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George W. Padberg - One of the best experts on this subject based on the ideXlab platform.
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Facioscapulohumeral Muscular Dystrophy
Nederlands Tijdschrift Voor Tandheelkunde, 2020Co-Authors: J. Wilbers, George W. Padberg, Baziel G M Van Engelen, Rune R. Frants, S.m. Van Der MaarelAbstract:Facioscapulohumeral Muscular Dystrophy is clinically mainly characterized by progressive weakness of the facial, shoulder and upper arm muscles. It is an autosomal dominant heriditary disease, caused by a contraction of a repetitive DNA element at the end of the long arm of chromosome 4. This contraction causes the local relaxation of the chromatin structure and likely dysregulation of one or more genes. Oral health care providers can play a significant role in the early recognition, as the often asymmetric facial weakness is frequently the first symptom. Adequate oral health care is needed because of the facial weakness.
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Respiratory function in Facioscapulohumeral Muscular Dystrophy 1
Neuromuscular Disorders, 2017Co-Authors: M. Wohlgemuth, Baziel G M Van Engelen, Corinne G.c. Horlings, E.l. Van Der Kooi, H.j. Gilhuis, Jan C.m. Hendriks, S.m. Van Der Maarel, Yvonne F. Heijdra, George W. PadbergAbstract:To test the hypothesis that wheelchair dependency and (kypho-)scoliosis are risk factors for developing respiratory insufficiency in Facioscapulohumeral Muscular Dystrophy, we examined 81 patients with Facioscapulohumeral Muscular Dystrophy 1 of varying degrees of severity ranging from ambulatory patients to wheelchair-bound patients. We examined the patients neurologically and by conducting pulmonary function tests: Forced Vital Capacity, Forced Expiratory Volume in 1 second, and static maximal inspiratory and expiratory mouth pressures. We did not find pulmonary function test abnormalities in ambulant Facioscapulohumeral Muscular Dystrophy patients. Even though none of the patients complained of respiratory dysfunction, mild to severe respiratory insufficiency was found in more than one third of the wheelchair-dependent patients. Maximal inspiratory pressures and maximal expiratory pressures were decreased in most patients, with a trend that maximal expiratory pressures were more affected than maximal inspiratory pressures. Wheelchair-dependent patients with (kypho-)scoliosis showed the most restricted lung function. Wheelchair-dependent patients with (kypho-)scoliosis are at risk for developing respiratory function impairment. We advise examining this group of Facioscapulohumeral Muscular Dystrophy patients periodically, even in the absence of symptoms of respiratory insufficiency, given its frequency and impact on daily life and the therapeutic consequences.
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a unifying genetic model for Facioscapulohumeral Muscular Dystrophy
Science, 2010Co-Authors: Richard J L F Lemmers, Rinse Klooster, J G Dauwerse, Lauren Snider, Kirsten R Straasheijm, Pilar Camaño, Patrick J. Van Der Vliet, Gertjan B Van Ommen, Sabrina Sacconi, George W. PadbergAbstract:Facioscapulohumeral Muscular Dystrophy (FSHD) is a common form of Muscular Dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain "permissive" chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.
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Facioscapulohumeral Muscular Dystrophy
Current Opinion in Neurology, 2009Co-Authors: George W. Padberg, Baziel G M Van EngelenAbstract:PURPOSE OF REVIEW: Knowledge of the pathogenetic mechanisms in Facioscapulohumeral Muscular Dystrophy is still scattered, but has recently been advanced through novel developments on the genetic scientific front. RECENT FINDINGS: The present brief review highlights some recent studies on the pathogenesis of Facioscapulohumeral Muscular Dystrophy pointing to major involvement of muscle development pathways and possibly vascular development pathways as well, which feeds into ideas about homeobox-related transcriptional dysregulation, which was originally suggested, based on the apparent descending order of muscle weakness. SUMMARY: The present findings and observations set a broad agenda for further research and possible therapeutic targets.
