Integrins, a subgroup of adhesion receptors, are transmembrane glycoproteins that mediate interactions between cytoplasm and the extracellular environment. These interactions influence, among others, ...events such as cell migration, proliferation, and differentiation. Differential expression of integrins is developmentally regulated in the peripheral nervous system (PNS) and is associated with crucial events in both physiological and pathological processes. Preliminary studies suggest that integrin expression influences neural crest cell migration, axonal outgrowth, and Schwann cell differentiation. Similarly, the abnormal expression of integrins or their ligands, is associated with degenerative, inflammatory, and malignant disorders of the PNS. Finally, integrins participate in the complex interactions that promote repair of the PNS. A better comprehension of the role of integrins in the PNS, their protein interactions and transducing signals is being achieved by selected biochemical and genetic experiments. Here we review a large bias of evidence suggesting the key functions for integrins in the PNS.
LMNA gene mutations have been associated with several diseases. Some of them are muscle disorders, including the autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (EDMD2 and ...EDMD3), limb-girdle muscular dystrophy 1B (LGMD1B) and congenital muscular dystrophy (MDCL). With few exceptions, most of the studies are focused on one of these phenotypes and data on large cohorts of myopathic patients are lacking. The aim of our study was to evaluate clinical, neurophysiologic, histological and molecular features of 77 myopathic patients mutated in LMNA gene and followed in different Italian neuromuscular centres. Patients with predominant or exclusively progeroid/lipodystrophic or cardiac phenotype were excluded. The cohort included 36 (46.8%) patients with LGMD1B phenotype, 30 (39%) with EDMD2 and 11 with MDCL (14.3%). Mean age at onset was 10.3 ± 12.3 years in patients with EDMD2, 29.5 ± 17.6 in LGMD1B and 0.4 ± 0.5 in MDCL. Independent walking was reached in all patients, with the exception of 4 (5.2%) MDCL, who never acquired the ability to stand up. Another 4 (5.2%) patients (3 LGMD1B and 1 EDMD2) lost ambulation, and 3 EDMD2 (3.9%), required monolateral support to walk. Cardiac involvement was found in 57 (74%) patients. Pacemaker or ICD were implanted in 42 (54.5%) patients (21 EDMD2, 18 LGMD1B and 3 MDCL), while heart transplant was performed in 5 (6.5%) patients (3 EDMD2 and 2 with LGMD1B). Six (7.8%) patients died due to cardiac problems (3 EDMD2 and 3 MDCL). Only 5 (6.5%) patients required non-invasive ventilation (4 EDMD2 and 1 CMD), confirming that respiratory problems are not a major issue in LMNA-associated myopathies. Ten novel mutations were detected. Despite EDMD2, LGMD1B and MDCL phenotypes are part of a continuum spectrum, their identification is clinically and prognostically relevant.
Abstract
Background
The current Risk Score for Life-Threatening Ventricular Tachyarrhythmias (LTVT) in LMNA cardiomyopathy does not consider the frequent association between cardiac and neuromuscular ...phenotypes as a part of a multisystemic disease. In particular, the prognostic value of tendon retractions (TR) has been recently described.
Objectives
We aimed to assess the prognostic role of TR in a cohort of probands with LMNA cardiomyopathy undergoing multidisciplinary workup at a referral center.
Methods
We included 28 probands with LMNA cardiomyopathy undergoing regular, prospective follow-up at a national referral center for laminopathies. All patients underwent extensive baseline characterization, including complete neuromuscular examination and systematic assessment of TR. Indications to implantable cardioverter defibrillators (ICD) for the primary prevention of sudden cardiac death were guideline-based. Patients were clustered in tertiles according to their baseline LMNA-Risk Score. The primary endpoint was the 5-year occurrence of LTVT, namely arrhythmic cardiac death, VF, sustained VT, or appropriate ICD shocks.
Results
Of the 28 probands with LMNA cardiomyopathy (mean age 33±15 years, 50% males, mean LVEF 55±14 %), neurological assessment identified 14 patients (50%) with TR, including 8 cases with no other signs of neuromuscular involvement. At baseline assessment, the median LMNA-Risk Score was 10% (IQR 6-20%). By 5-year follow-up, 9 patients (32%) met the primary endpoint, including three patients in the lowest tertiles of risk (median LMNA-Risk Score 23, range 6-15%). While other variables showed no remarkable differences between groups, the prevalence of TR was 78% among cases experiencing LTVT and 37% otherwise. The presence of either baseline LMNA-Risk score at the highest tertile (>17%) or TR was 100% predictive of 5-year LTVT (9/9 vs. 7/19, p=0.003). Results did not change after reassessment by the end of follow-up (15±5 years).
Conclusions
Our preliminary data suggest that the inclusion of TR in risk stratification may result in a better patient selection for primary prevention ICD implant in LMNA cardiomyopathy.
Abstract Six minute walk test (6MWT), timed items and North Star Ambulatory Assessment (NSAA) are increasingly used as possible outcome measures in clinical trials in Duchenne Muscular Dystrophy ...(DMD). Longitudinal data have previously been reported following changes in their scores over a 12 month period. The aim of the study was to assess 6MWT and NSAA in a cohort of 119 ambulant DMD boys over 24 months in order to establish the spectrum of possible changes over a longer period of time. The study is a longitudinal multicentric cohort study. 119 ambulant DMD patients were assessed using 6MWT, NSAA at baseline 12 and 24 months. Clinical data including age and steroid treatment were collected. During the 24 months of the study, we observed a progressive decline in both measures that was more obvious in the second year. Not all the DMD boys in our cohort showed a decline as young boys showed some improvement in their 6MWT and NSAA scores up to the age of 7. Fifteen patients (12.6%) lost the ability to walk independently: 2/15 by the end of the first year and the other 13 in the second year. Another 22 patients (21.1%) were still able to walk independently but were unable to get up from supine (8/22 at baseline, 4 at 12 months, 10 at 24 months). Four children also lost the ability to perform the 6MWT (2 at 12 months and the other 2 at 24 months). This study provides longitudinal data of NSAA and 6MWT over a 24 month period. These data can be useful when designing a clinical trial.
We performed a retrospective and prospective observational study to investigate whether the T lymphocyte activation antigen dipeptidyl peptidase 4 (DPP4)/CD26 is expressed in the skeletal muscle of ...patients with idiopathic inflammatory myopathies (IIM) and whether its expression offers clues to understand the events taking place in the tissue.
CD26 expression in the muscle, evaluated by immunofluorescence, was assessed in 32 patients with IIM and 5 healthy controls and compared among patients with dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), and polymyositis (PM). The relationship of CD26 expression and localization with clinical, serological and histological features was determined.
CD26 is selectively expressed in the skeletal muscle of patients with IIM. The highest levels of CD26 are found in the skeletal muscle from patients with DM and in particular in those characterized by tissue necrosis and vascular inflammation. CD26 expression is associated with decreased muscle performance and independently predicts the number of treatments before reaching disease stabilization or improvement (odds ratio, OR=1.2, p<0.05).
CD26 is expressed in the IIM skeletal muscle and may represent a target of molecular intervention for patients with treatment-refractory myositis.
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