Clinical variability in calpainopathy: What makes the difference?

Paula, Flavia; Vainzof, Mariz; Passos‐Bueno, Maria Rita; Pavanello, Rita de Cássia M.; Matioli, Sérgio Russo; Anderson, Louise V.B.; Nigro, Vincenzo; Zatz, Mayana

doi:10.1038/sj.ejhg.5200888

Cited by 85 publications

(71 citation statements)

References 29 publications

(44 reference statements)

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“…They showed slightly different clinical picture and evolution. Although in both the onset of symptoms was at 12 years, case 1 showed a faster progression, confirming the intra-family variability in calpainopathies, which had already been demonstrated in other studies 6,7 . Interestingly, both cases showed, in serial blood counts, persistent eosinophilia, which has been reported in patients with mutations in the CAPN3 gene and eosinophilic myositis 17 .…”

Section: Discussionsupporting

confidence: 85%

Limb-girdle muscular dystrophy type 2A in Brazilian children

Albuquerque

Neto

Silva

et al. 2015

Arq. Neuro-Psiquiatr.

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Calpainopathy is an autosomal recessive limb girdle muscular dystrophy (LGMD2A) caused by mutations in CAPN3 gene. Objective To present clinical and histological findings in six children with a molecular diagnosis of LGMD2A and additionally the MRI findings in two of them. Method We retrospectively assessed medical records of 6 patients with mutation on CAPN3 gene. Results All patients were female (three to 12 years). The mean of age of disease onset was 9 years. All of them showed progressive weakness with predominance in lower limbs. Other findings were scapular winging, joint contractures and calf hypertrophy. One female had a more severe phenotype than her dizygotic twin sister that was confirmed by muscle MRI. Muscle biopsies showed a dystrophic pattern in all patients. Conclusion In this cohort of children with LGMD2A, the clinical aspects were similar to adults with the same disorder.

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Section: Discussionsupporting

confidence: 85%

Limb-girdle muscular dystrophy type 2A in Brazilian children

Albuquerque

Neto

Silva

et al. 2015

Arq. Neuro-Psiquiatr.

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“…Interestingly, previous reports had indicated an early onset in men rather than in women, difference relative to wheelchair dependent patients between genders or a more rapid progression in men 23, 31, 32. Interestingly, a difference in fiber atrophy between genders has recently been reported in LGMD,33 a fact which may support of this dissimilarity.…”

Section: Discussionmentioning

confidence: 86%

Natural history of LGMD2A for delineating outcome measures in clinical trials

Richard

Hogrel

Stockholm

et al. 2016

Ann Clin Transl Neurol

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ObjectiveLimb‐girdle muscular dystophy 2A (LGMD2A, OMIM) is a slowly progressive myopathy caused by the deficiency in calpain 3, a calcium‐dependent cysteine protease of the skeletal muscle.MethodsIn this study, we carried out an observational study of clinical manifestations and disease progression in genetically confirmed LGMD2A patients for up to 4 years. A total of 85 patients, aged 14–65 years, were recruited in three centers located in metropolitan France, the Basque country, and the Reunion Island. They were followed up every 6 months for 2 years and a subgroup was assessed annually thereafter for two more years. Data collected for all patients included clinical history, blood parameters, muscle strength assessed by manual muscle testing (MMT) and quantitative muscle testing, functional scores, and pulmonary and cardiac functions. In addition, CT scans of the lower limbs were performed in a subgroup of patients.ResultsOur study confirms the clinical description of a slowly progressive disorder with onset in the first or second decade of life with some degree of variability related to gender and mutation type. The null mutations lead to a more severe phenotype while compound heterozygote patients are the least affected. Muscle weakness is remarkably symmetrical and predominant in the axial muscles of the trunk and proximal muscles of the lower limb. There was a high correlation between the weakness at individual muscle level as assessed by MMT and the loss of density in CT scan analysis.InterpretationAll the generated data will help to determine the endpoints for further clinical studies.

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“…LGMD2A patients with missense mutations may present a faint or almost normal 94-kDa calpain band (39,40), suggesting that some mutations may affect protein function without eliminating the protein from muscle. A normal amount of calpain was found in sarcoglycanopathies (40,41), and normal SG proteins were observed in calpain 3-deficient LGMD2A patients (37), suggesting no direct relationship between calpain 3 and the SG complex.…”

Section: Calpainopathymentioning

confidence: 99%

Protein defects in neuromuscular diseases

Vainzof

Zatz

2003

Braz J Med Biol Res

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Muscular dystrophies are a heterogeneous group of genetically determined progressive disorders of the muscle with a primary or predominant involvement of the pelvic or shoulder girdle musculature. The clinical course is highly variable, ranging from severe congenital forms with rapid progression to milder forms with later onset and a slower course. In recent years, several proteins from the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3), from the extracellular matrix (a2-laminin, collagen VI), from the sarcomere (telethonin, myotilin, titin, nebulin), from the muscle cytosol (calpain 3, TRIM32), from the nucleus (emerin, lamin A/C, survival motor neuron protein), and from the glycosylation pathway (fukutin, fukutin-related protein) have been identified. Mutations in their respective genes are responsible for different forms of neuromuscular diseases. Protein analysis using Western blotting or immunohistochemistry with specific antibodies is of the utmost importance for the differential diagnosis and elucidation of the physiopathology of each genetic disorder involved. Recent molecular studies have shown clinical inter-and intra-familial variability in several genetic disorders highlighting the importance of other factors in determining phenotypic expression and the role of possible modifying genes and protein interactions. Developmental studies can help elucidate the mechanism of normal muscle formation and thus muscle regeneration. In the last fifteen years, our research has focused on muscle protein expression, localization and possible interactions in patients affected by different forms of muscular dystrophies. The main objective of this review is to summarize the most recent findings in the field and our own contribution.

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Clinical variability in calpainopathy: What makes the difference?

Cited by 85 publications

References 29 publications

Limb-girdle muscular dystrophy type 2A in Brazilian children

Limb-girdle muscular dystrophy type 2A in Brazilian children

Natural history of LGMD2A for delineating outcome measures in clinical trials

Protein defects in neuromuscular diseases

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