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Job perspectives in Facioscapulohumeral Muscular Dystrophy
Disability and Rehabilitation, 2009Co-Authors: C.w.j. Wevers, George W. Padberg, Oebele F. Brouwer, Irene D. NijboerAbstract:The working career of 138 adult patients with autosomal dominant Facioscapulohumeral Muscular Dystrophy (FSHD) was studied using a mailing questionnaire. Of 126 patients with an occupational history, the average female and male working career was 15 to 30 years, respectively. Of 61 respondents actually holding a job, only nine had adjustments for disease-related handicaps. Reaching above and below shoulder level was required in 24 jobs, although shoulder weakness is a presenting symptom of FSHD. In spite of these physical problems, 52 patients (85%) labelled their job as satisfying. The duration of their working career and the satisfaction with their work despite frequent physical problems warrant a careful vocational guidance of FSHD patients in order to prevent or postpone unemployment. Similar working career studies in patients with other neuroMuscular disorders are worthwhile
S.m. Van Der Maarel - One of the best experts on this subject based on the ideXlab platform.
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Facioscapulohumeral Muscular Dystrophy
Nederlands Tijdschrift Voor Tandheelkunde, 2020Co-Authors: J. Wilbers, George W. Padberg, Baziel G M Van Engelen, Rune R. Frants, S.m. Van Der MaarelAbstract:Facioscapulohumeral Muscular Dystrophy is clinically mainly characterized by progressive weakness of the facial, shoulder and upper arm muscles. It is an autosomal dominant heriditary disease, caused by a contraction of a repetitive DNA element at the end of the long arm of chromosome 4. This contraction causes the local relaxation of the chromatin structure and likely dysregulation of one or more genes. Oral health care providers can play a significant role in the early recognition, as the often asymmetric facial weakness is frequently the first symptom. Adequate oral health care is needed because of the facial weakness.
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Respiratory function in Facioscapulohumeral Muscular Dystrophy 1
Neuromuscular Disorders, 2017Co-Authors: M. Wohlgemuth, Baziel G M Van Engelen, Corinne G.c. Horlings, E.l. Van Der Kooi, H.j. Gilhuis, Jan C.m. Hendriks, S.m. Van Der Maarel, Yvonne F. Heijdra, George W. PadbergAbstract:To test the hypothesis that wheelchair dependency and (kypho-)scoliosis are risk factors for developing respiratory insufficiency in Facioscapulohumeral Muscular Dystrophy, we examined 81 patients with Facioscapulohumeral Muscular Dystrophy 1 of varying degrees of severity ranging from ambulatory patients to wheelchair-bound patients. We examined the patients neurologically and by conducting pulmonary function tests: Forced Vital Capacity, Forced Expiratory Volume in 1 second, and static maximal inspiratory and expiratory mouth pressures. We did not find pulmonary function test abnormalities in ambulant Facioscapulohumeral Muscular Dystrophy patients. Even though none of the patients complained of respiratory dysfunction, mild to severe respiratory insufficiency was found in more than one third of the wheelchair-dependent patients. Maximal inspiratory pressures and maximal expiratory pressures were decreased in most patients, with a trend that maximal expiratory pressures were more affected than maximal inspiratory pressures. Wheelchair-dependent patients with (kypho-)scoliosis showed the most restricted lung function. Wheelchair-dependent patients with (kypho-)scoliosis are at risk for developing respiratory function impairment. We advise examining this group of Facioscapulohumeral Muscular Dystrophy patients periodically, even in the absence of symptoms of respiratory insufficiency, given its frequency and impact on daily life and the therapeutic consequences.
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Early-onset Facioscapulohumeral Muscular Dystrophy type 1 with some atypical features.
