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Background Visual Snow Syndrome is a recently recognized neurological condition presenting, continuous, tiny dots across the entire visual field, accompanied by nyctalopia, photophobia and palinopsia that persist for months. It may be part of migraine aura spectrum, yet its definition is still questionable. Diagnostic criteria for Visual Snow Syndrome are included in the supplemental material of ICHD-3. We aimed to summarize recent data to improve the understanding of Visual Snow Syndrome. Methods After presenting four new cases, we conducted a PRISMA systematic search in PubMed/MEDLINE and Embase databases using the keyword “visual snow” with specific inclusion and exclusion criteria. Results From the 855 articles identified 30 were included for the qualitative analysis. These reports covered five aspects related to Visual Snow Syndrome: epidemiology, clinical features, comorbidities, pathophysiology, and treatment. We found limited data concerning Visual Snow Syndrome’s epidemiology (one study). Clinical presentation (22 articles) and the comorbidities (migraine with aura and tinnitus most often, five reports) are described in detail. The pathophysiology of Visual Snow Syndrome is only approached with hypotheses, but several neuroimaging studies have been identified (seven articles). Treatment is based on single case reports only. Conclusion Data for Visual Snow Syndrome are few and not strong enough to support Visual Snow Syndrome as a medical identity. Further investigation is needed.

Spiliopoulou, P, Zaras, N, Methenitis, S, Papadimas, G, Papadopoulos, C, Bogdanis, GC, and Terzis, G. Effect of concurrent power training and high-intensity interval cycling on muscle morphology and performance. J Strength Cond Res 35(9): 2464-2471, 2021-The aim of the study was to examine the effect of performing high-intensity interval cycling on muscle morphology and performance immediately after power training (PT). Twenty healthy female physical education students were assigned into 2 training groups. One group performed PT, and the other group performed the same PT followed by high-intensity interval aerobic training on a cycle ergometer (PTC). Training was performed 3 days per week for 6 weeks. Countermovement jump (CMJ) height and CMJ power, half-squat maximal strength (1 repetition maximum), maximum aerobic power, vastus lateralis muscle fiber composition, and cross-sectional area (CSA) were evaluated before and after the intervention. Countermovement jump height increased after PT (10.1 ± 6.6%, p = 0.002) but not after PTC (-5.1 ± 10.5%, p = 0.099), with significant difference between groups (p = 0.001). Countermovement jump power increased after PT (4.5 ± 4.9%, p = 0.021) but not after PTC (-2.4 ± 6.4, p = 0.278), with significant difference between groups (p = 0.017). One repetition maximum increased similarly in both groups. Muscle fiber composition was not altered after either PT or PTC. Vastus lateralis muscle fiber CSA increased significantly and similarly after both PT (I: 16.9 ± 16.2%, p = 0.035, ΙΙΑ: 12.7 ± 10.9%, p = 0.008,ΙΙΧ: 15.5 ± 17.1%, p = 0.021) and PTC (Ι: 18.0 ± 23.7%, p = 0.033,ΙΙΑ: 18.2 ± 11.4%, p = 0.001,ΙΙΧ: 25.5 ± 19.6%, p = 0.003). These results suggest that the addition of high-intensity interval cycling to PT inhibits the anticipated increase in jumping performance induced by PT per se. This inhibition is not explained by changes in muscle fiber type composition or vastus lateralis muscle fiber CSA adaptations.

Myotonic Dystrophies (DM, Dystrophia Myotonia) are autosomal dominant inherited myopathies with a high prevalence across different ethnic regions. Despite some differences, mainly due to the pattern of muscle involvement and the age of onset, both forms, DM1 and DM2, share many clinical and genetic similarities. In this study, we retrospectively analyzed the medical record files of 561 Greek patients, 434 with DM1 and 127 with DM2 diagnosed in two large academic centers between 1994–2020. The mean age at onset of symptoms was 26.2 ± 15.3 years in DM1 versus 44.4 ± 17.0 years in DM2 patients, while the delay of diagnosis was 10 and 7 years for DM1 and DM2 patients, respectively. Muscle weakness was the first symptom in both types, while myotonia was more frequent in DM1 patients. Multisystemic involvement was detected in the great majority of patients, with cataracts being one of the most common extramuscular manifestations, even in the early stages of disease expression. In conclusion, the present work, despite some limitations arising from the retrospective collection of data, is the first record of a large number of Greek patients with myotonic dystrophy and emphasizes the need for specialized neuromuscular centers that can provide genetic counseling and a multidisciplinary approach.

