Publications by authors named "Giovanni Meola"

93 Publications

Case Report: Efficacy of Rituximab in a Patient With Familial Mediterranean Fever and Multiple Sclerosis.

Front Neurol 2020 6;11:591395. Epub 2021 Jan 6.

Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Donato, Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit & MS Centre, Milan, Italy.

Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disease characterized by recurrent episodes of fever and serositis caused by mutations in the MEFV gene, while Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the CNS with genetic and environmental etiology. The two diseases rarely occur in association with relevant implications for clinical management and drug choice. In this paper, we present the case of a 53-year-old male with an autosomal dominant FMF since childhood who presented acute paresthesia at the right part of the body. He performed a brain and spinal cord MRI, which showed multiple brain lesions and a gd-enhancing lesion in the cervical spinal cord, and then received a diagnosis of MS. He then started Interferonβ-1a which was effective but not tolerated and caused hepatotoxicity, and then shifted to Rituximab with 3-month clinical and neuroradiological efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.591395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874168PMC
January 2021

Lesion distribution and substrate of white matter damage in myotonic dystrophy type 1: Comparison with multiple sclerosis.

Neuroimage Clin 2021 14;29:102562. Epub 2021 Jan 14.

Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Brighton, United Kingdom; UOC Neurologia e Neurofisiopatologia, AO San Camillo Forlanini, Rome, Italy. Electronic address:

Myotonic Dystrophy type 1 (DM1) is an autosomal dominant condition caused by expansion of the CTG triplet repeats within the myotonic dystrophy protein of the kinase (DMPK) gene. The central nervous system is involved in the disease, with multiple symptoms including cognitive impairment. A typical feature of DM1 is the presence of widespread white matter (WM) lesions, whose total volume is associated with CTG triplet expansion. The aim of this study was to characterize the distribution and pathological substrate of these lesions as well as the normal appearing WM (NAWM) using quantitative magnetization transfer (qMT) MRI, and comparing data from DM1 patients with those from patients with multiple sclerosis (MS). Twenty-eight patients with DM1, 29 patients with relapsing-remitting MS, and 15 healthy controls had an MRI scan, including conventional and qMT imaging. The average pool size ratio (F), a proxy of myelination, was computed within lesions and NAWM for every participant. The lesion masks were warped into MNI space and lesion probability maps were obtained for each patient group. The lesion distribution, total lesion load and the tissue-specific mean F were compared between groups. The supratentorial distribution of lesions was similar in the 2 patient groups, although mean lesion volume was higher in MS than DM1. DM1 presented higher prevalence of anterior temporal lobe lesions, but none in the cerebellum and brainstem. Significantly reduced F values were found within DM1 lesions, suggesting a loss of myelin density. While F was reduced in the NAWM of MS patients, it did not differ between DM1 and controls. Our results provide further evidence for a need to compare histology and imaging using new MRI techniques in DM1 patients, in order to further our understanding of the underlying disease process contributing to WM disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2021.102562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848627PMC
January 2021

Myotonic dystrophy type 2: the 2020 update.

Authors:
Giovanni Meola

Acta Myol 2020 Dec 1;39(4):222-234. Epub 2020 Dec 1.

Department of Biomedical Sciences for Health, University of Milan, Italy.

The myotonic dystrophies are the commonest cause of adult-onset muscular dystrophy. Phenotypes of DM1 and DM2 are similar, but there are some important differences, including the presence or absence of congenital form, muscles primarily affected (distal vs proximal), involved muscle fiber types (type 1 vs type 2 fibers), and some associated multisystemic phenotypes. There is currently no cure for the myotonic dystrophies but effective management significantly reduces the morbidity and mortality of patients. For the enormous understanding of the molecular pathogenesis of myotonic dystrophy type 1 and myotonic dystrophy type 2, these diseases are now called "spliceopathies" and are mediated by a primary disorder of RNA rather than proteins. Despite clinical and genetic similarities, myotonic dystrophy type 1 and type 2 are distinct disorders requiring different diagnostic and management strategies. Gene therapy for myotonic dystrophy type 1 and myotonic dystrophy type 2 appears to be very close and the near future is an exciting time for clinicians and patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.36185/2532-1900-026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783423PMC
December 2020

Sodium Channel Myotonia Due to Novel Mutations in Domain I of Na1.4.

Front Neurol 2020 29;11:255. Epub 2020 Apr 29.

Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Sodium channel myotonia is a form of muscle channelopathy due to mutations that affect the Na1.4 channel. We describe seven families with a series of symptoms ranging from asymptomatic to clearly myotonic signs that have in common two novel mutations, p.Ile215Thr and p.Gly241Val, in the first domain of the Na1.4 channel. The families described have been clinically and genetically evaluated. p.Ile215Thr and p.Gly241Val lie, respectively, on extracellular and intracellular loops of the first domain of the Na1.4 channel. We assessed that the p.Ile215Thr mutation can be related to a founder effect in people from Southern Italy. Electrophysiological evaluation of the channel function showed that the voltage dependence of the activation for both the mutant channels was significantly shifted toward hyperpolarized potentials (Ile215Thr: -28.6 ± 1.5 mV and Gly241Val: -30.2 ± 1.3 mV vs. WT: -18.5 ± 1.3 mV). The slow inactivation was also significantly affected, whereas fast inactivation showed a different behavior in the two mutants. We characterized two novel mutations of the gene expanding the knowledge about genetics of mild forms of myotonia, and we present, to our knowledge, the first homozygous patient with sodium channel myotonia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201054PMC
April 2020

Ventral tegmental area dysfunction affects decision-making in patients with myotonic dystrophy type-1.

