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Objectives The aim of this study, part of our research to improve properties of resin composite blocks suitable for CAD/CAM and to better understand underlying mechanisms associated with high-temperature/high-pressure (HT/HP) polymerization, was to determine an optimum polymerization pressure of urethane dimethacrylate (UDMA) in the presence of an initiator (0.5% benzoyl peroxide) by determining the degree of conversion (DC) and viscoelastic properties of polymers obtained at 90 °C under varying HP. Methods DC and viscoelastic properties of 16 UDMA polymers, two controls (thermo-cured and thermo-cured followed by post-cure relaxation) and 14 experimental groups (HP polymers, in the range of 50–350 MPa, in 50 MPa increments, without and with post-cure relaxation) were determined via near infrared spectroscopic analysis and dynamic mechanical analysis, respectively. Results The results have shown that HP UDMA polymers have DC superior to that of the control group. With regards to E ′ and E ″, the results have shown no significant difference between control and HP polymers. The damping factor, tan δ , decreased with increasing pressure, while E ′ rub and T g increased. Polymerization at 150 MPa or higher resulted in significantly higher E ′ rub and T g . Significance The results of this study suggested that HP polymerization at 90 °C of UDMA reduced the number of defects and the free volume, leading to a more homogeneous polymer network. The results have also suggested that 200 MPa is an optimum polymerization pressure, resulting in polymers with significantly higher DC, E ′ rub , and T g , while maintaining adequate damping capacity (tan δ ). [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of this study was to compare the viscoelastic properties of high pressure (HP) polymerized urethane dimethacrylate (UDMA) with those of control, ambient pressure thermo-polymerized and photo-polymerized, UDMA and to assess the effect of varying polymerization parameters (protocol, temperature, and initiator) on the viscoelastic properties of HP polymerized UDMA. Methods: The viscoelastic properties of the two control polymers, polymerized under atmospheric pressure, and four experimental polymers, polymerized under HP, were determined via dynamic mechanical analysis (DMA), in three point bending configuration. Atomic force microscopy (AFM) was used to characterize fractured polymer surface morphologies. Results: The results showed that: HP-polymerization lead to a polymer with significantly higher T g and E′rub, indicative of a higher crosslink density; modifying the polymerization protocol resulted in a significant increase in tan δ; increasing the polymerization temperature lead to a significant decrease in E′rub and T g; and that the polymer with no initiator had the lowest E′, E″, T g, and E′rub and the highest tan δ, suggesting that under this conditions a polymer with significantly reduced crosslink density had been obtained. A characteristic nodular appearance was seen for the two control polymers under AFM, while a modified surface morphology was present in the case of HP polymerized materials. Significance: The DMA results suggest that polymerization under HP resulted in polymers with an increased crosslink density and that the higher polymerization temperature or the lack of initiator was detrimental to the viscoelastic properties determined. Changes in polymer network morphology were identified by AFM characterization. [Copyright &y& Elsevier]

Background: Homozygous mutations in ANO5, a gene encoding anoctamin 5, a putative calcium-activated chloride channel, have recently been reported in patients with adult-onset myopathies or isolated high-CK levels. Cardiomyopathy has not previously been reported in these populations despite a proven expression of anoctamin 5 in the cardiac muscle. Methods: Patients presenting for the management of high-CK levels or overt myopathy with proven ANO5 mutations were prospectively investigated between June 2010 and March 2012 in Pitié Salpêtrière Hospital, according to a standardised protocol. Neurological and cardiological clinical examinations, CK assessment, electrocardiogram (ECG), and echocardiography were performed, as well as cardiac MRI and coronary CT angiography in patients with left ventricular (LV) dysfunction. Results: Our study included 19 consecutive patients (male=15, age=46.2±12.7years) from 16 families. Five had asymptomatic high-CK levels and 14 had overt myopathy. One patient had a personal history of stable coronary artery disease with normal ventricular function. ECG showed ventricular premature beats in one patient. Echocardiography displayed LV dilatation in two patients, LV dysfunction in one, and both abnormalities in two who fulfilled criteria for dilated cardiomyopathy which was confirmed by cardiac MRI and normal CT angiography. Conclusions: Dilated cardiomyopathy is a potential complication in patients with myopathies due to mutations in the ANO5 gene whose screening requires specific procedures. [ABSTRACT FROM AUTHOR]

