linkage between genetic markers and dyslexia phenotype. RESULTS: Using parametric linkage analysis, we found strong evidence for a locus influencing dyslexia on Xq27.3 (multipoint lod = 3.68). Recombinations in two family members flanked an 8 cM region, comprising 11 currently confirmed genes. All four males carrying the risk haplotype had very low scores on the reading tests. The presentation in females was more variable, but 8/9 females carrying the risk haplotype were diagnosed dyslexic by our composite score, so we considered the putative risk allele to be dominant with reduced penetrance. Linkage was not found in an additional collection of affected sibling pairs. CONCLUSIONS: A locus influencing dyslexia risk is probably located between markers DXS1227 and DXS8091 on the X chromosome, closely situated to a locus indicated by a published genome scan of English sibling pairs. Although the locus may not be a common cause for dyslexia, the relatively small and gene poor region offers hope to identify the responsible gene.

Adolescent↗
PubMed2004

FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients.

BACKGROUND: Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with partial deletion of the subtelomeric D4Z4 repeat array on chromosome 4qter. This chromosomal rearrangement may result in regional chromatin relaxation and transcriptional deregulation of genes nearby. METHODS AND RESULTS: Here we describe the isolation and characterisation of FRG2, a member of a chromosomally dispersed gene family, mapping only 37 kb proximal to the D4Z4 repeat array. Homology and motif searches yielded no clues to the function of the predicted protein. FRG2 expression is undetectable in all tissues tested except for differentiating myoblasts of FSHD patients, which display low, yet distinct levels of FRG2 expression, partly from chromosome 4 but predominantly originating from its homologue on chromosome 10. However, in non-FSHD myopathy patients only distantly related FRG2 homologues are transcribed, while differentiating myoblasts from healthy controls fail to express any member of this gene family. Moreover, fibroblasts of FSHD patients and control individuals undergoing forced Ad5-MyoD mediated myogenesis show expression of FRG2 mainly originating from chromosome 10. Luciferase reporter assays show that the FRG2 promoter region can direct high levels of expression but is inhibited by increasing numbers of D4Z4 repeat units. Transient transfection experiments with FRG2 fusion-protein constructs reveal nuclear localisation and apparently FRG2 overexpression causes a wide range of morphological changes. CONCLUSION: The localisation of FRG2 genes close to the D4Z4 repeats on chromosome 4 and 10, their transcriptional upregulation specifically in FSHD myoblast cultures, potential involvement in myogenesis, and promoter properties qualify FRG2 as an attractive candidate for FSHD pathogenesis.

Amino Acid Sequence↗
PubMed2003

Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles.

OBJECTIVE: Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with a contraction of the D4Z4 repeat array on chromosome 4. So far, homozygosity or compound heterozygosity for FSHD alleles has not been described, and it has been debated whether the absence of such subjects is because of the rarity or the lethality of the disorder. METHODS: Two unrelated families in which the probands are compound heterozygous for two FSHD-sized alleles were studied. Clinical examination, pulsed-field gel electrophoresis (PFGE) studies of DNA with probes proximal and distal to D4Z4, and cytogenetic analysis of metaphase chromosomes by FISH were performed. RESULTS: Complementary molecular and cytogenetic approaches confirmed the chromosome 4qA origin of all FSHD-sized repeat arrays that segregate in the families. CONCLUSIONS: Heterozygosity for FSHD-sized alleles is compatible with life in men and women. A possible dosage effect was observed in both probands in whom each 4qA allele contributed to the FSHD phenotype. Because at least one of the FSHD alleles in both families showed an unusual low penetrance, the authors propose that susceptibility for FSHD is partly determined by intrinsic properties of the disease allele other than the residual D4Z4 repeat size alone.

Aged↗
PubMed2003

D4F104S1 deletion in facioscapulohumeral muscular dystrophy: phenotype, size, and detection.

BACKGROUND: The facioscapulohumeral muscular dystrophy (FSHD) locus maps to 4q35 where it is closely linked to D4F104S1 (p13E-11), a probe that recognizes the pathognomonic FSHD deletion involving the subtelomeric D4Z4 tandem repeat array. Extended deletions that include both the more proximal D4F104S1 region and the D4Z4 repeat array proper do, however, occur, albeit rarely, and such deletions can lead to difficulties of interpretation in the diagnostic setting. OBJECTIVE: To devise a means to determine the true frequency of proximally extended deletions in individuals with FSHD. METHODS: Three families selected for this study were originally identified during routine FSHD analysis on the basis that the affected individuals in each family had failed to exhibit a small (<38-kb) EcoRI fragment. High molecular weight DNA from these families was analyzed with both conventional and pulsed-field gel electrophoresis using DNA markers p13E-11, 9B6A, B31, 4qA, and 4qB. RESULTS: Large genomic deletions were identified involving both D4Z4 and D4F104S1. The precise number of D4Z4 repeat units borne by the p13E11 deletion allele was established by the use of an additional restriction enzyme (MseI) digest. All three cases carry different sizes of deletion proximal to the D4Z4 repeat units. With use of a recently described telomeric probe, 4qA, a method was developed that identifies large genomic deletions involving both D4Z4 and D4F104S1 using conventional gel electrophoresis. CONCLUSION: Proximally extended deletions can be found in patients with a normal spectrum of the disease. This assay promises to allow estimation of the true frequency of proximally extended deletions and should improve the accuracy and reliability of molecular diagnostic testing for FSHD.

Adult↗
PubMed2003

Face mask spirometry and respiratory pressures in normal subjects.

Spirometry and maximal respiratory pressures are pulmonary function parameters commonly used to evaluate respiratory function. Prediction values are available for conventional lung function devices using a standard tube or flanged type of mouthpiece connection. This equipment is not suitable for patients with facial or buccal muscle weakness, because of air leakage around the mouthpiece. A face mask was used for the portable lung function devices used in the neuromuscular department. The aim of this study was to compare the face mask and the conventional mouthpiece for the measurement of spirometry and of respiratory pressures in 22 healthy subjects. Values obtained with the conventional mouthpiece differed significantly from values obtained with the face mask. With the mask, forced vital capacity and forced expiratory volume in one second were 200 mL lower, and maximal expiratory pressure was 3.2 kPa lower than with the mouthpiece. Subsequently, new prediction values for face mask spirometry and maximal respiratory pressures were obtained from 252 other healthy subjects, from which new prediction equations were derived. It was concluded that the face mask connection to the lung function device is a valid alternative, is easy to use and is most useful to monitor changes in patients. This study confirms the importance of appropriate prediction equations, depending on subject-instrument interfaces.

Adolescent↗
PubMed2001

Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis.

Facioscapulohumeral muscular dystrophy is caused by partial deletion of the D4Z4 repeat array on chromosome 4q35. Genetic diagnosis is based on sizing of this repeat array, which is complicated by cross-hybridization of a homologous polymorphic repeat array on chromosome 10 and by the frequent exchanges between these chromosomal regions. The restriction enzyme XapI optimizes the diagnosis of facioscapulohumeral muscular dystrophy by uniquely digesting 4-derived repeat units and leaving 10-derived repeat units undigested, thus complementing BlnI, which uniquely digests 10-derived repeat units. A triple analysis with EcoRI, EcoRI/BlnI, and XapI unequivocally allows characterization of each of the four alleles, whether homogeneous or hybrid. This is particularly useful in the case of identical sized 4-derived and 10-derived arrays, in situations of suspected facioscapulohumeral muscular dystrophy with nonstandard allele configurations, and for assignment of hybrid fragments to their original alleles.

Aged↗