Myopathy with muscle spindle excess: A new congenital neuromuscular syndrome?

Selcen, Duygu; Kupsky, William J.; Benjamins, David

doi:10.1002/1097-4598(200101)24:1<138::aid-mus22>3.0.co;2-3

Cited by 24 publications

(5 citation statements)

References 21 publications

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“…Muscle biopsies from CS individuals have shown excess muscle spindles (Burgt, 2007;de Boode et al, 1996;Selcen et al, 2001), and we reported that skeletal muscle biopsies from CS patients showed excessively small skeletal muscle fibers with a type 2 myofiber predominance (Tidyman et al, 2011).…”

Section: Introductionmentioning

confidence: 72%

MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

Tidyman

Goodwin

Maeda

et al. 2021

Disease Models &Amp; Mechanisms

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Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes due to mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due in part to an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction of p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.

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Section: Introductionmentioning

confidence: 72%

MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

Tidyman

Goodwin

Maeda

et al. 2021

Disease Models &Amp; Mechanisms

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“…It is difficult to discern if this is due to activity levels, limitations of movement either from central or peripheral neuropathies, or a primary myopathy. However, several individuals with Costello syndrome have been reported with weakness and an increased density of muscle spindles were shown in skeletal muscle biopsies in five individuals in which creatine kinase concentrations were normal and electromyogram measurements normal except for one individual with a myopathic pattern [de Boode et al, 1996; Selcen et al, 2001; Stassou et al, 2005; van der Burgt et al, 2007].…”

Section: Musculoskeletal Overlapmentioning

confidence: 99%

The musculoskeletal phenotype of the RASopathies

Stevenson

Yang

2011

American J of Med Genetics Pt C

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The Ras/MAPK signal transduction pathway is critical for the regulation of proliferation and differentiation of multiple cell types. Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in the NF1 gene resulting in an increased Ras signaling cascade. Subsequently, additional syndromes with some overlapping physical manifestations such as Noonan syndrome, Costello syndrome, and cardiofaciocutaneous (CFC) syndrome were also shown to be due in many cases to mutations in genes encoding for proteins interacting with the Ras/MAPK pathway. Although neurocutaneous manifestations have been considered hallmark features for these disorders, multiple organ systems including the musculoskeletal system are affected. Some of the overlapping musculoskeletal phenotypes include scoliosis, kyphosis, anterior chest wall anomalies, pes planus, osteopenia, and hand anomalies. However, there are also discordant skeletal phenotypes such as sphenoid wing dysplasia and tibial pseudarthrosis seen only in NF1. We provide an overview of the concordant and discordant musculoskeletal manifestations in the RASopathies.

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“…The link between skeletal myopathy and RASopathies first emerged from early case reports on hypotonic infants with CS- or NS-like clinical features. Skeletal muscle biopsies from these patients revealed an increase in the number of intrafusal muscle fibers ( Box 1 ), or muscle spindles ( Box 1 ), and the presence, in most, of small, atrophic, extrafusal muscle fibers ( de Boode et al, 1996 ; Selcen et al, 2001 ; Stassou et al, 2005 ; van der Burgt et al, 2007 ). These histological findings, together with the weakened muscles observed in patients upon clinical examination, led to a more detailed, systematic examination of skeletal muscle in patients with RASopathy, including assessment of muscle biopsies obtained from a cohort of patients aged 11 weeks to 8 years with a molecular diagnosis of CS or CFC ( Tidyman et al, 2011 ).…”

Section: Skeletal Muscle Histology In Rasopathiesmentioning

confidence: 99%

RASopathies – what they reveal about RAS/MAPK signaling in skeletal muscle development

Rauen,

Tidyman

2024

Disease Models &Amp; Mechanisms

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RASopathies are rare developmental genetic syndromes caused by germline pathogenic variants in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Although the incidence of each RASopathy syndrome is rare, collectively, they represent one of the largest groups of multiple congenital anomaly syndromes and have severe developmental consequences. Here, we review our understanding of how RAS/MAPK dysregulation in RASopathies impacts skeletal muscle development and the importance of RAS/MAPK pathway regulation for embryonic myogenesis. We also discuss the complex interactions of this pathway with other intracellular signaling pathways in the regulation of skeletal muscle development and growth, and the opportunities that RASopathy animal models provide for exploring the use of pathway inhibitors, typically used for cancer treatment, to correct the unique skeletal myopathy caused by the dysregulation of this pathway.

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Myopathy with muscle spindle excess: A new congenital neuromuscular syndrome?

Cited by 24 publications

References 21 publications

MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

The musculoskeletal phenotype of the RASopathies

RASopathies – what they reveal about RAS/MAPK signaling in skeletal muscle development

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