Tangier disease (TD) (OMIM#205400) is a rare autosomal recessive disorder resulting from mutations in the ABCA1 gene, leading to decreased levels of plasma high-density lipoproteins (HDL). Peripheral neuropathy is a common finding in this disease, and may present as relapsing/remitting mono/polyneuropathies or as syringomyelia-like neuropathy. We retrospectively analyzed four patients, and report here their clinical, biological, electrophysiological, imaging, and genetic findings. Three patients had a typical pseudosyringomyelic neuropathy including facial diplegia, but asymmetrical onset was observed in one patient who had first been misdiagnosed with Lewis-Sumner syndrome. Electrophysiological pattern was heterogeneous, showing both signs of demyelination and axonal degeneration. Truncating mutations of the ABCA1 gene, including two previously undescribed mutations, were constantly found. Atypical symptom onset and demyelinating features on electrophysiological examination can be misleading in case of pseudosyringomyelic neuropathy. These reports illustrate two different neurological phenotypes in TD, namely the pseudosyringomyelic type and the Lewis-Sumner-like type, and advocate for a systematic assessment of lipid profile including HDL cholesterol in demyelinating neuropathies. [ABSTRACT FROM AUTHOR]

Abstract: To determine incidence and type of major cardiac adverse events in patients with mutated desmin (DES) gene, we retrospectively reviewed baseline medical information, and examined the long-term outcomes of 28 DES patients (17 men, baseline mean age=37.7±14.4years [min=9, max=71]) from 19 families. Baseline studies revealed skeletal muscle involvement in 21 patients and cardiac abnormalities in all but one patient. Over a mean follow-up of 10.4±9.4years [min=1, max=35], cardiac death occurred in three patients, death due to cardiac comorbidities in two, one or more major cardiac adverse events in 13 patients. Among the 19 patients with mild conduction defects at baseline, eight developed high-degree conduction blocks requiring permanent pacing. Cardiac involvement was neither correlated with the type of DES mutation nor with the severity of skeletal muscle involvement. Our study underscores that in DES patients in-depth cardiac investigations are needed to prevent cardiac conduction system disease. [Copyright &y& Elsevier]

Background: Neuropathies associated with lymphoma (NAL) are rare and present a great clinical heterogeneity, making them difficult to diagnose and worsening their prognosis. Objectives: (1) To report the different patterns of NAL and discuss the mechanisms encountered; (2) to determine the relationship between a given type of lymphoma and a specific type of neuropathy; and (3) to assess the prognosis of NAL. Methods: Among 150 patients with lymphoma and neuropathy, we selected 26 in whom the neuropathy was not related to drug induced or IgM-antimyelin associated glycoprotein neuropathies. The pattern of neuropathy was defined in terms of its clinical and electrophysiological features. Neurological improvement, haematological remission and occurrence of death were taken into account to determine the prognosis. Results: 13 patients (50%) had a demyelinating polyneuropathy (PNP), seven (27%) had a radiculopathy linked to proximal root tumoral infiltration and six (23%) had an axonal multiple mononeuropathy (MM) related to distal lymphomatous infiltration or to paraneoplastic microvasculitis. Hodgkins lymphoma was only associated with demyelinating PNP. High grade B cell lymphoma was strongly associated with radiculopathy. Neurological improvement was observed in 69% of patients with demyelinating PNP, 29% with radiculopathy and 50% with MM. Haematological remission was observed in 46% of patients with demyelinating PNP, 29% with radiculopathy and 83% with MM. Conclusions: Demyelinating PNP, the most frequently observed neuropathy in this study, had the best neurological prognosis. Chemotherapy combined with immune mediated treatment was the most effective treatment in this group. Identifying the type and mechanism of NAL is crucial in order to define the therapeutic strategy and improve the prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Anti-MuSK antibodies have been reported in about 40–50% of patients with seronegative myasthenia gravis. Curiously, this condition has never been reported in association with fetal or transient neonatal myasthenia gravis, despite a known female predominance. We report the case of a 22-year-old woman who developed seronegative, mild steroid-responsive myasthenia gravis. When aged 26, she gave birth to a baby boy with neonatal myasthenia gravis characterized by hypotonia, stridor and sucking difficulties. Intubation was required for a few weeks. Anti-MuSK antibodies were assessed and found positive in both patients. Progressive hydramnios during the last trimester, with a decrease in spontaneous fetal mobility in the last weeks, long-lasting stridor, ptosis and occasional difficulties in swallowing liquids till two years of age, despite anti-MuSK antibodies becoming negative, suggest a fetal onset. The possible pathophysiology of this disorder, based on recent findings on the expression and function of MuSK protein, is reviewed. [Copyright &y& Elsevier]