Cortex 2020 07 8;128:192-202. Epub 2020 Apr 8.

Neuroimaging Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Neuroscience, Brighton & Sussex Medical School, University of Sussex, Brighton, East Sussex, United Kingdom. Electronic address:

The clinical manifestations of Myotonic Dystrophy type-1 (DM1) are associated with a complex mixture of multisystem features including cognitive dysfunctions that strongly impact on patients' social and occupational functioning. Decision making, a function controlled by dopaminergic circuitry, is critical for succeeding in one's social and professional life. We tested here the hypothesis that altered connectivity of the ventral tegmental area (VTA), one of the major sources of diffuse dopaminergic projections in the brain, might account for some higher-level dysfunctions observed in patients with DM1. In this case-control study, we recruited 31 patients with DM1 and 26 healthy controls who underwent the IOWA Gambling task and resting-state functional MRI (RS-fMRI) at 3T. Functional connectivity of the VTA was assessed using RS-fMRI. VTA connectivity was compared between 25 DM1 patients and all the controls, and the presence of associations between VTA connectivity and IOWA Gambling task performance was also investigated. DM1 patients performed significantly worse than controls at the IOWA Gambling task. A significant increase of functional connectivity was observed between VTA and the left supramarginal and superior temporal gyri in DM1 patients. Patients' IOWA Gambling task net-scores were strictly associated with VTA-driven functional connectivity in the bilateral supplementary motor area and right precentral gyrus. This study demonstrates a prominent deficit of decision-making in patients with DM1. It might be related to increased connectivity between VTA and brain areas critically involved in the reward/punishment system and social cognition. These findings indicate that dopaminergic function is a potential target for pharmacological and non-pharmacological interventions in DM1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2020.03.022DOI Listing
July 2020

Guidelines on clinical presentation and management of nondystrophic myotonias.

Muscle Nerve 2020 10 27;62(4):430-444. Epub 2020 May 27.

Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas.

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26887DOI Listing
October 2020

Rare Disease: Cardiac Risk Assessment With MRI in Patients With Myotonic Dystrophy Type 1.

Front Neurol 2020 19;11:192. Epub 2020 Mar 19.

Unit of Radiology, IRCCS Policlinico San Donato, San Donato Milanese, Italy.

To evaluate myocardial strain and extracellular volume in myotonic dystrophy type 1 (DM1) patients as potential imaging biomarkers of subclinical cardiac pathology. We retrospectively analyzed 9 DM1 patients without apparent cardiac disease who had undergone cardiac magnetic resonance at our center. Patients were age- and sex-matched with healthy controls. The Mann-Whitney U test was used to compare cardiac strain between the two groups. The -test was used to compare the extracellular volume obtained in DM1 patients with that in healthy subject. Spearman's ρ was used for studying the associations among imaging parameters. Global cardiac strain (median -19.1%; IQR -20.5%, -16.5%) in DM1 patients was lower ( = 0.011) than that in controls (median-21.7%; IQR-22.7%,-21.3%). Global extracellular volume in DM1 patients (median 32.3%; IQR 29.3%,36.8%) was significantly ( = 0.008) higher than that reported in literature in healthy subjects (median 25.6%; IQR 19.9%,31.9%). Global cardiac strain showed a strong, positive correlation with septal strain (ρ = 0.767, = 0.016) and with both global (ρ = 0.733 = 0.025) and septal extracellular volume (ρ = 0.767, = 0.016). The increase in cardiac extracellular volume and decrease in strain are signs of early cardiac pathology in DM1. Physicians dealing with DM1 may take into consideration cardiac magnetic resonance as a screening tool to identify early cardiac involvement in this condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098463PMC
March 2020

Abnormal Cortical Thickness Is Associated With Deficits in Social Cognition in Patients With Myotonic Dystrophy Type 1.

Front Neurol 2020 28;11:113. Epub 2020 Feb 28.

Neuroimaging Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy.

To investigate the cortical thickness in myotonic dystrophy type 1 (DM1) and its potential association with patients' genetic triplet expansion and social cognition deficits. Thirty patients with DM1 underwent the Social Cognition Battery Test and magnetic resonance imaging (MRI) scanning at 3 T. Twenty-five healthy subjects (HSs) were enrolled in the study to serve as a control group for structural MRI data. To assess changes in cortical thickness in DM1 patients, they were compared to HSs using a -test model. Correlations were used to assess potential associations between genetic and clinical characteristics and social cognition performances in the patient group. Additionally, multiple regression models were used to explore associations between cortical thickness, CTG triplet expansion size, and scores obtained by DM1 patients on the Social Cognition Battery. DM1 patients showed low performances in several subtests of the Social Cognition Battery. Specifically, they obtained pathological scores at Emotion Attribution Test (i.e., Sadness, Embarrassment, Happiness, and Anger) and at the Social Situations Test (i.e., recognition of normal situation, recognition of aberrant behavior). Significant negative correlations were found between CTG triplet expansion size and Embarrassment, and Severity of Aberrant Behavior. Similarly, a negative correlation was found between patients' MIRS scores and Sadness. DM1 patients compared to HSs showed reduced thickness in the right premotor cortex, angular gyrus, precuneus, and inferior parietal lobule. Significant associations were found between patients' CTG triplet expansion size and thickness in left postcentral gyrus and in the left primary somatosensory cortex, in the posterior cingulate cortex bilaterally, and in the right lingual gyrus. Finally, significant associations were found between cortical thickness and sadness in the superior temporal gyrus, the right precentral gyrus, the right angular gyrus, and the left medial frontal gyrus bilaterally. DM1 patients showed a negative correlation between cortical thickness in the bilateral precuneus and in the left lateral occipital cortex and performance at the Social Situations Test. Finally, DM1 patients showed a negative correlation between cortical thickness in the left precuneus and in the superior frontal gyrus and scores at the Moral Distinction Test. The present study shows both cortical thickness changes in DM1 patients compared to controls and significant associations between cortical thickness and patients' social cognition performances. These data confirm the presence of widespread brain damages associated with cognitive impairment in DM1 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059122PMC
February 2020

