The clinical course of calpainopathy (LGMD2A) and dysferlinopathy (LGMD2B)

Angelini, C.; Nardetto, Lucia; Borsato, C.; Padoan, Roberta; Fanin, Marina; Nascimbeni, Anna Chiara; Tasca, Elisabetta

doi:10.1179/174313209x380847

Cited by 61 publications

(60 citation statements)

References 24 publications

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“…These diseases are established as late-adult onset both clinically (Gordon et al, 1993; Klinge et al, 2008; Angelini et al, 2010, 2011; Gayathri et al, 2011) as well as in preclinical models (Turk et al, 2006; Nemoto et al, 2007; Ng et al, 2012). While these disorders have been linked to the mutation or ablation of the dysferlin gene ( DYSF ) (Illarioshkin et al, 2000; Vainzof et al, 2001; Nguyen et al, 2005; Cacciottolo et al, 2011), a consensus on the mechanistic basis of disease has not been reached.…”

Section: Discussionmentioning

confidence: 99%

Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle

et al. 2014

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Oxidative stress is a critical disease modifier in the muscular dystrophies. Recently, we discovered a pathway by which mechanical stretch activates NADPH Oxidase 2 (Nox2) dependent ROS generation (X-ROS). Our work in dystrophic skeletal muscle revealed that X-ROS is excessive in dystrophin-deficient (mdx) skeletal muscle and contributes to muscle injury susceptibility, a hallmark of the dystrophic process. We also observed widespread alterations in the expression of genes associated with the X-ROS pathway and redox homeostasis in muscles from both Duchenne muscular dystrophy patients and mdx mice. As nuclear factor erythroid 2-related factor 2 (Nrf2) plays an essential role in the transcriptional regulation of genes involved in redox homeostasis, we hypothesized that Nrf2 deficiency may contribute to enhanced X-ROS signaling by reducing redox buffering. To directly test the effect of diminished Nrf2 activity, Nrf2 was genetically silenced in the A/J model of dysferlinopathy—a model with a mild histopathologic and functional phenotype. Nrf2-deficient A/J mice exhibited significant muscle-specific functional deficits, histopathologic abnormalities, and dramatically enhanced X-ROS compared to control A/J and WT mice, both with functional Nrf2. Having identified that reduced Nrf2 activity is a negative disease modifier, we propose that strategies targeting Nrf2 activation may address the generalized reduction in redox homeostasis to halt or slow dystrophic progression.

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Section: Discussionmentioning

confidence: 99%

Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle

et al. 2014

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“…However, the clinical course is characterized by great variability, ranging from severe forms with onset in the first decade and rapid progression to milder forms with later onset and slower course [1,2]. Serum creatine kinase is usually highly elevated and the muscle morphology shows dystrophic features.…”

Section: Introductionmentioning

confidence: 99%

Calpain 3 is important for muscle regeneration: Evidence from patients with limb girdle muscular dystrophies

Hauerslev

Sveen

Dunø

et al. 2012

BMC Musculoskelet Disord

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BackgroundLimb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration.MethodsWe studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers.ResultsWe found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the CAPN3 gene.ConclusionsOur findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes.

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“…For example, calpain 3 ( CAPN3 ) mutations have been associated with autosomal recessive limb girdle muscular dystrophy type 2A (LGMD2A), which, in a subgroup of patients, may present with scapulohumeral muscle weakness resembling FSHD, a milder phenotype compared to the classic form, with later onset and no contractures 20. Diagnosis of LGMD2A is currently based on western blot analysis of a muscle biopsy, but genetically confirmed patients with normal protein expression levels have been reported,21 22 and, interestingly, some of them displayed a scapulohumeral phenotype 20…”

Section: Introductionmentioning

confidence: 99%

Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity

et al. 2011

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Objective To identify the genetic and epigenetic defects in patients presenting with a facioscapulohumeral (FSHD) clinical phenotype without D4Z4 contractions on chromosome 4q35 tested by linear gel electrophoresis (LGE) and Southern blot analysis. Design and patients We studied 16 patients displaying an FSHD-like phenotype, with normal cardiovascular and respiratory function, a myopathic pattern on EMG, and a muscle biopsy being normal or displaying only mild and a specific dystrophic changes. We sequenced the genes calpain 3 (CAPN3), valosin containing protein (VCP) and four and a half LIM domains protein 1 (FHL1) and we analyzed the D4Z4 repeat arrays by extensive genotyping and DNA methylation analysis. Results We identified one patient carrying a complex rearrangement in the FSHD locus that masked the D4Z4 contraction associated with FSHD1 in standard genetic testing, one patient with somatic mosaicism for the D4Z4 4q35 contraction, six patients that were diagnosed with FSHD2, four patients with CAPN3 mutations, two patients with a VCP mutation, No mutations were detected in FHL1, and in two patients we could not identify the genetic defect. Conclusions In patients presenting an FSHD-like clinical phenotype with a negative molecular testing for FSHD consider: 1) detailed genetic testing including D4Z4 contraction of permissive hybrid D4Z4 repeat arrays, p13E-11 probe deletions, D4Z4 hypomethylation in absence of repeat contraction as observed in FSHD2, 2) mutations in CAPN3 even in the absence of protein deficiency on western blot analysis 3) VCP mutations even in the absence cognitive impairment, Paget disease and typical inclusion in muscle biopsy.

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The clinical course of calpainopathy (LGMD2A) and dysferlinopathy (LGMD2B)

Abstract: Our data show that besides the clinical differences within each group of patients, the two forms of LGMD present distinctive clinical features. The various phenotypes and courses can be attributed to specific pathogenetic mechanisms and might suggest differential therapeutic strategies.

Cited by 61 publications

References 24 publications

Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle

Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle

Calpain 3 is important for muscle regeneration: Evidence from patients with limb girdle muscular dystrophies

Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity

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