Background and purpose: Late onset Pompe disease (LOPD) is a rare neuromuscular disorder caused by a deficit in acid alpha‐glucosidase. Macroglossia and swallowing disorders have already been reported, but no study has focused yet on its frequency and functional impact on patients' daily life. Methods: We reviewed 100 adult LOPD patients followed in 17 hospitals in France included in the French national Pompe disease registry. The Swallowing Quality of Life Questionnaire and the Sydney Swallow Questionnaire were completed by patients, and a specialist carried out a medical examination focused on swallowing and assigned a Salassa score to each patient. Respiratory and motor functions were also recorded. Subgroup analysis compared patients with and without swallowing difficulties based on Salassa score. Results: Thirty‐two percent of patients presented with swallowing difficulties, often mild but sometimes severe enough to require percutaneous endoscopic gastrostomy (1%). Daily dysphagia was reported for 20% of our patients and aspirations for 18%; 9.5% were unable to eat away from home. Macroglossia was described in 18% of our patients, and 11% had lingual atrophy. Only 15% of patients presenting with swallowing disorders were followed by a speech therapist. Swallowing difficulties were significantly associated with macroglossia (p = 0.015), longer duration of illness (p = 0.032), and a lower body mass index (p = 0.047). Conclusions: Swallowing difficulties in LOPD are common and have significant functional impact. Increased awareness by physicians of these symptoms with systematic examination of the tongue and questions about swallowing can lead to appropriate multidisciplinary care with a speech therapist and dietitian if needed. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the treatment of a patient with non-AIDS-related progressive multifocal leucoencephalopathy.

Background: Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients affected by desmin mutations remain unclear due in part, to the lack of relevant human cardiomyocyte models. Methods: To shed light on the role of mitochondria in these mechanisms, we investigated cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DESE439K mutation that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cardiomyocytes were either cultured on an anisotropic micropatterned surface to obtain elongated and aligned cardiomyocytes, or as a cardiac spheroid to create a micro-tissue. Moreover, when applicable, results from cardiomyocytes were confirmed with heart biopsies of suddenly died patient of the same family harboring DESE439K mutation, and post-mortem heart samples from five control healthy donors. Results: The heterozygous DESE439K mutation leads to dramatic changes in the overall cytoarchitecture of cardiomyocytes, including cell size and morphology. Most importantly, mutant cardiomyocytes display altered mitochondrial architecture, mitochondrial respiratory capacity and metabolic activity reminiscent of defects observed in patient's heart tissue. Finally, to challenge the pathological mechanism, we transferred normal mitochondria inside the mutant cardiomyocytes and demonstrated that this treatment was able to restore mitochondrial and contractile functions of cardiomyocytes. Conclusions: This work highlights the deleterious effects of DESE439K mutation, demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens up new potential therapeutic perspectives for this disease. [ABSTRACT FROM AUTHOR]

Background and purpose: CAV3 gene mutations, mostly inherited as an autosomal dominant trait, cause various skeletal muscle diseases. Clinical presentations encompass proximal myopathy, distal myopathy, or isolated persistent high creatine kinase (CK) with a major overlapping phenotype. Methods: Twenty‐three patients with CAV3 symptomatic mutations, from 16 different families, were included in a retrospective cohort. Mean follow‐up duration was 24.2 ± 15.0 years. Clinical and functional data were collected during the follow‐up. The results of muscle imaging, electroneuromyography, muscle histopathology, immunohistochemistry, and caveolin‐3 Western blot analysis were also compiled. Results: Exercise intolerance was the most common phenotype (52%). Eighty percent of patients had calf hypertrophy, and only 65% of patients presented rippling. One patient presented initially with camptocormia. A walking aid was required in only two patients. Electroneuromyography was mostly normal. CK level was elevated in all patients. No patient had cardiac or respiratory impairment. Muscle imaging showed fatty involvement of semimembranosus, semitendinosus, rectus femoris, biceps brachialis, and spinal muscles. Almost all (87%) of the biopsies were abnormal but without any specific pattern. Whereas a quarter of patients had normal caveolin‐3 immunohistochemistry results, Western blots disclosed a reduced amount of the protein. We report nine mutations, including four not previously described. No phenotype–genotype correlation was evidenced. Conclusions: Caveolinopathy has diverse clinical, muscle imaging, and histological presentations but often has limited functional impact. Mild forms of the disease, an atypical phenotype, and normal caveolin‐3 immunostaining are pitfalls leading to misdiagnosis. [ABSTRACT FROM AUTHOR]