Missplicing in Skeletal Muscle as a Cardiac Biomarker in Myotonic Dystrophy Type 1 but Not in Myotonic Dystrophy Type 2.

Front Neurol 2019 27;10:992. Epub 2019 Sep 27.

Laboratory of Muscle Histopathology and Molecular Biology, IRCCS-Policlinico San Donato, Milan, Italy.

Cardiac involvement is one of the most important manifestations of the multisystemic phenotype of patients affected by myotonic dystrophy (DM) and represents the second cause of premature death. Molecular mechanisms responsible for DM cardiac defects are still unclear; however, missplicing of the cardiac isoform of troponin T () and of the cardiac sodium channel () genes might contribute to the reduced myocardial function and conduction abnormalities seen in DM patients. Since, in DM skeletal muscle, the gene shows the same aberrant splicing pattern observed in cardiac muscle, the principal aim of this work was to verify if the aberrant fetal isoform expression could be secondary to myopathic changes or could reflect the DM cardiac phenotype. Analysis of alternative splicing of and of several genes involved in DM pathology has been performed on muscle biopsies from patients affected by DM type 1 (DM1) or type 2 (DM2) with or without cardiac involvement. Our analysis shows that missplicing of muscle-specific genes is higher in DM1 and DM2 than in regenerating control muscles, indicating that these missplicing could be effectively important in DM skeletal muscle pathology. When considering the gene, missplicing appears to be more evident in DM1 than in DM2 muscles since, in DM2, the fetal isoform appears to be less expressed than the adult isoform. This evidence does not seem to be related to less severe muscle histopathological alterations that appear to be similar in DM1 and DM2 muscles. These results seem to indicate that the more severe missplicing observed in DM1 could not be related only to myopathic changes but could reflect the more severe general phenotype compared to DM2, including cardiac problems that appear to be more severe and frequent in DM1 than in DM2 patients. Moreover, missplicing significantly correlates with the QRS cardiac parameter in DM1 but not in DM2 patients, indicating that this splicing event has good potential to function as a biomarker of DM1 severity and it should be considered in pharmacological clinical trials to monitor the possible effects of different therapeutic approaches on skeletal muscle tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2019.00992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776629PMC
September 2019

Consensus-based care recommendations for adults with myotonic dystrophy type 2.

Neurol Clin Pract 2019 Aug;9(4):343-353

Ludwig-Maximilians- Universität (BS); Friedrich-Baur-Institut (FM), Munich, Germany; Institut de Myologie (GB), Paris, France; U.O. Neurologia (BF), IRCCS Policlinico San Donato, Milan, Italy; Vall d'Hebron University Hospital (JG), Barcelona, Spain; University of Rochester (CH, JH, RM, CT), Rochester, NY; University Hospital of Bonn (CK), Germany; Medical University of Warsaw (AK-P), Poland; University of Texas (RK) MD Anderson cancer center; Medical University of Warsaw (AL), Poland; Department of Biomedical Sciences for health (GM), University of Milan, Italy; Tampere University (BU), Finland; Myotonic Dystrophy Foundation (PF), San Francisco.

Purpose Of Review: Myotonic dystrophy type 2 (DM2) is a rare, progressive multisystem disease particularly affecting the skeletal muscle. A causal therapy is not yet available; however, prompt, appropriate symptomatic treatments are essential to limit disease-related complications. Evidence-based guidelines to assist medical practitioners in the care of DM2 patients do not exist.

Recent Findings: The Myotonic Dystrophy Foundation (MDF) previously worked with an international group of 66 clinicians to develop consensus-based care recommendations for myotonic dystrophy type 1. Following a similar approach, the MDF recruited 15 international clinicians with long-standing experience in the care of DM2 patients to develop consensus-based care recommendations. The single text procedure was adopted. This process generated a 4-page Quick Reference Guide and a comprehensive 55-page document that provides care recommendations for DM2 patients.

Summary: The resulting recommendations will help standardize and improve care for DM2 patients and facilitate appropriate management in centers without neuromuscular specialists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/CPJ.0000000000000645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745739PMC
August 2019

Dysregulation of Circular RNAs in Myotonic Dystrophy Type 1.

Int J Mol Sci 2019 Apr 19;20(8). Epub 2019 Apr 19.

Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy.