Journal of Child Neurology, 2014Co-Authors: Małgorzata Dorobek, Richard J L F Lemmers, S.m. Van Der Maarel, Barbara Ryniewicz, Dagmara Kabzińska, Rune R. Frants, Malgorzata Gawel, Jerzy Walecki, Irena Hausmanowa-petrusewiczAbstract:Facioscapulohumeral Muscular Dystrophy cases with facial weakness before the age of 5 and signs of shoulder weakness by the age of 10 are defined as early onset. Contraction of the D4Z4 repeat on chromosome 4q35 is causally related to Facioscapulohumeral Muscular Dystrophy type 1, and the residual size of the D4Z4 repeat shows a roughly inverse correlation with the severity of the disease. Contraction of the D4Z4 repeat on chromosome 4q35 is believed to induce a local change in chromatin structure and consequent transcriptional deregulation of 4qter genes. We present early-onset cases in the Polish population that amounted to 21% of our total population with Facioscapulohumeral Muscular Dystrophy. More than 27% of them presented with severe phenotypes (wheelchair dependency). The residual D4Z4 repeat sizes ranged from 1 to 4 units. In addition, even within early-onset Facioscapulohumeral Muscular Dystrophy type 1 phenotypes, some cases had uncommon features (head drop, early disabling contractures, progre...
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Facioscapulohumeral Muscular Dystrophy and dux4 breaking the silence
Trends in Molecular Medicine, 2011Co-Authors: S.m. Van Der Maarel, Rabi Tawil, Stephen J TapscottAbstract:Autosomal dominant Facioscapulohumeral Muscular Dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4 , is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.
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epigenetic mechanisms of Facioscapulohumeral Muscular Dystrophy
Mutation Research, 2008Co-Authors: Jessica C De Greef, Rune R. Frants, S.m. Van Der MaarelAbstract:Facioscapulohumeral Muscular Dystrophy (FSHD) seems to be caused by a complex epigenetic disease mechanism as a result of contraction of the polymorphic macrosatellite repeat D4Z4 on chromosome 4qter. Currently, the exact mechanism causing the FSHD phenotype is still not elucidated. In this review, we discuss the genetic and epigenetic changes observed in patients with FSHD and the possible disease mechanisms that may be associated with FSHD pathogenesis.
Rabi Tawil - One of the best experts on this subject based on the ideXlab platform.
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Case Studies on the Genetic and Clinical Diagnosis of Facioscapulohumeral Muscular Dystrophy.
Neurologic Clinics, 2020Co-Authors: Johanna Hamel, Rabi TawilAbstract:Facioscapulohumeral Muscular Dystrophy is the second most common adult Muscular Dystrophy and is caused by DUX4 protein. DUX4 is expressed when the locus on chromosome 4q35 is hypomethylated. The clinical features can be nearly pathognomonic with facial weakness, scapular winging, and abdominal weakness with a positive Beevor sign. Diagnosis of late-onset or milder disease is often more challenging. Diseases mimicking the Facioscapulohumeral Muscular Dystrophy phenotype should be recognized. We present 6 cases to illustrate both clinical and genetic diagnostic challenges in Facioscapulohumeral Muscular Dystrophy and provide examples on how to navigate the different steps of genetic testing.
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Facioscapulohumeral Muscular Dystrophy
Handbook of Clinical Neurology, 2018Co-Authors: Rabi TawilAbstract:: Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most common forms of Muscular Dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of the genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline. In about 5% of individuals with phenotypic FSHD, there is no contraction in the D4Z4 repeats and yet similar chromatin changes are present, resulting in the inappropriate expression of the DUX4 gene. The chromatin changes in this form of FSHD (FSHD2) are the result, in most cases, of mutations in SMCHD1, a gene on chromosome 18 involved in chromatin regulation. The recent identification of aberrant activation of DUX4 transcription in FSHD as the root cause of FSHD now allows for a targeted approach to therapeutic development.