During three previously reported clinical trials of avalglucosidase alfa in patients with Pompe disease, 17 out of 142 participants were considered by the investigators to be appropriate candidates for home infusion. During their respective trials, these participants received a total of 419 avalglucosidase alfa infusions at home under healthcare professional supervision. They were clinically stable with no history of moderate or severe infusion-associated reactions within at least 12 months prior to starting home infusions. As of February 25, 2022, the 15 participants with late-onset Pompe disease (LOPD) had received between 2 and 48 home infusions and the 2 participants with infantile-onset Pompe disease (IOPD) had received 19 and 20 infusions. Adverse events occurred in 8 (53 %) participants with LOPD and neither of the participants with IOPD. Seven participants with LOPD had a total of 15 non-treatment-related, non-serious adverse events. One participant with LOPD experienced infusion-associated reactions of eyelid edema and flushing during the first home infusion; both were non-serious adverse events classified as grade 1 (mild). Home infusion was later resumed for this participant. Among LOPD participants, event rates for home infusions were comparable to those for clinic infusions: overall adverse events (0.028 vs 0.039 participants with events/infusion, respectively) and adverse events classified as infusion-associated reactions (0.003 vs. 0.006, respectively). No medication errors occurred during home infusion. These data suggest that infusion of avalglucosidase alfa at home is feasible and does not compromise safety for patients who have not experienced an infusion-associated reaction during the preceding 12 months of infusions in a clinical setting. Evaluation of real-world experience with avalglucosidase alfa home infusion in countries where it is already approved is ongoing. • We assessed safety of avalglucosidase alfa home infusions in three clinical trials. • Most adverse events during home infusion were non-serious and not treatment related. • Adverse event rates were comparable for home infusions and clinic infusions. • Patient safety was not compromised with home infusion of avalglucosidase alfa. [ABSTRACT FROM AUTHOR]

The article focuses on the risk of Venous Thromboembolism in Myotonic Dystrophy. It includes information on Myopathy's association with cardiovascular mortality and facioscapulohumeral. It also offers information on topics including muscular dystrophies, Wilcoxon rank-sum test and Fisher exact test, and cause of cardiovascular death after sudden cardiac death.

• Interpretation of novel or unknown significance variants in CMS-related genes is challenging. • We propose a simple, painless ENMG protocol based on 3Hz-repetitive nerve stimulation. • 5 ENMG patterns based on the presence of R-CMAPs and the distribution of decrements in selected muscles. • ENMG patterns significantly correlated with the genetic findings. • This algorithm may improve diagnosis and therapeutic monitoring in CMS patients. Congenital myasthenic syndromes (CMS) are a group of heterogeneous diseases of the neuromuscular junction. We report electrodiagnostic testing (EDX) and genetic findings in a series of 120 CMS patients tested with a simple non-invasive EDX workup with surface recording of CMAPs and 3Hz repetitive nerve stimulation of accessory, radial and deep fibular nerves. Five ENMG phenotypes were retrieved based on the presence or not of R-CMAPs and the distribution pattern of decremental CMAP responses which significantly correlated with genetic findings (p <0.00001). R-CMAPs were found in all COLQ -mutated patients (CMS1A) and Slow Channel CMS (SCCMS) (CMS1B). CMS1A exhibited greater decrements in accessory nerve RNS than CMS1B. Patients without R-CMAPs were classified into CMS2A (DOK7-, MUSK-, GFPT1-, GMPPB-, TOR1AIP -mutated) when exhibiting predominant accessory nerve RNS decrements, CMS2B (CHRNE, CHRND, RAPSN) with predominant radial nerve RNS decrements, or CMS2C (AGRN) if there were predominant fibular decrements. Our algorithm may have a major impact on diagnostic and therapeutic monitoring in CMS patients, as well as for validation of the pathogenicity of genetic variants. It should also be part of the evaluation of unexplained muscle weakness or complex neuromuscular phenotypes. [ABSTRACT FROM AUTHOR]

Background: Patients with mitochondrial diseases are at risk of heart failure (HF) and arrhythmic major adverse cardiac events (MACE).Objectives: We developed prediction models to estimate the risk of HF and arrhythmic MACE in this population.Methods: We determined the incidence and searched for predictors of HF and arrhythmic MACE using Cox regression in 600 adult patients from a multicenter registry with genetically confirmed mitochondrial diseases.Results: Over a median follow-up time of 6.67 years, 29 patients (4.9%) reached the HF endpoint, including 19 hospitalizations for nonterminal HF, 2 cardiac transplantations, and 8 deaths from HF. Thirty others (5.1%) reached the arrhythmic MACE, including 21 with third-degree or type II second-degree atrioventricular blocks, 4 with sinus node dysfunction, and 5 sudden cardiac deaths. Predictors of HF were the m.3243A>G variant (HR: 4.3; 95% CI: 1.8-10.1), conduction defects (HR: 3.0; 95% CI: 1.3-6.9), left ventricular (LV) hypertrophy (HR: 2.6; 95% CI: 1.1-5.8), LV ejection fraction <50% (HR: 10.2; 95% CI: 4.6-22.3), and premature ventricular beats (HR: 4.1; 95% CI: 1.7-9.9). Independent predictors for arrhythmia were single, large-scale mtDNA deletions (HR: 4.3; 95% CI: 1.7-10.4), conduction defects (HR: 6.8; 95% CI: 3.0-15.4), and LV ejection fraction <50% (HR: 2.7; 95% CI: 1.1-7.1). C-indexes of the Cox regression models were 0.91 (95% CI: 0.88-0.95) and 0.80 (95% CI: 0.70-0.90) for the HF and arrhythmic MACE, respectively.Conclusions: We developed the first prediction models for HF and arrhythmic MACE in patients with mitochondrial diseases using genetic variant type and simple cardiac assessments. [ABSTRACT FROM AUTHOR]

