The myotonic dystrophies: molecular, clinical, and therapeutic challenges

Udd, Bjarne; Krahe, Ralf

doi:10.1016/s1474-4422(12)70204-1

Cited by 409 publications

(386 citation statements)

References 144 publications

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“…Sequestration of several RNA binding proteins by abnormally long GGG GCC repeats has been suggested to be an important pathogenic factor in C9 ALS/FTD, similar to what is thought to happen in myotonic dystrophy [45]. In this disease, the sequestration of the protein muscleblind by the CUG repeat may explain the phenotype.…”

Section: Discussionmentioning

confidence: 92%

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGG GCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

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Section: Discussionmentioning

confidence: 92%

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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“…Its best-known function is in the pathogenesis of myotonic dystrophy 1 (DM1), a common multisystem disorder that chiefly affects the skeletal and cardiac muscles. In DM1, the disease gene DMPK1 harbors an expansion of CUG triplet repeats on its 3′ UTR which misregulate the RNA-binding factors MBNL1 and Celf1 (49). Both MBNL1 and Celf1 contribute to DM1 pathogenesis, but only Celf1 is responsible for muscle wasting and weakness.…”

Section: Discussionmentioning

confidence: 99%

miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification

Shen

Soibam

Benham

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the mechanisms of early cardiac fate determination may lead to better approaches in promoting heart regeneration. We used a mesoderm posterior 1 (Mesp1)-Cre/Rosa26-EYFP reporter system to identify microRNAs (miRNAs) enriched in early cardiac progenitor cells. Most of these miRNA genes bear MESP1-binding sites and active histone signatures. In a calcium transient-based screening assay, we identified miRNAs that may promote the cardiomyocyte program. An X-chromosome miRNA cluster, miR-322/-503, is the most enriched in the Mesp1 lineage and is the most potent in the screening assay. It is specifically expressed in the looping heart. Ectopic miR-322/-503 mimicking the endogenous temporal patterns specifically drives a cardiomyocyte program while inhibiting neural lineages, likely by targeting the RNA-binding protein CUG-binding protein Elav-like family member 1 (Celf1). Thus, early miRNAs in lineage-committed cells may play powerful roles in cell-fate determination by cross-suppressing other lineages. miRNAs identified in this study, especially miR-322/-503, are potent regulators of early cardiac fate.

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“…The deletion of D4Z4 units in 4q35 impairs DNA methylation and alters the expression of the DUX4 gene 13,14 . Patients with myotonic dystrophy type 1 may present subtle myotonia and it may be necessary to search for tenar muscle percussion myotonia 15 . Myotonic dystrophy type 2 presents clinical myotonia in less than half of the patients; myotonia may be absent even at neurophysiological investigation 15 .…”

Section: How Do We Know If Our Patients Have a Limb Girdle Muscular Dmentioning

confidence: 99%

“…Patients with myotonic dystrophy type 1 may present subtle myotonia and it may be necessary to search for tenar muscle percussion myotonia 15 . Myotonic dystrophy type 2 presents clinical myotonia in less than half of the patients; myotonia may be absent even at neurophysiological investigation 15 . Few patients with myotonic dystrophy type 2 present cataracts 15 .…”

Section: How Do We Know If Our Patients Have a Limb Girdle Muscular Dmentioning

confidence: 99%

“…Myotonic dystrophy type 2 presents clinical myotonia in less than half of the patients; myotonia may be absent even at neurophysiological investigation 15 . Few patients with myotonic dystrophy type 2 present cataracts 15 . Facial and jaw weakness, temporal atrophy, and ptosis are common in myotonic dystrophy type 1 patients.…”

Section: How Do We Know If Our Patients Have a Limb Girdle Muscular Dmentioning

confidence: 99%

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Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

Cotta¹,

Carvalho²,

da-Cunha-Júnior³

et al. 2014

Arq. Neuro-Psiquiatr.

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Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype.Keywords: muscular dystrophies, ultrasonography, biopsy, magnetic resonance imaging, neuromuscular diseases. RESUMOAs distrofias musculares progressivas cintura-membros são desordens neuromusculares hereditárias autossômicas heterogêneas. Elas produzem alterações distróficas à biópsia muscular e estão associadas a mutações em diversos genes envolvidos na estrutura e função muscular. Fluxograma diagnóstico, fotos, tabelas e diagramas ilustrados dos aspectos clínicos, laboratoriais e de imagem são apresentados para o diagnóstico diferencial de distrofias musculares cintura-membros autossômicas recessivas comuns, diagnosticadas atualmente em um centro de referência no Brasil. Exames de imagem pré-operatórios direcionam o local da biópsia muscular. O padrão de envolvimento muscular difere de acordo com o subtipo de distrofia muscular cintura-membros. A substituição fibroadiposa do tecido muscular é mais acentuada no compartimento posterior da coxa na calpainopatia e proteinopatia relacionada à fukutina; anterior da coxa na sarcoglicanopatia; difusa na coxa na disferlinopatia e teletoninopatia. O diagnóstico diferencial preciso das distrofias musculares cintura-membros é importante para o aconselhamento genético, orientação prognóstica, tratamento cardíaco e respiratório. Além disso poderá, no futuro, provavelmente, propiciar terapias gênicas específicas para cada subtipo.Palavras-chave: distrofias musculares, ultrassonografia, biópsia, imagem por ressonância magnética, doenças neuromusculares.

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The myotonic dystrophies: molecular, clinical, and therapeutic challenges

Cited by 409 publications

References 144 publications

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification

Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

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