Objective: Mutations in the prion-like domain of RNA binding proteins cause dysfunctional stress responses and associated aggregate pathology in patients with neurogenic and myopathic phenotypes. Recently, mutations in ANXA11 have been reported in patients with amyotrophic lateral sclerosis and multisystem proteinopathy. Here we studied families with an autosomal dominant muscle disease caused by ANXA11:c.118G > T;p.D40Y. Methods: We performed deep phenotyping and exome sequencing of patients from four large Greek families, including seven affected individuals with progressive muscle disease but no family history of multi-organ involvement or ALS. Results: In our study, all patients presented with an autosomal dominant muscular dystrophy without any Paget disease of bone nor signs of frontotemporal dementia or Parkinson's disease. Histopathological analysis showed rimmed vacuoles with annexin A11 accumulations. Electron microscopy analysis showed myofibrillar abnormalities with disorganization of the sarcomeric structure and Z-disc dissolution, and subsarcolemmal autophagic material with myeloid formations. Molecular genetic analysis revealed ANXA11:c.118G > T;p.D40Y segregating with the phenotype. Interpretation: Although the pathogenic mechanisms associated with p.D40Y mutation in the prion-like domain of Annexin A11 need to be further clarified, our study provides robust and clear genetic evidence to support the expansion of the phenotypic spectrum of ANXA11. publishedVersion

The short-term mortality and rehospitalization rates after admission for acute heart failure (AHF) remain high, despite the high level of adherence to contemporary practice guidelines. Observational data from non-randomized studies in AHF strongly support the in-hospital administration of oral evidence-based modifying chronic heart failure (HF) medications (i.e., b-blockers, ACE inhibitors, mineralocorticoid receptor antagonists) to reduce morbidity and mortality. Interestingly, a well-designed prospective randomized multicenter study (PIONEER-HF) showed an improved clinical outcome and stress/injury biomarker profile after in-hospital administration of sacubitril/valsartan (sac/val) as compared to enalapril, in hemodynamically stable patients with AHF. However, sac/val implementation during hospitalization remains suboptimal due to the lack of an integrated individualized plan or well-defined appropriateness criteria for transition to oral therapies, an absence of specific guidelines regarding dose selection and the up-titration process, and uncertainty regarding patient eligibility. In the present expert consensus position paper, clinical practical recommendations are proposed, together with an action plan algorithm, to encourage and facilitate sac/val administration during hospitalization after an AHF episode with the aim of improving efficiencies of care and resource utilization.

Introduction Spinal muscular atrophy (SMA) most prominently affects proximal limb and bulbar muscles. Despite older case descriptions, ocular motor neuron palsies or other oculomotor abnormalities are not considered part of the phenotype. Methods We investigated oculomotor function by testing saccadic eye movements of 15 patients with SMA. Their performance was compared with that of age-matched healthy controls. Horizontal rightward and leftward saccades were recorded by means of video-oculography, whereas subjects looked at light-emitting diode targets placed at ±5°, ±10°, and ±15° eccentricities. Results No differences in saccade amplitude gains, peak velocities, peak velocity-to-amplitude ratios, or durations were observed between controls and patients. More specifically, for 5° target eccentricities, patients had a mean saccadic peak velocity of 153°/s, whereas for 10° and 15° these values were 268°/s and 298°/s, respectively. The corresponding mean peak velocities of the control group were 151°/s, 264°/s, and 291°/s. Discussion Our results indicate that patients with SMA perform fast and accurate horizontal saccades without evidence of extraocular muscle weakness. These quantitative oculomotor data corroborate clinical experience that neuro-ophthalmic symptoms in SMA are not common and, if present, should prompt suspicion for an alternative neuromuscular disorder.

Background Myotonic dystrophy type 2 (DM2) is a neuromuscular disorder characterized by myotonia and muscle weakness, with no medical treatment to prevent a decline in decline. It is unknown whether exercise training is effective in DM2. The aim of this study was to investigate the effect of exercise training on functional capacity and body composition in these patients. Methods Body composition and functional capacity were evaluated at the beginning (T1) and end (T2) of a 12 wk control period, and again after 16 wk of exercise training (T3) in 10 patients. Results No changes were recorded after the control period. Handgrip strength, 5× sit to stand, timed up and go, 6 min walk distance, lean body mass (LBM), and bone mineral density (BMD) increased while arterial pressure decreased after training. Conclusions These results suggest that supervised exercise training improves functional capacity, LBM, and BMD in ambulatory DM2 patients.