Objectives: Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression.Methods: In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment.Results: Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM.Conclusions: Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement.Key Points: • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases. [ABSTRACT FROM AUTHOR]

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation.Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range].Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach.Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185. [ABSTRACT FROM AUTHOR]

Background: To evaluate the prevalence of cardiac involvement in patients with congenital myopathies and the association to specific genotypes. Methods: We evaluated patients with physical examination, electrocardiogram, echocardiography, and 48-h Holter monitoring. Follow-up was performed for major events. Results: We included 130 patients, 55 men (42%), with a mean age of 34 ± 17 years. A genetic diagnosis was established in 97 patients (75%). Right bundle branch block was observed in three patients: 2/34 patients with a ryanodine receptor 1 (RYR1) and 1/6 with a tropomyosin two gene (TPM2) gene mutation. Echocardiography showed left-ventricular hypertrophy in five patients: 2/17 and 3/34 patients with a Dynamin 2 (DNM2) and a RYR1 mutation, respectively. One patient with a myosin heavy-chain (MYH7) mutation had dilated cardiomyopathy and heart failure. On Holter monitoring, frequent ventricular premature contractions were observed in one patient with a DNM2 mutation. Two patients with a TPM2 and a RYR1 mutation, respectively, had a single short run of non-sustained ventricular tachycardia. Atrioventricular nodal re-entry tachycardia was observed in a 20-year-old man with an actin 1 gene mutation. During follow-up (median 8.4 years), four patients died, all of non-cardiac causes. Conclusion: Congenital myopathies are generally associated with a mild cardiac phenotype. Our findings substantiate the literature and indicate that, except for patients with specific genotypes, such as MYH7 and TTN mutations, repeated cardiac assessments can be minimized, given a normal initial cardiac screening at time of diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: In this study we evaluated the role of an electrodiagnostic provocative test (long exercise test) in McArdle disease.Methods: Twenty-five McArdle patients and 2 control groups underwent an electrodiagnostic protocol with long exercise test (LET), consisting of recording the compound muscle action potential (CMAP) before and after 5 minutes of isometric contraction.Results: The LET disclosed a postexercise decrease in CMAP amplitude in 23 of 25 McArdle patients. The immediate and long-lasting decrease differentiated McArdle patients from controls. Patients with a normal LET demonstrated milder symptoms and/or residual myophosphorylase activity.Discussion: The LET is a sensitive, safe, and noninvasive provocative test that may guide clinicians toward molecular analysis of the myophosphorylase gene. The abnormalities observed on LET point toward complex biochemical mechanisms determined by the absence of myophosphorylase, beyond simple glycolytic blockade (ionic pump dysfunction, sarcolemmal inexcitability). The normal LET in patients with milder symptoms indicates a relationship of the LET with clinical severity, thus identifying it as a potential outcome measure. Muscle Nerve, 2018. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to compare the physical and mechanical properties of stereolithography (SLA)- manufactured alumina ceramics of different composition to those of subtractive- manufactured ceramics and to produce suitable dental crown frameworks. Methods The physical and mechanical properties of a control and six experimental SLA ceramics prepared from slurries with small (S) and large (L) particles (0.46 ± 0.03 and 1.56 ± 0.04 μm, respectively) and three dry matter contents (70%, 75%, 80%) were evaluated by dynamic rheometry, hydrostatic weighing, three3-point flexural strength measurements, and Weibull analyses, and by the micrometrics measurement of shrinkage ratio before and after the heat treatments. Results S75 was the only small particle slurry with a significantly higher viscosity than L70. The viscosity of the S80 slurry made it impossible to take rheological measurements. The viscosities of the S75 and S80 slurries caused deformations in the printed layers during SLA manufacturing and were excluded from further consideration. SLA samples with low dry matter content had significantly lower and densityflexural strengths. Only SLA samples with a large particle size and high dry matter content (L75 and L80) were similar in density and flexural strength to the subtractive- manufactured samples. The 95% confidence intervals of the Weibull modulus of the L80 ceramic were higher (no overlap fraction) than those of the L75 ceramic and were similar to the control (overlap fraction). The Weibull characteristics of L80 ceramic were higher than those of L75 ceramic and the control. SLA can be used to process suitable crown frameworks but shows results in anisotropic shrinkage. Significance The hH High particle size and dry matter content of the L80 slurry allowed made it possible to produce a reliable ceramic by SLA manufacturing with an anisotropic shrinkage, and a density, and flexural strength similar to those of a subtractive-manufactured ceramic. SLA allowed made it possible to build up a dense 3D alumina crown framework with controlled shape. Further studies on the marginal adaptation and shrinkage model of alumina crown frameworks will be required to optimize the process. [ABSTRACT FROM AUTHOR]

