904 research outputs found
Prognostic factors in mild dystrophinopathies.
No full textAngelini C, Fanin M, Freda MP, Martinello F, Miorin M, Melacini P, Siciliano G, Pegoraro E, Rosa M, Danieli G
Protein and genetic diagnosis of limb girdle muscular dystrophy type 2A: The yield and the pitfalls
No full textLimb girdle muscular dystrophy type 2A (LGMD2A) is the most frequent form of LGMD worldwide. Comprehensive clinical assessment and laboratory testing is essential for diagnosis of LGMD2A. Muscle immunoblot analysis of calpain-3 is the most useful tool to direct genetic testing, as detection of calpain-3 deficiency has high diagnostic value. However, calpain-3 immunoblot testing lacks sensitivity in about 30% of cases due to gene mutations that inactivate the enzyme. The best diagnostic strategy should be determined on a case-by-case basis, depending on which tissues are available, and which molecular and/or genetic methods are adopted. In this work we survey the current knowledge, advantages, limitations, and pitfalls of protein testing and mutation detection in LGMD2A and provide an update of genetic epidemiology
Average Case Complexity of Unbounded Fanin Circuits
No full textHastad has shown that functions like PARITY cannot be computed by unbounded fanin circuits of small depth and polynomial size. We generalize this result in two directions. First, we obtain the same tight lower bound for the average case. This is done by estimating the average delay -- the natural generalization of circuit depth to an average case measure -- of unbounded fanin circuits of polynomial size, resp. their error probability given an upper bound on the maximal delay. These bounds are obtained by extending the probabilistic restriction method to an average case setting. Secondly, we completely classify the set of parallel prefix functions -- for which PARITY is just one example -- with respect to their average delay in unbounded fanin circuits of a given size. It is shown that only two cases can occur: a parallel prefix functions either has the same complexity as PARITY, that is the average delay has to be of order \Theta(log n= log log s) for circuit of size s , or it can be c..
Pathogenesis, clinical features and diagnosis of sarcoglycanopathies
No full textIntroduction: By reviewing the literature from the last twenty years we present an accurate assessment of the state of the art in the pathogenesis and clinical presentations of sarcoglycanopathies, as well as the progress in diagnosis and treatment. Areas covered: Sarcoglycanopathies usually have a childhood onset but they can occur in adults with a limb girdle phenotype. Four main genes are expressed in the sarcoglycan complex. Cases with beta- or delta-sarcoglycan primary deficiency often present severe cardiac and respiratory complications. A defect of nitric oxide synthase might contribute to the pathogenesis of cardiac involvement and fatigue. Neuroimaging shows that muscle involvement affects mainly proximal muscle groups, followed by fibro-fatty replacement. Expert opinion: In cases of children with high creatine kinase levels and weakness or adults with limb girdle weakness, immunolabelling of muscle biopsy with anti-sarcoglycan antibodies may suggest the diagnosis, which should be confirmed by mutation analysis in the sarcoglycan genes. New genetic technologies, such as next generation sequencing, might be useful to obtain a molecular diagnosis, which is necessary for genetic counselling
Defective assembly of sarcoglycan complex in patients with β-sarcoglycan gene mutations. Study of aneural and innervated cultured myotubes
No full textMutations in the sarcoglycan (SG) genes cause autosomal recessive muscular dystrophies. The absence of each SG complex component in muscle impairs the proper assembly of the entire SG complex, resulting in sarcolemmal damage. We investigated the consequences of β-SG gene mutations in cultured muscle from two β-SG mutated patients, and analysed each individual SG protein expression by cross-sectional immunocytochemistry and Western blot in aneural and innervated myotubes. Patients' muscle biopsy showed total loss of SG complex; however, a limited amount of β-SG was detected in aneural and innervated myotubes, where the protein was localized to the plasma membrane. This paradoxical β-SG expression can be attributable to antibody cross-reaction or to the expression of an unknown SG isoform specific of immature muscle. In our cultured myotubes, the other components of the SG complex were absent, suggesting that β-SG gene mutations result in a defective assembly of the entire SG complex in early stages of muscle development, and that the role of β-SG is crucial for the normal structure and/or function of the SG complex in the sarcolemma
Muscle atrophy in Limb Girdle Muscular Dystrophy 2A: A morphometric and molecular study