Circular RNAs (circRNAs) constitute a recently re-discovered class of non-coding RNAs functioning as sponges for miRNAs and proteins, affecting RNA splicing and regulating transcription. CircRNAs are generated by "back-splicing", which is the linking covalently of 3'- and 5'-ends of exons. Thus, circRNA levels might be deregulated in conditions associated with altered RNA-splicing. Significantly, growing evidence indicates their role in human diseases. Specifically, myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the gene which results in abnormal mRNA-splicing. In this investigation, circRNAs expressed in DM1 skeletal muscles were identified by analyzing RNA-sequencing data-sets followed by qPCR validation. In muscle biopsies, out of nine tested, four transcripts showed an increased circular fraction: CDYL, HIPK3, RTN4_03, and ZNF609. Their circular fraction values correlated with skeletal muscle strength and with splicing biomarkers of disease severity, and displayed higher values in more severely affected patients. Moreover, Receiver-Operating-Characteristics curves of these four circRNAs discriminated DM1 patients from controls. The identified circRNAs were also detectable in peripheral-blood-mononuclear-cells (PBMCs) and the plasma of DM1 patients, but they were not regulated significantly. Finally, increased circular fractions of RTN4_03 and ZNF609 were also observed in differentiated myogenic cell lines derived from DM1 patients. In conclusion, this pilot study identified circRNA dysregulation in DM1 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20081938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515344PMC
April 2019

Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related myopathies.

Hum Mutat 2019 07 1;40(7):962-974. Epub 2019 Apr 1.

Department of Biomedicine, Basel University Hospital, Basel, Switzerland.

Congenital myopathies are early onset, slowly progressive neuromuscular disorders of variable severity. They are genetically and phenotypically heterogeneous and caused by pathogenic variants in several genes. Multi-minicore Disease, one of the more common congenital myopathies, is frequently caused by recessive variants in either SELENON, encoding the endoplasmic reticulum glycoprotein selenoprotein N or RYR1, encoding a protein involved in calcium homeostasis and excitation-contraction coupling. The mechanism by which recessive SELENON variants cause Multiminicore disease (MmD) is unclear. Here, we extensively investigated muscle physiological, biochemical and epigenetic modifications, including DNA methylation, histone modification, and noncoding RNA expression, to understand the pathomechanism of MmD. We identified biochemical changes that are common in patients harboring recessive RYR1 and SELENON variants, including depletion of transcripts encoding proteins involved in skeletal muscle calcium homeostasis, increased levels of Class II histone deacetylases (HDACs) and DNA methyltransferases. CpG methylation analysis of genomic DNA of patients with RYR1 and SELENON variants identified >3,500 common aberrantly methylated genes, many of which are involved in calcium signaling. These results provide the proof of concept for the potential use of drugs targeting HDACs and DNA methyltransferases to treat patients with specific forms of congenital myopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660981PMC
July 2019

Aberrant insulin receptor expression is associated with insulin resistance and skeletal muscle atrophy in myotonic dystrophies.

PLoS One 2019 22;14(3):e0214254. Epub 2019 Mar 22.

Laboratory of Muscle Histopathology and Molecular Biology, IRCCS-Policlinico San Donato, San Donato Milanese, Milan, Italy.

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant multisystemic disorders linked to two different genetic loci and characterized by several features including myotonia, muscle atrophy and insulin resistance. The aberrant alternative splicing of insulin receptor (IR) gene and post-receptor signalling abnormalities have been associated with insulin resistance, however the precise molecular defects that cause metabolic dysfunctions are still unknown. Thus, the aims of this study were to investigate in DM skeletal muscle biopsies if beyond INSR missplicing, altered IR protein expression could play a role in insulin resistance and to verify if the lack of insulin pathway activation could contribute to skeletal muscle wasting. Our analysis showed that DM skeletal muscle exhibits a lower expression of the insulin receptor in type 1 fibers which can contribute to the defective activation of the insulin pathway. Moreover, the aberrant insulin signalling activation leads to a lower activation of mTOR and to an increase in MuRF1 and Atrogin-1/MAFbx expression, possible explaining DM skeletal muscle fiber atrophy. Taken together our data indicate that the defective insulin signalling activation can contribute to skeletal muscle features in DM patients and are probably linked to an aberrant specific-fiber type expression of the insulin receptor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430513PMC
December 2019

Consensus-based care recommendations for adults with myotonic dystrophy type 1.

Neurol Clin Pract 2018 Dec;8(6):507-520

Purpose Of Review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit.

Recent Findings: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations.

Summary: The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/CPJ.0000000000000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294540PMC
December 2018

Neuropsychological and Psychological Functioning Aspects in Myotonic Dystrophy Type 1 Patients in Italy.

Front Neurol 2018 19;9:751. Epub 2018 Sep 19.

Department of Neurology, IRCCS Policlinico San Donato, San Donato Milanese, Italy.

Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant genetic illness, characterized by a progressive loss of strength. Important deficits in cognitive functioning and a significant prevalence of psychiatric disorders have been previously reported. A neuropsychological and psychological assessment was carried out in 31 DM1 patients (61% males) in order to measure the cognitive functioning and explore their personality profiles. The MMSE Mini-Mental State Examination, Frontal Assessment Battery (FAB), ENB-2 Battery assessing memory (short term, long term and working memory), integration capacities, visual-spatial ability, attention (selective, divided, shifting/switching) executive functions, praxis, discrimination and logic capabilities and psychopathology Symptom Check List 90-R (SCL-90-R) were administered. The neuropsychological and psychological evaluation of DM1 patients was carried out taking into consideration the clinical parameters (CTG repeat, age at onset, disease duration, Muscular Impairment Rate Scale (MIRS), Medical Research Council Scale (MRC) and the Epworth Sleepiness Scales (EPS)). Regarding psychopathology 19.4% of patients scored a moderate or high level of symptoms intensity index (GSI), 12.9% reported a high number of symptoms (PST) and 16.1% reported a high intensity level of the perceived symptoms (PSDI). Fatigue and daytime sleepiness resulted as being associated with higher levels of psychoticism (PSY). Only 1 patient reported a severe impairment in the spatial and temporal orientation, memory, language, praxis, attention and calculation. Longer disease duration was also associated with cognitive impairment evaluated through ENB-2 ( < 0.05). There are indications of the utility of neuropsychological and psychological screening and support for these patients and their families due to the link between disease duration and cognitive performances. A proposal of a clinical protocol, with an illustration of a clinical case report of a family is presented.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2018.00751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160752PMC
September 2018

Editorial: Beyond Borders: Myotonic Dystrophies-A European Perception.

Front Neurol 2018 20;9:787. Epub 2018 Sep 20.

Department of Biomedical Sciences for Health University of Milan, Milan, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2018.00787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158325PMC
September 2018

Report of the third outcome measures in myotonic dystrophy type 1 (OMMYD-3) international workshop Paris, France, June 8, 2015.

J Neuromuscul Dis 2018 ;5(4):523-537

Functional Area Occupational Therapy & Physiotherapy, Allied Health Professionals Function, Karolinska University Hospital, Stockholm, Sweden.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-180329DOI Listing
January 2019

Sporadic MM-1 Type Creutzfeldt-Jakob Disease With Hemiballic Presentation and No Cognitive Impairment Until Death: How New NCJDRSU Diagnostic Criteria May Allow Early Diagnosis.

Front Neurol 2018 5;9:739. Epub 2018 Sep 5.

Department of Biomedical Sciences for Health, University of Milan, IRCCS Policlinico San Donato, Milan, Italy.

Sporadic Creutzfeldt-Jakob disease is the most common human prion disorder. Although associated with heterogeneous clinical phenotypes, its distinctive feature is the presence of a rapidly progressive multidomain cognitive impairment. We describe the atypical case of a patient affected by sporadic Methionine/Methionine type 1 Creutzfeldt-Jakob disease (typically associated with early cognitive decline) who presented with an isolated hemiballic syndrome and no signs of cognitive involvement until death. We review sporadic Creutzfeldt-Jakob disease diagnostic criteria and their updates since their first formulation, highlighting their limitations in clinical diagnostic work-up. Finally, we discuss the recently introduced National Creutzfeldt-Jakob Disease Research and Surveillance Unit diagnostic criteria, suggesting how their application could support an early clinical diagnosis, even in atypical cases, such as the one presented.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2018.00739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134320PMC
September 2018

Generation and Neuronal Differentiation of hiPSCs From Patients With Myotonic Dystrophy Type 2.

Front Physiol 2018 27;9:967. Epub 2018 Jul 27.

Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

Human induced pluripotent stem cells (hiPSCs)-patient specific are an innovative tool to reproduce a model of disease and summarize the pathological phenotype and the disease etiopathology. Myotonic dystrophy type 2 (DM2) is caused by an unstable (CCTG)n expansion in intron 1 of the gene, leading to a progressive multisystemic disease with muscle, heart and central nervous dysfunctions. The pathogenesis of CNS involvement in DM2 is poorly understood since no cellular or animal models fully recapitulate the molecular and clinical neurodegenerative phenotype of patients. In this study, we generated for the first time, two DM2 and two wild type hiPSC lines from dermal fibroblasts by polycistronic lentiviral vector (hSTEMCCA-loxP) expressing , , , and genes and containing loxP-sites, excisable by Cre recombinase. Specific morphological, molecular and immunocytochemical markers have confirmed the stemness of DM2 and wild type-derived hiPSCs. These cells are able to differentiate into neuronal population (NP) expressing tissue specific markers. hiPSCs-derived NP cells maintain (CCTG)n repeat expansion and intranuclear RNA foci exhibiting sequestration of MBNL1 protein, which are pathognomonic of the disease. DM2 hiPSCs represent an important tool for the study of CNS pathogenesis in patients, opening new perspectives for the development of cell-based therapies in the field of personalized medicine and drug screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2018.00967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074094PMC
July 2018

SCN4A as modifier gene in patients with myotonic dystrophy type 2.

Sci Rep 2018 07 23;8(1):11058. Epub 2018 Jul 23.

Laboratory of Muscle Histopathology and Molecular Biology, IRCCS-Policlinico San Donato, Milan, Italy.

A patient with an early severe myotonia diagnosed for Myotonic Dystrophy type 2 (DM2) was found bearing the combined effects of DM2 mutation and Nav1.4 S906T substitution. To investigate the mechanism underlying his atypical phenotype,whole-cell patch-clamp in voltage- and current-clamp mode was performed in myoblasts and myotubes obtained from his muscle biopsy. Results characterizing the properties of the sodium current and of the action potentials have been compared to those obtained in muscle cells derived from his mother, also affected by DM2, but without the S906T polymorphism. A faster inactivation kinetics and a +5 mV shift in the availability curve were found in the sodium current recorded in patient's myoblasts compared to his mother. 27% of his myotubes displayed spontaneous activity. Patient's myotubes showing a stable resting membrane potential had a lower rheobase current respect to the mother's while the overshoot and the maximum slope of the depolarizing phase of action potential were higher. These findings suggest that SCN4A polymorphisms may be responsible for a higher excitability of DM2 patients sarcolemma, supporting the severe myotonic phenotype observed. We suggest SCN4A as a modifier factor and that its screening should be performed in DM2 patients with uncommon clinical features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-29302-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056531PMC
July 2018

High-throughput analysis of the RNA-induced silencing complex in myotonic dystrophy type 1 patients identifies the dysregulation of miR-29c and its target ASB2.