Background and purpose Our aim was to determine the prognostic value of urine and blood heteroplasmy in patients with the m.3243A>G mutation. Methods Adults with the m.3243A>G mutation referred to our institution between January 2000 and May 2014 were retrospectively included. The relationship between their baseline clinical characteristics, their mutation load in urine and blood, and major adverse events ( MAEs) during follow-up, defined as medical complications requiring a hospitalization or complicated by death, was studied. Results Of the 43 patients (age 45.6 ± 13.3 years) included in the study, 36 patients were symptomatic, including nine with evidence of focal brain involvement, and seven were asymptomatic. Over a 5.5 ± 4.0 year mean follow-up duration, 14 patients (33%) developed MAEs. Patients with MAEs had a higher mutation load than others in urine (60.1% ± 13.8% vs. 40.6% ± 26.2%, P = 0.01) and in blood (26.9% ± 18.4% vs. 16.0% ± 12.1%, P = 0.03). Optimal cutoff values for the prediction of MAEs were 45% for urine and 35% for blood. In multivariate analysis, mutation load in urine ≥45% [odds ratio 25.3; 95% confidence interval ( CI) 1.1-567.8; P = 0.04], left ventricular hypertrophy (odds ratio 16.7; 95% CI 1.3- 222.5; P = 0.03) and seizures (odds ratio 48.3; 95% CI 2.5-933; P = 0.01) were associated with MAEs. Conclusions Patients with the m.3243A>G mutation are at high risk of MAEs, which can be independently predicted by mutation load in urine ≥45%, a personal history of seizures, and left ventricular hypertrophy. [ABSTRACT FROM AUTHOR]

Pompe disease is a rare hereditary glycogen storage disorder due to lysosomal acid alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is the only available treatment. Infusion-associated reactions (IAR) are challenging since there are no guidelines for ERT rechallenge after a drug hypersensitivity reaction (DHR) in Pompe disease. The objective of the present study was to describe IAR and their management in late-onset Pompe disease (LOPD) patients in France, and to discuss the various possibilities of ERT rechallenge. An exhaustive screening of LOPD patients receiving ERT between 2006 and 2020 from the 31-participating hospital-based or reference centers was performed. The patients who had presented at least one hypersensitivity IAR (=DHR) episode were included. Demographic characteristics of the patients, IAR onset and timing, were retrospectively collected from the French Pompe Registry. Fifteen patients among 115 treated LOPD patients in France presented at least 1 IAR; 80.0% were women. Twenty-nine IAR were reported; 18 (62.1%) IAR were Grade I reactions, 10 (34.5%) IAR were Grade II, and 1 (3.4%) IAR was Grade III. IgE-mediated hypersensitivity was found in 2/15 patients (13.3%). The median [IQR] time from ERT introduction to the first IAR was 15.0 months [11.0–24.0]. ERT was safely and effectively re-introduced either with premedication alone, or in combination with either modified regimen or desensitization protocol, in all 9 rechallenged patients; including in patients with IgE-mediated hypersensitivity, in the patient with the Grade III reaction, as well as in patients with very high anti-GAA titer. Based on the results herein and previous reports, we discuss premedication and modified regimen for Grade I reactions, and desensitization in Grade II and III reactions. In conclusion, ERT-induced IAR can be safely and effectively managed with a modified regimen or desensitization protocol in LOPD patients. • Most hypersensitivity reactions were Grade I and due to non-IgE hypersensitivity. • Most hypersensitivity reactions occurred in female LOPD patients. • Hypersensitivity reactions may occur after one year of well-tolerated ERT. • Modified regimen and desensitization were safe and effective to reintroduce ERT. [ABSTRACT FROM AUTHOR]

The prevalence and the incidence of atrial flutter in patients with myotonic dystrophy type 1 (DM1) and the most appropriate strategies for its management are unknown. We retrospectively included in the DM1 Heart Registry 929 adult patients with DM1 admitted to our Institutions between January 2000 and September 2013. We selected patients presenting with atrial flutter and analysed data relative to the occurrence of arterial thromboembolism, severe bradyarrhythmias and atrial flutter recurrences. Atrial flutter was present in 79 of the 929 patients included in our Registry, representing a 8.5% prevalence. Patients with atrial flutter were older, had a higher muscular disability rating scale score and had higher prevalence of other cardiac manifestations of DM1. Sixty patients presented with a first episode of atrial flutter, representing a 4.6% incidence. Severe bradyarrhythmias requiring permanent pacing were present in 4 patients (6.7%). Over a 53 ± 28 months mean follow-up duration, 2 patients (3.3%) had ischaemic stroke and 12 (20%) had atrial flutter recurrences. Patients who underwent radiofrequency ablation were more frequently free of atrial flutter recurrence than other patients (95 vs. 61%; HR = 0.17; P  = 0.04). Atrial flutter is a common manifestation of DM1, potentially complicated by arterial thromboembolism or severe bradyarrhythmias. Radiofrequency catheter ablation is associated with a lower risk for recurrences. [ABSTRACT FROM AUTHOR]