Pompe disease is a rare autosomal recessive disorder caused by the deficiency of acid α-glycosidase resulting in accumulation of glycogen in the lysosomes. The late-onset form of the disease (LOPD) causes primarily progressive muscle weakness and respiratory insufficiency. Enzyme replacement therapy (ERT) introduced in 2006, showed mild improvement or stabilization of the symptoms although long-term data are limited. Aim of the study was to describe the progression of body composition and walking ability in LOPD patients receiving ERT consistently for 9 years.Lean body mass, bone mineral density, body fat and 6 min walking distance were assessed in three male and three female LOPD patients (height 165.8 ± 11.2 cm, age 42.3 ± 11.8yrs, body mass 71.1 ± 20.8 kg, at study entry), every three years, for 9 years since ERT initiation (T0, T3, T6, T9).Total body and upper extremities' lean mass remained unchanged (The current data show that enzyme replacement therapy may preserve lean body mass, bone mineral density and walking capacity in LOPD patients.

Background: Promising genetic treatments targeting the molecular defect of severe early-onset genetic conditions are expected to dramatically improve patients’ quality of life and disease epidemiology. Spinal Muscular Atrophy (SMA), is one of these conditions and approved therapeutic approaches have recently become available to patients. Objective: Analysis of genetic and clinical data from SMA patients referred to the single public-sector provider of genetic services for the disease throughout Greece followed by a retrospective assessment in the context of epidemiology and genotype-phenotype associations. Methods: Molecular genetic analysis and retrospective evaluation of findings for 361 patients tested positive for SMA- and 862 apparently healthy subjects from the general population. Spearman rank test and generalized linear models were applied to evaluate secondary modifying factors with respect to their impact on clinical severity and age of onset. Results: Causative variations- including 5 novel variants- were detected indicating a minimal incidence of about 1/12,000, and a prevalence of at least 1.5/100,000. For prognosis a minimal model pertaining disease onset before 18 months was proposed to include copy numbers of NAIP (OR = 9.9;95% CI, 4.7 to 21) and SMN2 (OR = 6.2;95% CI, 2.5–15.2) genes as well as gender (OR = 2.2;95% CI, 1.04 to 4.6). Conclusions: This long-term survey shares valuable information on the current status and practices for SMA diagnosis on a population basis and provides an important reference point for the future assessment of strategic advances towards disease prevention and health care planning.

Muscular dystrophies are a group of rare and severe inherited disorders mainly affecting the muscle tissue. Duchene Muscular Dystrophy, Myotonic Dystrophy types 1 and 2, Limb Girdle Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy are some of the members of this family of disorders. In addition to the current diagnostic tools, there is an increasing interest for the development of novel non-invasive biomarkers for the diagnosis and monitoring of these diseases. miRNAs are small RNA molecules characterized by high stability in blood thus making them ideal biomarker candidates for various diseases. In this study, we present the first genome-wide next-generation small RNA sequencing in serum samples of five different types of muscular dystrophy patients and healthy individuals. We identified many small RNAs including miRNAs, lncRNAs, tRNAs, snoRNAs and snRNAs, that differentially discriminate the muscular dystrophy patients from the healthy individuals. Further analysis of the identified miRNAs showed that some miRNAs can distinguish the muscular dystrophy patients from controls and other miRNAs are specific to the type of muscular dystrophy. Bioinformatics analysis of the target genes for the most significant miRNAs and the biological role of these genes revealed different pathways that the dysregulated miRNAs are involved in each type of muscular dystrophy investigated. In conclusion, this study shows unique signatures of small RNAs circulating in five types of muscular dystrophy patients and provides a useful resource for future studies for the development of miRNA biomarkers in muscular dystrophies and for their involvement in the pathogenesis of the disorders. This Project (the european regional development fund and the republic of Cyprus through the research and innovation foundation POST-DOC/0916/0235) was co-financed by the European Regional Development Fund and the Republic of Cyprus through the Research and Innovation Foundation. A.C.K, A.O., M.T. and G.M.S. were funded by the European Commission Research Executive Agency Grant BIORISE [number the spreading excellence, widening participation, science with and for society framework 669026], under the Spreading Excellence, Widening Participation, Science with and for Society Framework. HL receives support from the Canadian Institutes of Health Research (Foundation Grant the canadian institutes of health research FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (the Canada foundation for innovation CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, the Canada research chairs program 950-232279)

