Congenital myopathies: not only a paediatric topic

Jungbluth, Heinz; Voermans, Nicol C.

doi:10.1097/wco.0000000000000372

Cited by 36 publications

(9 citation statements)

References 86 publications

(115 reference statements)

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“… 2 There is substantial variability in the course and degree of functional impairment among the various CNMs. 6 , 7 , 8 Patients may present within the spectrum of the floppy infant syndrome, or with variable degrees of weakness with delayed gross motor milestones, respiratory and/or bulbar involvement. 7 , 9 , 10 , 11 Presentation is predominantly in infancy and childhood, but some patients do not present until their teens or adolescence with reduced exercise tolerance and mild ptosis, and often remain ambulatory throughout adult life.…”

Section: Introductionmentioning

confidence: 99%

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

et al. 2021

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Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic

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Section: Introductionmentioning

confidence: 99%

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

et al. 2021

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“…Muscle atrophy is a serious problem in most RyR1 myopathies155152. The CSA of Type I and IIa fibres in the IT mice are decreased at least in part due to decreased muscle protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…The ultrastructural changes detected in these mice were found to be consistent with premature muscle ageing14. However, for the most part, RyR1 myopathies are early onset and non-progressive or slowly progressive15 suggesting that the subset of I4895T mice with the severe, age-dependent phenotype are not truly representative of human early onset, slowly progressive RyR1 myopathy. In the present study we demonstrate that persistent endoplasmic reticulum (ER) stress/UPR and excessive mitochondrial reactive oxygen species (ROS) production contribute to muscle weakness and atrophy in mice with the I4895T mutation in RyR1 and that both the weakness and the atrophy are reversed by the treatment of these IT mice with a chemical chaperone, 4-phenylbutyrate (4PBA).…”

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confidence: 91%

A chemical chaperone improves muscle function in mice with a RyR1 mutation

et al. 2017

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Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca2+ release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticulum (SR) Ca2+ transient, resting cytosolic Ca2+ levels, muscle triadin content and calsequestrin (CSQ) localization to the junctional SR, and increases endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and mitochondrial ROS production. Treatment of mice carrying the I4895T mutation with a chemical chaperone, sodium 4-phenylbutyrate (4PBA), reduces ER stress/UPR and improves muscle function, but does not restore SR Ca2+ transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca2+ release is not the major driver of the myopathy. These findings suggest that 4PBA, an FDA-approved drug, has potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress.

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“…Clinical phenotype, in isolation, remains an inadequate basis for distinguishing between the different types of congenital myopathy, as it is often poorly specific, usually consisting of hypotonia and weakness (present at birth or appearing in infancy) and a static or slowly progressive clinical course. The clinical spectrum is nevertheless recognized to range from severe neonatal forms with congenital arthrogryposis to mild childhood-onset forms with non-progressive hyposthenia and low muscle tone [ 1 , 3 ].…”

Section: Clinical Characteristicsmentioning

confidence: 99%

Congenital myopathies: clinical phenotypes and new diagnostic tools

et al. 2017

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Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually from birth, and a static or slowly progressive clinical course. Historically, congenital myopathies have been classified on the basis of major morphological features seen on muscle biopsy. However, different genes have now been identified as associated with the various phenotypic and histological expressions of these disorders, and in recent years, because of their unexpectedly wide genetic and clinical heterogeneity, next-generation sequencing has increasingly been used for their diagnosis. We reviewed clinical and genetic forms of congenital myopathy and defined possible strategies to improve cost-effectiveness in histological and imaging diagnosis.

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Congenital myopathies: not only a paediatric topic

Cited by 36 publications

References 86 publications

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

A chemical chaperone improves muscle function in mice with a RyR1 mutation

Congenital myopathies: clinical phenotypes and new diagnostic tools

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