Cell Death Dis 2018 06 28;9(7):729. Epub 2018 Jun 28.

Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, Milan, Italy.

Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by abnormally expanded stretches of CTG DNA triplets in the DMPK gene, leading to mutated-transcript RNA-toxicity. MicroRNAs (miRNAs) are short non-coding RNAs that, after maturation, are loaded onto the RISC effector complex that destabilizes target mRNAs and represses their translation. In DM1 muscle biopsies not only the expression, but also the intracellular localization of specific miRNAs is disrupted, leading to the dysregulation of the relevant mRNA targets. To investigate the functional alterations of the miRNA/target interactions in DM1, we analyzed by RNA-sequencing the RISC-associated RNAs in skeletal muscle biopsies derived from DM1 patients and matched controls. The mRNAs found deregulated in DM1 biopsies were involved in pathways and functions relevant for the disease, such as energetic metabolism, calcium signaling, muscle contraction and p53-dependent apoptosis. Bioinformatic analysis of the miRNA/mRNA interactions based on the RISC enrichment profiles, identified 24 miRNA/mRNA correlations. Following validation in 21 independent samples, we focused on the couple miR-29c/ASB2 because of the role of miR-29c in fibrosis (a feature of late-stage DM1 patients) and of ASB2 in the regulation of muscle mass. Luciferase reporter assay confirmed the direct interaction between miR-29c and ASB2. Moreover, decreased miR-29c and increased ASB2 levels were verified also in immortalized myogenic cells and primary fibroblasts, derived from biopsies of DM1 patients and controls. CRISPR/Cas9-mediated deletion of CTG expansions rescued normal miR-29c and ASB2 levels, indicating a direct link between the mutant repeats and the miRNA/target expression. In conclusion, functionally relevant miRNA/mRNA interactions were identified in skeletal muscles of DM1 patients, highlighting the dysfunction of miR-29c and ASB2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-018-0769-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023919PMC
June 2018

The analysis of myotonia congenita mutations discloses functional clusters of amino acids within the CBS2 domain and the C-terminal peptide of the ClC-1 channel.

Hum Mutat 2018 09 4;39(9):1273-1283. Epub 2018 Jul 4.

Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Polyclinic, Bari, Italy.

Myotonia congenita (MC) is a skeletal-muscle hyperexcitability disorder caused by loss-of-function mutations in the ClC-1 chloride channel. Mutations are scattered over the entire sequence of the channel protein, with more than 30 mutations located in the poorly characterized cytosolic C-terminal domain. In this study, we characterized, through patch clamp, seven ClC-1 mutations identified in patients affected by MC of various severities and located in the C-terminal region. The p.Val829Met, p.Thr832Ile, p.Val851Met, p.Gly859Val, and p.Leu861Pro mutations reside in the CBS2 domain, while p.Pro883Thr and p.Val947Glu are in the C-terminal peptide. We showed that the functional properties of mutant channels correlated with the clinical phenotypes of affected individuals. In addition, we defined clusters of ClC-1 mutations within CBS2 and C-terminal peptide subdomains that share the same functional defect: mutations between 829 and 835 residues and in residue 883 induced an alteration of voltage dependence, mutations between 851 and 859 residues, and in residue 947 induced a reduction of chloride currents, whereas mutations on 861 residue showed no obvious change in ClC-1 function. This study improves our understanding of the mechanisms underlying MC, sheds light on the role of the C-terminal region in ClC-1 function, and provides information to develop new antimyotonic drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23581DOI Listing
September 2018

Flecainide-Induced Brugada Syndrome in a Patient With Skeletal Muscle Sodium Channelopathy: A Case Report With Critical Therapeutical Implications and Review of the Literature.

Front Neurol 2018 30;9:385. Epub 2018 May 30.

Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.

Skeletal muscle sodium channelopathies are a group of neuromuscular disorders associated with mutations in the gene. Because principal sodium channel isoforms expressed in the skeletal muscles and the heart are distinct one from the other, this condition usually spares cardiac functioning. Nonetheless, evidence on a possible link between skeletal muscle and cardiac sodium channelopathies has emerged in recent years. To date, eight patients bearing pathogenetic mutations in the gene and manifesting cardiac electrophysiological alterations have been reported in literature. Among these patients, three presented a phenotype compatible with Brugada syndrome. We report the case of a 29-year-old patient affected by non-dystrophic myotonia associated with a p.G1306E mutation in the gene, who presented symptoms of syncope and palpitation after the introduction of flecainide as an anti-myotonic agent. ECG and ajmaline challenge were consistent with the diagnosis of Brugada syndrome, leading to the implantation of a cardioverter defibrillator. No mutation in causative genes for Brugada syndrome was detected. Mexiletine treatment reduced myotonia without any cardiac adverse events. This case report highlights the clinical relevance of the recognition of cardiac electrophysiological alterations in skeletal muscle sodium channelopathies. The discovery of a possible pathogenetic linkage between skeletal muscle and cardiac sodium channelopathies may have significant implications in patients' management, also in light of the fact that class 1C anti-arrhythmics are potential triggers for life-threatening arrhythmias in patients with Brugada syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2018.00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988887PMC
May 2018

Incidence of amplification failure in DMPK allele due to allelic dropout event in a diagnostic laboratory.