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Facioscapulohumeral Muscular Dystrophy
Continuum (Minneapolis Minn.), 2016Co-Authors: Jeffrey M Statland, Rabi TawilAbstract:ABSTRACTPurpose of Review: This article describes the clinical characteristics, diagnosis, molecular pathogenesis, and treatment of Facioscapulohumeral Muscular Dystrophy (FSHD).Recent Findings: FSHD comprises two genetically distinct types that converge on a common downstream pathway of the express
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Facioscapulohumeral Muscular Dystrophy
Neurologic Clinics, 2014Co-Authors: Jeffrey M Statland, Rabi TawilAbstract:Facioscapulohumeral Muscular Dystrophy (FSHSD) is one of the most common adult Muscular dystrophies and is divided into types 1 and 2 based on genetic mutation. Clinically both FSHD types 1 and 2 demonstrate often asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms, followed by the distal and then proximal lower extremities later in the disease course. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both FSHD types 1 and 2 share a common downstream mechanism making it possible that future disease-directed therapies will be effective for both FSHD types 1 and 2.
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patient identified disease burden in Facioscapulohumeral Muscular Dystrophy
Muscle & Nerve, 2012Co-Authors: Nicholas E Johnson, Rabi Tawil, Christine Quinn, Eileen Eastwood, Chad HeatwoleAbstract:Introduction: The multitude of symptoms associated with Facioscapulohumeral Muscular Dystrophy (FSHD) disease burden are of varying importance. The extent of these symptoms and their cumulative effect on the FSHD population is unknown. Methods: We conducted interviews with adult FSHD patients to identify which symptoms have the greatest effect on their lives. Each interview was recorded, transcribed, coded, and analyzed using a qualitative framework technique, triangulation, and a three-investigator consensus approach. Results: One thousand three hundred seventy-five quotes were obtained through 20 patient interviews. Two hundred fifty-one symptoms of importance were identified representing 14 themes of FSHD disease burden. Symptoms associated with mobility impairment, activity limitation, and social role limitation were most frequently mentioned by participants. Conclusions: There are multiple themes and symptoms, some previously underrecognized, that play a key role in FSHD disease burden. Muscle Nerve, 2012
Rossella Tupler - One of the best experts on this subject based on the ideXlab platform.
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Facioscapulohumeral Muscular Dystrophy a multicenter study on hearing function
Audiology and Neuro-otology, 2008Co-Authors: C P Trevisan, Ebe Pastorello, C Angelini, Giuliano Tomelleri, Paola Tonin, Tiziana Mongini, L Palmucci, Giuliana Galluzzi, Mario Ermani, Rossella TuplerAbstract:Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant progressive myopathy, characteristically associated with a 4q35 deletion. In the unusual infantile-onset form of this degenerativ
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Facioscapulohumeral Muscular Dystrophy type 1A in northwestern Tuscany: a molecular genetics-based epidemiological and genotype-phenotype study.
Genetic Testing, 2005Co-Authors: R Sposito, Rossella Tupler, Livia Pasquali, F Galluzzi, Anna Rocchi, B Solito, D. Soragna, Gabriele SicilianoAbstract:Facioscapulohumeral Muscular Dystrophy type 1A (FSHD1A) is an autosomal dominant inherited disorder characterized by early involvement of facial and scapular muscles with eventual spreading to pelv...
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molecular basis of Facioscapulohumeral Muscular Dystrophy
Cellular and Molecular Life Sciences, 2004Co-Authors: Rossella Tupler, Davide GabelliniAbstract:Facioscapulohumeral Muscular Dystrophy (FSHD), the third most common myopathy, is an autosomal dominant disease with an insidious onset and progression. Almost all FSHD patients carry deletions of an integral number of tandem 3.3 kb repeats, termed D4Z4, located on chromosome 4q35. In FSHD patients a deletion of the integral number of D4Z4 repeats generates a fragment that is usually smaller than 35 kb (fewer than 11 repeats), whereas in normal controls the size usually ranges from 50 to 300 kb (between 11 and 150 units). D4Z4 is a repetitive element with heterochromatic features. Recently, 4q35 genes located upstream of D4Z4 have been found to be inappropriately overexpressed specifically in FSHD muscle. An element within D4Z4 has been shown to behave as a silencer that provides a binding site for a transcriptional repressing complex. These results suggest a model in which deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease.
Richard J L F Lemmers - One of the best experts on this subject based on the ideXlab platform.
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Early-onset Facioscapulohumeral Muscular Dystrophy type 1 with some atypical features.