Background and purpose This was a retrospective study to assess the diagnostic value of the non-ischaemic forearm exercise test in detecting McArdle's disease. Methods The study is a retrospective diagnostic study over 15 years (1999-2013) on a referred sample of patients suffering from exercise intolerance and various muscle complaints, generally with elevated creatine kinase (CK). In all, 1226 patients underwent the non-ischaemic forearm exercise test. Blood lactate, ammonia and CK levels were analyzed. DNA analyses and/or muscle biopsies were assessed to confirm the diagnosis of McArdle's disease. The results of 60 volunteers were used to compare with the results of study subjects. Results In this cohort, 40 patients were finally diagnosed with McArdle's disease. Absolute values of lactate and ammonia rise were used to discriminate all McArdle patients from healthy patients. A sensitivity and specificity of respectively 100% and 99.7% were calculated. The 24-h CK level showed no significant difference from the CK level at the day of the test and confirms the safety of the test. Conclusions This study has formally assessed the diagnostic value of the non-ischaemic forearm exercise test in the detection of McArdle's disease. Very high sensitivity and specificity were observed. Furthermore, the test is easy to set up and to perform, it is non-traumatic and cost effective. It may circumvent a muscle biopsy in McArdle patients presenting the most common mutations. Hence, it is a perfect and safe screening instrument to detect patients with McArdle's disease. Glycogen storage disease type III patients, however, may show similar patterns to McArdle patients. [ABSTRACT FROM AUTHOR]

Objective: Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases. Our objective was the evaluation of the specificity and sensitivity of the signs encountered with POLG mutations. Design: Forty-four patients out of 154 with sequenced POLG gene had mutations affecting either one (POLG+/- group) or two POLG alleles (POLG+/+ group). Phenotyping included clinical signs, electroneuromyography and brain imaging while mitochondrial investigations encompassed muscle histochemistry, respiratory chain assays and search for multiple mitochondrial deletions. The specificity and sensitivity of the signs associated with POLG mutations were analysed by comparison between POLG+/+ and patients without POLG mutation. Results: High sensitivity but low specificity was observed with single signs such as axonal sensory neuropathy, cerebellar syndrome, movement disorders and weakness involving ocular, pharyngeal, axial and/or limb muscles. Specificity was increased with combination of previous signs plus psychiatric symptoms, cognitive impairment and epilepsy. High specificity and sensitivity was only obtained with sensory neuronopathy associated with one of the following signs: weakness of ocular, pharyngeal, axial and/ or limb muscles. Mitochondrial investigations did not suffice for diagnosis. The widespread neuromuscular signs were often present since disease onset and were the rule above 50 years of age leading to a very low probability of POLG mutations in patients with less than three signs and absent sensory neuropathy. Conclusions: Phenotypes associated with POLG mutations follow a reproducible pattern, which allows establishing a diagnostic flow chart. [ABSTRACT FROM AUTHOR]

The article discusses a study on the association of an invasive strategy based on systemic electrophysiological studies and prophylactic permanent pacing with longer survival rate in patients with myotonic dystrophy type 1 and conduction system disease. The study focused on 914 patients included in the DM1 Heart Registry who were more than 18 years old and were admitted to the Neurological Unit of the Myology Institute of Pitié-Salpêtrière Hospital in Paris, France from January 2000 to December 2009. Fifty patients in the invasive strategy group died while in the noninvasive strategy group, 30 patients died over a median follow-up of 7.4 years. The study showed that an invasive strategy was linked with a higher survival rate compared with a noninvasive strategy.

Abstract: New classification of idiopathic inflammatory myopathy (IIM) defined three major entities, polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (s-IBM). We report the clinical, electrophysiological and pathological characteristics of three patients with a rare form of IIM not fulfilling the diagnostic criteria for any of these three major entities. The three patients presented with a subacute, distal asymmetrical weakness in upper limbs. Muscle biopsy showed an active myositis, with necrosis and regeneration, T cell infiltrates with invasion of non-necrotic fibers, without rimmed vacuoles, and diffuse major histocompatibility complex-I (MHC-I) immunostaining in muscle fibers. All patients responded to immunosuppressive agents. Seven others cases were identified in the literature. It is important to recognize this atypical presentation as it seems to respond to immunosuppressive agents. [Copyright &y& Elsevier]