No full textAims: The peculiar clinical features and the pathogenic mechanism related to calpain-3 deficiency (impaired sarcomere remodelling) suggest that the ubiquitin-proteasome degradation pathway may have a crucial role in Limb Girdle Muscular Dystrophy 2A (LGMD2A). We therefore investigated muscle atrophy and the role of the ubiquitin-proteasome and lysosomal-autophagic degradation pathways. Methods: We selected 25 adult male LGMD2A patients (and seven controls), classified them using clinical severity score, analysed muscle fibre size by morphometry and protein and/or transcriptional expression levels of the most important atrophy- and autophagy-related genes (MuRF1,atrogin1,LC3,p62,Bnip3). Results: Muscle fibre size was significantly lower in LGMD2A than in controls and it was significantly correlated with patients' clinical disability score recorded at the time of biopsy, suggesting that functional and structural muscle impairment are dependent. The large majority of atrophic fibres originate from a mechanism different from regeneration, as assessed by neonatal myosin immunolabelling. As compared with controls, LGMD2A muscles have higher MuRF1 (but not atrogin1) protein and MuRF1 gene expression levels, and MuRF1 protein levels significantly correlated with both muscle fibre size and clinical disability score. LGMD2A muscles have slightly increased levels of LC3-II and p62 proteins and a significant up-regulation of p62 and Bnip3 gene expression. Conclusions: In LGMD2A muscles the activation of the atrophy programme appeared to depend mainly upon induction of the ubiquitin-proteasome system and, to a lesser extent, the autophagic-lysosomal degradation pathway. © 2013 British Neuropathological Society
Autophagy in Natural History and After ERT in Glycogenosis Type II
No full textWe studied the role of autophagy in a series of 10 infantile-, juvenile-, and adult-onset GSDII patients and investigated autophagy blockade in successive biopsies of adult cases during disease natural history. We also correlated the autophagosome accumulation and efficiency of enzyme replacement therapy (ERT) in four treated cases (two infantile and two juvenile-adult onsets). The autophagic flux was monitored by measuring the amount of p62-positive protein aggregates and compared, together with fibre vacuolisation, to fibre atrophy. A blocked autophagic flux resulted in p62 accumulation, increased vacuolisation, and progressive atrophy of muscle fibres in biopsies collected from patients during natural history. On the contrary, in the GSDII cases early treated with ERT, the autophagic flux improved and muscle fibre atrophy, fibre vacuolisation, and acid phosphatase activity decreased. The functionality of the autophagy-lysosome system is essential in GSDII muscle, which is characterised by the presence of swollen glycogen-filled lysosomes and autophagic build-up. Defining the role of autophagy and its relationship with muscle loss is critical for understanding the disease pathogenesis, for developing new therapies, and for improving ERT efficacy in GSDII
Gender difference in limb-girdle muscular dystrophy: A muscle fiber morphometric study in 101 patients
No full textAims: Limb girdle muscular dystrophies (LGMD), a genetically and clinically heterogeneous group of neuromuscular disorders, may show gender differences in the disease severity. We aimed to measure the extent of muscle fiber atrophy and evaluate possible gender differences at fiber level. Methods: We conducted a thorough morphometric analysis of muscle fiber size and fiber area in 101 muscles from patients with various forms of LGMD (43 LGMD2A, 30 LGMD2B, 21 LGMD2C-2D-2E, 7 LGMD1C) and 12 normal controls. Results: Reduced fiber size (atrophy) was pronounced in LGMD2A and LGMD2B, while LGMD1C showed a significant fiber hypertrophy. When we compared LGMD patients and controls of the same gender, males with LGMD2A and LGMD2B showed significantly higher fiber atrophy than control males, whereas female LGMD patients had similar values to female controls, suggesting a gender difference in muscle fiber atrophy. Discussion: Less recovery to disuse atrophy in men than in women has been attributed to the possibility that in women a smaller initial muscle size associated to endocrine factors could attenuate gender-specific muscle loss. The possibility that males with LGMD may be clinically more severely affected than females has been explored, but the mechanism remains elusive. © 2014 Dustri-Verlag Dr. K. Feistle
Muscle atrophy, ubiquitin-proteasome, and autophagic pathways in dysferlinopathy
No full textIntroduction: Muscle fiber atrophy and the molecular pathways underlying this process have not been investigated in dysferlinopathy patients. Methods: In 22 muscles from dysferlinopathy patients we investigated fiber atrophy by morphometry and ubiquitin-proteasome and autophagic pathways using protein and/or transcriptional analysis of atrophy- and autophagy-related genes (MuRF1, atrogin1, LC3, p62, Bnip3). Results: Dysferlinopathy showed significant fiber atrophy and higher MuRF-1 protein and mRNA levels, which correlated with fiber size, suggesting activation of the atrophy program by proteasome induction. Conclusions: Some of the MuRF-1 upregulation and proteasome induction may be attributed to the prominent regeneration found. A potential role of impaired autophagy was suggested by p62-positive protein aggregates in atrophic fibers and significantly higher levels of LC3-II and p62 proteins and overexpression of p62 and Bnip3 mRNA. Damaged muscle fibers and prominent inflammatory changes may also enhance autophagy due to the insufficient level of proteasomal degradation of mutant dysferlin. © 2014 Wiley Periodicals, Inc
Correction to: Correlation between IPSET‐t risk at diagnosis and subsequent hemorrhage in patients with essential thrombocythemia; a single institution experience (Annals of Hematology, (2024), 103, 2, (443-448), 10.1007/s00277-023-05578-8)
No full textThe author regrets that in the original publication, the name of Matteo Liberi who contributed to data collection and analysis, has not been included. The correct authors’ list is presented below. Luca Tosoni1, Matteo Liberi1, Gianluca Morelli1, Maria Elena Zannier1, Davide Lazzarotto1, Carla Filì1, Erica Simeone1, Giulia Battaglia1, Chiara Callegari1, Matteo Fanin1, Daniela Damiani1,2, Renato Fanin1,2, Mario Tiribelli1,2 The author would like to apologize for any inconvenience caused. The original article has been corrected
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