Journal of Child Neurology, 2014Co-Authors: Małgorzata Dorobek, Richard J L F Lemmers, S.m. Van Der Maarel, Barbara Ryniewicz, Dagmara Kabzińska, Rune R. Frants, Malgorzata Gawel, Jerzy Walecki, Irena Hausmanowa-petrusewiczAbstract:Facioscapulohumeral Muscular Dystrophy cases with facial weakness before the age of 5 and signs of shoulder weakness by the age of 10 are defined as early onset. Contraction of the D4Z4 repeat on chromosome 4q35 is causally related to Facioscapulohumeral Muscular Dystrophy type 1, and the residual size of the D4Z4 repeat shows a roughly inverse correlation with the severity of the disease. Contraction of the D4Z4 repeat on chromosome 4q35 is believed to induce a local change in chromatin structure and consequent transcriptional deregulation of 4qter genes. We present early-onset cases in the Polish population that amounted to 21% of our total population with Facioscapulohumeral Muscular Dystrophy. More than 27% of them presented with severe phenotypes (wheelchair dependency). The residual D4Z4 repeat sizes ranged from 1 to 4 units. In addition, even within early-onset Facioscapulohumeral Muscular Dystrophy type 1 phenotypes, some cases had uncommon features (head drop, early disabling contractures, progre...
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a unifying genetic model for Facioscapulohumeral Muscular Dystrophy
Science, 2010Co-Authors: Richard J L F Lemmers, Rinse Klooster, J G Dauwerse, Lauren Snider, Kirsten R Straasheijm, Pilar Camaño, Patrick J. Van Der Vliet, Gertjan B Van Ommen, Sabrina Sacconi, George W. PadbergAbstract:Facioscapulohumeral Muscular Dystrophy (FSHD) is a common form of Muscular Dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain "permissive" chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.
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Phenotype of combined Duchenne and Facioscapulohumeral Muscular Dystrophy.
Neuromuscular Disorders, 2008Co-Authors: Lawrence Korngut, Richard J L F Lemmers, Shannon L. Venance, Simon Levin, Julia Keith, Craig CampbellAbstract:Abstract This case report describes a young boy with concomitant genetically-confirmed Duchenne Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy with a novel dystrophin mutation in exon 6 and a D4Z4 fragment of 31 kb. This child presented with a more severe phenotype than expected for either individual disease process and underscores the role for thorough diagnostic investigation in identifying atypical clinical presentations.
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Atypical facet of Möbius syndrome: association with Facioscapulohumeral Muscular Dystrophy.
Muscle & Nerve, 2007Co-Authors: Hanna Kolski, Richard J L F Lemmers, Norma J. Leonard, John S. BamforthAbstract:We describe a patient with Facioscapulohumeral Muscular Dystrophy (FSHD) associated with Mobius syndrome and congenital ophthalmoplegia. This 7-year-old girl had profound limitation of extraocular movements since birth, congenital facial diplegia, neonatal hypotonia, and progressive limb-girdle weakness. FSHD genetic testing revealed a pathogenic haplotype with a D4Z4 repeat of 30 kb. The father carries the same allele, although is minimally affected. This unusual case expands the genotypic–phenotypic spectrum of FSHD. Muscle Nerve, 2007
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Diagnostic challenges in Facioscapulohumeral Muscular Dystrophy.
Neurology, 2006Co-Authors: Sabrina Sacconi, Richard J L F Lemmers, Leonardo Salviati, Isabelle Bourget, D Figarella, Yann Péréon, S.m. Van Der Maarel, Claude DesnuelleAbstract:The diagnosis of Facioscapulohumeral Muscular Dystrophy (FSHD) can be difficult due to its clinical variability and complex genetic cause. We present three challenging cases: one misdiagnosis of FSHD, one patient with FSHD resembling mitochondrial myopathy, and one patient with combined FSHD and limb girdle Muscular Dystrophy 2A. Detailed clinical and genetic evaluation, including 4qA/4qB allele determination, may be needed for the diagnosis of FSHD.