Clin Chim Acta 2018 Sep 24;484:111-116. Epub 2018 May 24.

Research Laboratories, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.; Service of Laboratory Medicine, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.

Background: Myotonic dystrophy type 1 (DM1) is caused by an expanded CTG repeat in the non-coding 3' UTR of the DMPK gene. PCR and Southern Blot Analysis (SBA) of long-range PCR represent the routine molecular testing most widely used for DM1 diagnosis. However, in these conventional methods artifacts such as allele dropout (ADO) represent a risk of misdiagnosis for DM1. Subjects, who show a single product by conventional methods, require a complementary technique such as triplet repeat primed PCR (TP-PCR).

Object: To estimate and minimize the incidence of allele dropout event in our diagnostic molecular laboratory by the use of new kit TP-PCR-based.

Methods: We retrospectively studied 190 DMPK alleles, on blood samples from to ninety-five subjects, previously genotyped by traditional methods to validate a new assay. The pedigree of a DM1 family was used to expand our analysis.

Results: TP-PCR assay correctly identified all 95/95 (100%) subjects and these results were in agreement with the other molecular laboratory. By conventional methods the amplification failure due to allele dropout in our cohort was in 12/190 (6.3%) DMPK alleles analyzed. When these 12 alleles were detected and solved by new assay, we found that the 2.6% was caused by primer sequence-dependent and the remaining 3.6% by polymerase-hindering secondary structures.

Conclusions: Allele dropout could be considered as a potentially important problem in DM1 diagnosis that may lead to the attribution of a wrong genotype with long-term consequences for both proband and family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cca.2018.05.040DOI Listing
September 2018

rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences.

Nat Commun 2018 05 22;9(1):2009. Epub 2018 May 22.

IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, 67404, Illkirch, France.

Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-04370-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964235PMC
May 2018

MSA Mimic? Rare Occurrence of Anti-Hu Autonomic Failure and Thymoma in a Patient with Parkinsonism: Case Report and Literature Review.

Front Neurosci 2018 24;12:17. Epub 2018 Jan 24.

Department of Biomedical Sciences for Health, University of Milan, IRCCS Policlinico San Donato, Milan, Italy.

Thymoma is a tumor originating from thymic gland, frequently manifesting with paraneoplastic neurological disorders. Its association with paraneoplastic dysautonomia is relatively uncommon. Here, we describe the challenging case of a 71 year-old female who developed subacute autonomic failure with digestive pseudo-obstruction, dysphagia, urinary tract dysfunction and orthostatic hypotension complicating an underlying extrapyramidal syndrome that had started 3 months before hospital admission. Autonomic symptoms had 2-month course and acutely worsened just before and during hospitalization. Combination of severe dysautonomia and parkinsonism mimicked rapidly progressing multiple system atrophy. However, diagnostic exams showed thymic tumor with positive anti-Hu antibodies on both serum and cerebrospinal fluid. Complete response of dysautonomia to immunoglobulins followed by thymectomy confirmed the diagnosis of anti-Hu-related paraneoplastic neurological syndrome. With regards to extrapyramidal symptoms, despite previous descriptions of paraneoplastic parkinsonism caused by other antineuronal antibodies, in our case no relation between anti-Hu and parkinsonism could be identified. A literature review of published reports describing anti-Hu positivity in thymic neoplasms highlighted that a definite autonomic disease due to anti-Hu antibodies is extremely rare in patients with thymoma but without myasthenia gravis, with only one case published so far.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2018.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787932PMC
January 2018

CRISPR/Cas9-Mediated Deletion of CTG Expansions Recovers Normal Phenotype in Myogenic Cells Derived from Myotonic Dystrophy 1 Patients.

Mol Ther Nucleic Acids 2017 Dec 14;9:337-348. Epub 2017 Oct 14.

Institute of Cell Biology and Neurobiology, National Research Council, Monterotondo, Rome, Italy. Electronic address:

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy, characterized by progressive myopathy, myotonia, and multi-organ involvement. This dystrophy is an inherited autosomal dominant disease caused by a (CTG)n expansion within the 3' untranslated region of the DMPK gene. Expression of the mutated gene results in production of toxic transcripts that aggregate as nuclear foci and sequester RNA-binding proteins, resulting in mis-splicing of several transcripts, defective translation, and microRNA dysregulation. No effective therapy is yet available for treatment of the disease. In this study, myogenic cell models were generated from myotonic dystrophy patient-derived fibroblasts. These cells exhibit typical disease-associated ribonuclear aggregates, containing CUG repeats and muscleblind-like 1 protein, and alternative splicing alterations. We exploited these cell models to develop new gene therapy strategies aimed at eliminating the toxic mutant repeats. Using the CRISPR/Cas9 gene-editing system, the repeat expansions were removed, therefore preventing nuclear foci formation and splicing alterations. Compared with the previously reported strategies of inhibition/degradation of CUG expanded transcripts by various techniques, the advantage of this approach is that affected cells can be permanently reverted to a normal phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omtn.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684470PMC
December 2017

Circulating Irisin Is Reduced in Male Patients with Type 1 and Type 2 Myotonic Dystrophies.

