Limb girdle muscular dystrophy: A pathological and immunohistochemical reevaluation

Kooi, Anneke J. van der; Ginjaar, H.B.; Busch, H. F. M.; Wokke, John H. J.; Barth, Peter; Visser, Marjolein

doi:10.1002/(sici)1097-4598(199805)21:5<584::aid-mus4>3.0.co;2-4

Cited by 13 publications

(1 citation statement)

References 55 publications

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“…Although muscle biopsy findings strongly indicated a primary neurogenic defect, NCV studies revealed almost normal findings. Given that neurogenic changes in muscle biopsies could also be found in several limb-girdle-muscular-dystrophies (LGMDs) [19], in combination with the proximal weakness in our case, a primary myopathic disease was assumed. He developed severe dysphagia and respiratory insufficiency later before he lost his ability to walk in his early teens due to the active progression.…”

Section: Clinical and Microscopic Findings Of The P(a20s)-sptlc1-patientmentioning

confidence: 90%

New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1

Kölbel

Kraft

Hentschel

et al. 2022

Genes

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Serine palmitoyltransferase long chain base subunit 1 (SPTLC1) encodes a serine palmitoyltransferase (SPT) resident in the endoplasmic reticulum (ER). Pathological SPTLC1 variants cause a form of hereditary sensory and autonomic neuropathy (HSAN1A), and have recently been linked to unrestrained sphingoid base synthesis, causing a monogenic form of amyotrophic lateral sclerosis (ALS). It was postulated that the phenotypes associated with dominant variants in SPTLC1 may represent a continuum between neuropathy and ALS in some cases, complicated by additional symptoms such as cognitive impairment. A biochemical explanation for this clinical observation does not exist. By performing proteomic profiling on immortalized lymphoblastoid cells derived from one patient harbouring an alanine to serine amino acid substitution at position 20, we identified a subset of dysregulated proteins playing significant roles in neuronal homeostasis and might have a potential impact on the manifestation of symptoms. Notably, the identified p.(A20S)-SPTLC1 variant is associated with decrease of transcript and protein level. Moreover, we describe associated muscle pathology findings, including signs of mild inflammation accompanied by dysregulation of respective markers on both the protein and transcript levels. By performing coherent anti-Stokes Raman scattering microscopy, presence of protein and lipid aggregates could be excluded.

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Section: Clinical and Microscopic Findings Of The P(a20s)-sptlc1-patientmentioning

confidence: 90%

New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1

Kölbel

Kraft

Hentschel

et al. 2022

Genes

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Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients

et al. 2005

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Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal-recessive disorder characterized by selective atrophy and progressive weakness of proximal girdle muscles. LGMD2A, the most prevalent form of LGMD, is caused by mutations in the CAPN3 gene that encodes the skeletal muscle-specific member of the calpain family, calpain-3 (p 94). We examined the histopathologic and molecular pathologic findings in 14 Czech LGMD2A patients. Analysis of the CAPN3 gene was performed at the mRNA level, using reverse transcription-polymerase chain reaction (RT-PCR) and sequencing, and/or DNA level, using PCR and denaturing high-performance liquid chromatography (DHPLC). Our results confirm that mutation 550 delA is the most frequent CAPN3 defect in Czech LGMD2A patients (9 alleles of 28). Furthermore, we established that, in a patient with the 550 delA/R490W genotype, mRNA carrying frameshift mutation 550 delA was not detected, probably due to its degradation by nonsense-mediated mRNA decay. In muscle biopsies of two LGMD2A patients, a neurogenic pattern simulating a neurogenic lesion was observed. Immunoblot analysis revealed the deficiency of p 94 in all genetically confirmed cases of LGMD2A, and secondary dysferlin deficiency was demonstrated on muscle membranes in 6 patients using immunofluorescence. Thus, we find a combination of DNA and mRNA mutational analysis to be useful in the diagnosis of LGMD2A. Moreover, our study expands the spectrum of calpainopathies to cases that simulate a neurogenic lesion in muscle biopsies, and the knowledge of possible secondary deficiencies of muscular proteins also contributes to a diagnosis of LGMD2A.

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The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy

et al. 2005

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Oxidative stress and nuclear factor-kappaB (NF-kappaB) activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand N(epsilon)-carboxymethyllysine (CML) results in the activation of NF-kappaB and the production of proinflammatory cytokines. To determine whether engagement of RAGE contributes to the pathogenesis of inflammatory myopathies, we performed immunohistochemical studies on the presence of CML-modified proteins, RAGE and activated NF-kappaB in muscle biopsies of patients with polymyositis (PM, n=10), dermatomyositis (DM, n=10), limb girdle muscular dystrophy (LGMD, n=10) and in 10 controls with normal muscle biopsy results. In inflammatory myopathies CML, RAGE and NF-kappaB were detected in mononuclear cells and in regenerating muscle fibers. CML, NF-kappaB and, to a lesser extent, RAGE were also found in degenerating muscle fibers, but colocalization of CML, RAGE and NF-kappaB was only seen in infiltrating mononuclear cells and regenerating muscle fibers. Immunofluorescence double labeling demonstrated an expression of CML, RAGE and NF-kappaB in CD4-, CD8-, CD22- and CD68-positive mononuclear cells. Western blot analysis showed an increased immunoreactivity for CML-modified proteins in PM and DM. In LGMD, CML, RAGE and NF-kappaB were found in regenerating muscle fibers and less frequently in degenerating muscle fibers, and with lower staining intensities than in inflammatory myopathies. Our data suggests that the CML-RAGE-NF-kappaB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM. RAGE-mediated NF-kappaB activation may be involved in muscle fiber regeneration in inflammatory myopathies and LGMD.

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Limb girdle muscular dystrophy: A pathological and immunohistochemical reevaluation

Cited by 13 publications

References 55 publications

New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1

New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1

Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients

The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy

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