In the past fifteen years, more than 1200 patients underwent the non-ischemic forearm exercise test (NIFET) in our referral center as a first screening tool for the detection of metabolic myopathies. Finally 40 patients were diagnosed so far with a McArdle disease (glycogenosis type V). As a consequence of the absence of phosphorylase enzyme, no rise of lactate and an elevated rise of ammonia are generally described after exercise. The aim of this retrospective study was to formally assess the results of the NIFET to determine optimal diagnostic criteria as the first screening instrument in the diagnostic process in McArdle disease (sensitivity), and to check if other diagnoses were inferred using these diagnostic criteria (specificity). Forty patients with McArdle disease were definitively diagnosed; 21 were males, 19 females. They were aged between 8 and 72 years. The mean age of diagnosis was 35.6 ± 16.1 years. Most of them had muscle complaints since their childhood. Half of them experienced at least one episode of rhabdomyolysis in their life marked by dark urine. Finally all the patients had previous elevated CK levels above 500 IU/L and recognized the second wind phenomenon, which is pathognomonic for McArdle disease. Diagnosis was confirmed by genetic analysis of the PYGM gene. Three quarters of the patients were homozygous or compound heterozygous for the most frequent p.Arg50X mutation. Four novel mutations were revealed. A lactate rise <1.0 mmol/L and an ammonia rise >40 μmol/L discriminated all the McArdle patients from normal subjects. Three patients with glycogenosis type III were also found with these values. A sensitivity and specificity of respectively 100 % and 99.8% were calculated. The safety of the test was confirmed by the fact that the 24H-CK level showed no significant difference of the CK level at the day of the test. This retrospective analysis proves that the NIFET is safe and highly efficient for the detection of McArdle disease with no false positive results. [ABSTRACT FROM AUTHOR]

Abstract: Beta-tropomyosin 2 (TPM2) gene mutations are a rare cause of congenital myopathy with variable clinical and histological features. We describe muscle involvement using Whole-Body muscle Magnetic Resonance Imaging (WBMRI) in 8 individuals with genetically proven TPM2 mutations and different clinical and histological features (nemaline myopathy, ‘cap disease’, Bethlem-like phenotype, arthrogryposis). Most patients shared a recognizable MRI pattern with the involvement of masticatory and distal lower leg muscles. The lower leg showed constant soleus muscle involvement, and often also involvement of peroneus, tibialis anterior, and toe flexor muscles. Pelvic and shoulder girdles, and upper limbs muscles were quite spared. Two adult subjects (a patient and a paucisymptomatic parent) had a more diffuse involvement with striking fat infiltration of the rectus femoris muscle. Two children showed variant findings: one presented with masseter involvement associated with severe axial fat infiltration, the second had masticatory and distal leg muscle involvement (soleus and gastrocnemius muscles). Our study suggests that, independently of the clinical and histological presentation, most patients with TPM2 mutations show a predominant involvement of masticatory and distal leg muscles with the other regions relatively spared. More spread involvement may be observed. This cephalic-distal MRI pattern is not frequent in other known myopathies. [Copyright &y& Elsevier]

Abstract: Up to one-third of patients with myotonic dystrophy type 1 (DM1) die suddenly. Thus far, no intervention has effectively prevented sudden death. The objective was to determine whether an invasive strategy (IS) based on systematic electrophysiological studies and prophylactic permanent pacing is associated with longer survival in patients presenting with DM1 and major infranodal conduction delays than a noninvasive strategy (NIS). A retrospective study, the DM1 Heart Registry, included 914 consecutive patients older than 18years with genetically confirmed DM1 who were admitted to the Myology Institute of Pitié-Salpêtrière Hospital, between January 2000 and December 2009. Among 486 patients whose electrocardiogram showed a PR interval greater than 200ms, a QRS duration greater than 100ms, or both, we compared the outcome of 341 (70.2%) who underwent an IS was compared with 145 (29.8%) who underwent a NIS. A propensity score risk adjustment and propensity-based matching analysis was used to account for selection biases. Over a median follow-up of 7.4years (range 0–9.9years), 50 patients died in the IS group and 30 died in the NIS group (hazard ratio [HR], 0.74 [95 CI, 0.47–1.16]; P =.19), corresponding to an overall 9-year survival of 74.4% (95% CI, 69.2%–79.9%). Regardless of the technique used to adjust for between-group differences in baseline characteristics, the IS was associated with a longer survival, with adjusted HRs ranging from 0.47 (95% CI, 0.26–0.84; P =.01) to 0.61 (95% CI, 0.38–0.99; P =.047). The survival difference was largely attributable to a lower incidence of sudden death, which occurred in 10 patients in the IS group and in 16 patients in the NIS group, with HRs ranging from 0.24 (95% CI, 0.10–0.56; P =.001) to 0.28 (95% CI, 0.13–0.61; P =.001). Among patients with DM1, an invasive strategy was associated with a higher rate of 9-year survival than a noninvasive strategy. [Copyright &y& Elsevier]