Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC International Workshop, 23–24 November 2001, Naarden, The Netherlands

Pepe, Guglielmina; Bertini, Enrico; Bonaldo, Paolo; Bushby, Kate; Giusti, Betti; Visser, Marjolein; Guicheney, Pascale; Lattanzi, Giovanna; Merlini, Luciano; Muntoni, F.; Nishino, Ichizo; Nonaka, Ikuya; Yaou, Rabah Ben; Sabatelli, Patrizia; Sewry, Caroline A.; Topaloǧlu, Haluk; Kooi, Anneke J. van der

doi:10.1016/s0960-8966(02)00139-6

Cited by 79 publications

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References 17 publications

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“…3), and Col6A3 (2 q37) that encode respectively the alpha-1, alpha-2 and alpha-3 chains of collagen VI, cause two types of muscle disorders: Bethlem myopathy, with mild or moderate phenotype, and Ullrich CMD, with severe phenotype [1][2][3][4]6,7,69,117 . Bethlem myopathy is a slowly progressive disorder with variable age of onset, congenital or within the first or second decade of life, and marked flexion contractures of several joints 7,69,76,77,[117][118][119] . Ullrich CMD is an early onset condition with severe weakness and progressive course that manifests proximal joint contractures and marked distal hyperlaxity.…”

Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 99%

“…Patients reported with a heterozygous in-frame deletion in the triple-helical domain resulting in exon skipping in the Col6A1 gene have either a typical clinical picture with finger contractures 125 or a course more severe than that commonly reported 128 . some data indicate that large deletions and mutations inside the triple-helical collagen VI monomer he-Congenital muscular dystrophy: Part II reed lix formed by alpha-1, 2 and 3 polypeptides are associated with a phenotype more severe than those mutations occurring in the amino-terminal globular region 118 . Pepe et al 129 found two large and highly similar heterozygous Col6A1 genomic deletions, spanning from intron 8 to exon 13 or intron 13, in two patients, one with Bethlem myopathy and the other with moderate Ullrich CMD.…”

Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 99%

“…In relation to Ullrich phenotype, the initial molecular studies in Col6A2 and Col6A3 genes pointed only to recessive mutations 73,74,118 . lampe and Bushby 69 revised the literature about the type of mutations in Ullrich CMD and reported a large number of the mutations that introduce premature termination codons with consequent nonsense mediated mrNA decay and loss of the mutated chain; another common type of mutation is by splicing that leads to in-frame exonic deletions as well as in-frame genomic deletions.…”

Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 99%

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Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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-The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscleeye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.Key WorDs: congenital muscular dystrophy, MDC1A, collagen VI related disorders, glycosylation of alphadystroglycan, Fukuyama DMC, muscle-eye-brain (MeB) disease, Walker-Warburg syndrome, rigid spine syndrome. distrofia muscular congênita. parte ii: revisão da patogênese e perspectivas terapêuticas resumo -As distrofias musculares congênitas (DMCs) são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. são caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. o quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. os aspectos clínicos e diagnósticos dos principais subtipos de DMC foram apresentados no número anterior deste periódico, como primeira parte desta revisão. Nesta segunda parte apresentaremos os principais mecanismos patogênicos e as perspectivas terapêuticas dos subtipos mais comuns de DMC: DMC tipo 1A com deficiência de merosina, DMCs relacionadas com alterações do colágeno VI (Ullrich e Bethlem), e DMCs com anormalidades de glicosilação da alfa-distroglicana (DMC Fukuyama, DMC "Muscle-eye-brain" ou MeB, síndrome de Walker Warburg, DMC tipo 1C, DMC tipo 1D). A DMC com espinha rígida, mais rara e não relacionada com alterações do complexo distrofina-glicoproteínas associadas-matriz extracelular também será abordada quanto aos mesmos aspectos patogênicos e terapêuticos.PAlAVrAs-ChAVes: distrofia muscular congênita, merosina, colágeno VI, glicosila...

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Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 99%

Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 99%

Section: Collagen VI Related Muscle Disorders Pathogenesismentioning

confidence: 99%

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Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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“…Diagnosis depends on typical clinical features, with the serum creatine kinase concentration usually being normal or only mildly elevated and muscle biopsy showing myopathic or dystrophic changes. 8 In BM, collagen VI immunolabeling of muscle is usually normal or shows only subtle alterations. In older individuals, a secondary reduction of laminin ␤1 labeling may be observed.…”

Section: Diagnosismentioning

confidence: 99%

“…7 Ullrich congenital muscular dystrophy is an autosomal recessive severe disorder characterized by congenital muscle weakness with axial and proximal joint contractures and coexisting distal joint hypermobility. 8 The presentation is usually at birth, with hypotonia, congenital hip dislocation, prominent calcanei, and a transient kyphotic deformity. Motor milestones are delayed, and most of the children never acquire the ability to walk independently.…”

Section: Introductionmentioning

confidence: 99%

Therapy of Collagen VI-Related Myopathies (Bethlem and Ullrich)

Merlini

Bernardi

2008

Neurotherapeutics

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Summary:The collagen VI-related myopathies comprise two major forms, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. Specific diagnosis requires molecular genetic testing showing mutation in one of the three genes involved. This review summarizes current treatments, in particular indication for physiotherapy, orthopedic treatment for correction of foot deformity, scoliosis, and flexion contractures of elbows, and treatment of respiratory failure. The turning point in basic research on collagen VI myopathies was the discovery of an unexpected mitochondrial dysfunction as a pathogenetic mechanism underlying the myopathic syndrome seen in Col6a1 null mice. Treatment of Col6a1 Ϫ/Ϫ mice with cyclosporin A (CsA) rescued the mitochondrial dysfunction and decreased apoptosis. Similar mitochondrial defects were revealed in cultures of UCMD patients. The results of an open pilot trial with CsA in five patients with collagen VIrelated myopathies are summarized and discussed. With the availability of new potential effective treatments, several challenges must be addressed in conducting trials in orphan diseases and in neuromuscular disorders in particular. Outcome measures are discussed in the context of the expected effect of the cure. Randomized clinical trials often are not feasible for rare diseases, and sometimes would be ethically inappropriate. The need to develop alternative outcome measures or biomarkers using platforms such as genomics and proteomics is stressed in this context.

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Ullrich congenital muscular dystrophy: Connective tissue abnormalities in the skin support overlap with Ehlers–Danlos syndromes

Kirschner

Haußer

Zou

et al. 2004

American J of Med Genetics Pt A

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Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in the three genes coding for the alpha chains of collagen VI and characterized by generalized muscle weakness, striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints, and normal intellectual development. The diagnosis is supported by abnormal immunoreactivity for collagen VI on muscle biopsies. As patients with UCMD show clinical characteristics typical of classical disorders of connective tissue such as Ehlers-Danlos syndromes (EDS), we investigated the ultrastructure of skin biopsy samples from patients with UCMD (n=5). Electron microscopy of skin biopsies revealed ultrastructural abnormalities in all cases, including alterations of collagen fibril morphology (variation in size and composite fibers) and increase in ground substance, which resemble those seen in patients with EDS. Our findings suggest that there is a true connective tissue component as part of the phenotypic spectrum of UCMD and that there is considerable clinical as well as morphological overlap between UCMD and classic connective tissue disorders.

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Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC International Workshop, 23–24 November 2001, Naarden, The Netherlands

Cited by 79 publications

References 17 publications

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Therapy of Collagen VI-Related Myopathies (Bethlem and Ullrich)

Ullrich congenital muscular dystrophy: Connective tissue abnormalities in the skin support overlap with Ehlers–Danlos syndromes

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