Front Endocrinol (Lausanne) 2017 14;8:320. Epub 2017 Nov 14.

Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.

Context: Myotonic dystrophies (DM) are dominantly inherited muscle disorders characterized by myotonia, muscle weakness, and wasting. The reasons for sarcopenia in DMs are uncleared and multiple factors are involved. Irisin, a positive hormone regulator of muscle growth and bone, may play a role.

Objectives: To investigate (1) circulating irisin in a series of DM1 and DM2 male patients compared with healthy controls and (2) the relationships between irisin and anthropometric, metabolic and hormonal parameters.

Design And Study Participants: This is a cross-sectional study. Fasting blood samples for glucometabolic, gonadic, bone markers, and irisin were collected from 28 ambulatory DM1, 10 DM2, and 23 age-matched healthy male subjects. Body composition and bone mineralization [bone mineral density (BMD)] were measured by DEXA. Echocardiographic assessment and visceral adiposity, namely, liver and epicardial fat, were investigated by ultrasound. Irisin released from cultured myotubes derived from 3 DM1, 3 DM2, and 3 healthy donors was assayed.

Results: Plasma irisin levels were definitely lower in both DM1 and DM2 patients than in controls with no difference between DM1 and DM2. Irisin released from DM1 and DM2 myotubes was similar to that released from myotubes of the non-DM donors, though diabetic DM2 myotubes released more irisin than DM1 myotubes. There was no correlation between irisin and muscle strength or lean mass in both DM1 and DM2 patients. In DM1 patients, plasma irisin levels correlated negatively with oxygen consumption and positively with insulin resistance, while in DM2 patients plasma irisin levels positively correlated with fat mass at arms and legs levels. No correlation with visceral fat, left ventricular mass, and gonadal hormones could be detected. In both DM1 and DM2 patients, legs BMD parameters positively correlated with plasma irisin levels.

Conclusion: Plasma irisin is reduced in both DM1 and DM2 male patients likely reflecting muscle mass reduction. Moreover, insulin resistance may contribute to modulation of plasma irisin in DM1 patients. The irisin-mediated cross talk muscle-adipose tissue-bone may be active also in the male myotonic dystrophies' model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2017.00320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694592PMC
November 2017

Cardiac involvement in myotonic dystrophy: The role of troponins and N-terminal pro B-type natriuretic peptide.

Atherosclerosis 2017 Dec 21;267:110-115. Epub 2017 Oct 21.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. Electronic address:

Background And Aims: Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are dominant inherited muscular dystrophies with multiple systemic involvement, often producing cardiac injury. This study sought to determine the clinical significance of elevated high sensitivity cardiac troponin T and I (hs-cTnT and hs-cTnI), and N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in this population.

Methods: Sixty DM patients (35 men and 25 women; mean age: 45.1 years, range: 12-73 years) underwent clinical cardiac investigations and measurements of serum hs-cTnT, hs-cTnI, creatine kinase (CK), and NT-proBNP. Left ventricular (LV) ejection fraction (EF) was assessed by echocardiography.

Results: Genetic analysis revealed that 46 of the 60 patients were DM1, and 14 DM2. Blood measurements showed persistent elevation of hs-cTnT and CK in 55/60 DM patients (91.73%). In contrast, hs-cTnI values were persistently normal throughout the study. Only 2 patients showed an EF <50%, being the overall range of this population between 40% and 79%. We found ECG abnormalities in 19 patients. Of these patients, 13 showed first or second-degree atrio ventricular (AV) blocks (PR interval ≥ 200 ms), 4 showed a left bundle branch block (LBBB) prolonged (QRS duration ≥120 ms), and 2 had an incomplete bundle branch block (QRS duration between 110 and 119 ms). After excluding patients with EF <50%, NT-pro-BNP measurement > 125 pg/mL was an independent predictor of ECG abnormalities.

Conclusions: NT-pro-BNP levels may be considered to be used clinically to identify DM patients at increased risk of developing myocardial conduction abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2017.10.020DOI Listing
December 2017

Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle.

PLoS One 2017 15;12(9):e0184987. Epub 2017 Sep 15.

Laboratory of Muscle Histopathology and Molecular Biology, IRCCS-Policlinico San Donato, San Donato Milanese, Milan, Italy.

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant multisystemic disorders caused by expansion of microsatellite repeats. In both forms, the mutant transcripts accumulate in nuclear foci altering the function of alternative splicing regulators which are necessary for the physiological mRNA processing. Missplicing of insulin receptor (IR) gene (INSR) has been associated with insulin resistance, however, it cannot be excluded that post-receptor signalling abnormalities could also contribute to this feature in DM. We have analysed the insulin pathway in skeletal muscle biopsies and in myotube cultures from DM patients to assess whether downstream metabolism might be dysregulated and to better characterize the mechanism inducing insulin resistance. DM skeletal muscle exhibits alterations of basal phosphorylation levels of Akt/PKB, p70S6K, GSK3β and ERK1/2, suggesting that these changes might be accompanied by a lack of further insulin stimulation. Alterations of insulin pathway have been confirmed on control and DM myotubes expressing fetal INSR isoform (INSR-A). The results indicate that insulin action appears to be lower in DM than in control myotubes in terms of protein activation and glucose uptake. Our data indicate that post-receptor signalling abnormalities might contribute to DM insulin resistance regardless the alteration of INSR splicing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184987PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600405PMC
October 2017