In contrast to myotonic dystrophy type 1, the cognitive and radiologic profile of myotonic dystrophy type 2 (DM2) is relatively poorly characterized.To conduct a pilot study to systematically evaluate cognitive and radiologic features in a cohort of Greek individuals with DM2.Eleven genetically confirmed individuals with DM2 and 26 age- and education-matched healthy controls were administered the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) to screen for impairment in multiple cognitive domains. MRI data were evaluated by morphometric analyses to identify disease-specific gray and white matter alterations. The following statistical thresholds were used for cognitive comparisons: PFDR0.05 and Bayes factor (BF 10 )10.The DM2 group exhibited cognitive impairment (ECAS Total score; PFDR = 0.001; BF 10 = 108.887), which was dominated by executive impairment ( PFDR = 0.003; BF 10 = 25.330). A trend toward verbal fluency impairment was also identified. No significant impairments in memory, language, or visuospatial function were captured. The analysis of subscores revealed severe impairments in social cognition and alternation. Voxel-based morphometry identified widespread frontal, occipital, and subcortical gray matter atrophy, including the left superior medial frontal gyrus, right medial orbitofrontal gyrus, right operculum, right precuneus, bilateral fusiform gyri, and bilateral thalami.DM2 may be associated with multifocal cortical and thalamic atrophy, which is likely to underpin the range of cognitive manifestations mostly characterized by executive impairment and specifically by impaired social cognition.

Assessing long-term mortality and identifying predictors of death in adults with mitochondrial diseases. We retrospectively included adult patients with genetically proven mitochondrial diseases referred to our centre between January 2000 and June 2016, and collected information relative to their genetic testing, clinical assessments, and vital status. We performed single and multiple variable analyses in search of predictors of total mortality, and calculated hazard ratios (HR) and 95% confidence intervals (CI). We included 267 patients (women 59%; median age 43.3 [31.3-54.2] years), including 111 with mitochondrial DNA (mtDNA) single large-scale deletions, 65 with m.3243A>G, 24 with m.8344A>G, 32 with other mtDNA point mutations, and 36 patients with nuclear genes mutations. Over a median follow-up of 8.9 years (0.3 to 18.7), 61 patients (22.8%) died, at a median age of 50.7 (37.9-51.9) years. Primary cause of death was cardiovascular disease in 16 patients (26.2%), respiratory in 11 (18.0%), and gastrointestinal in 5 (8.1%). By multiple variable analysis, diabetes (HR 2.75; 95% CI 1.46-5.18), intraventricular cardiac conduction defects (HR 3.38; 95% CI 1.71-6.76) and focal brain involvement (HR 2.39; 95% CI 1.25-4.57) were independent predictors of death. Adult patients with mitochondrial diseases present high morbidity that can be independently predicted by the presence of diabetes, intraventricular cardiac conduction defects, and focal brain involvement.

Late onset Pompe disease (LOPD) is a slowly progressive metabolic myopathy with variable clinical severity. The advent of enzyme replacement therapy (ERT) has modified the natural course of the disease, though the treatment effect on adult patients is modest compared to infants with the classic form. This study aims to describe the long-term clinical outcome of the Greek LOPD cohort, as assessed by 6 min walk test, muscle strength using MRC grading scale and spirometry. ERT efficacy was estimated using statistical methodology that is novel in the context of Pompe disease, which at the same time is well-suited to longitudinal studies with small samples and missing data (local non-linear regression analysis). Improvement over baseline was significant at 1 year for motor performance and muscle strength (p0.05), and at 2 years for FVC-U and FVC-S (p0.05). A subgroup analysis showed that the onset of the disease before adulthood (18 years), a male gender, and a latency of more than 2 years between the onset of symptoms and ERT administration are unfavorable prognostic factors. Conclusively, this study presents longitudinal data from the Greek LOPD cohort supporting previous observations, that therapeutic delay is related to worse prognosis and treatment effects may decline after several years of ERT.

This study aimed to investigate the effect of 3 different eccentric-only power training volumes on muscle fiber type composition and power performance. Twenty-nine females were assigned into 3 groups and performed 10 weeks of either 3 (low volume), 6 (moderate volume), or 9 (high volume) sets/session of 4 fast-velocity eccentric-only half-squats against 70% of concentric 1-repetition maximum (1RM), followed by 3 maximum countermovement jumps (CMJs) after each set. Half-squat 1RM, CMJ height/power, maximum isometric force, rate of force development (RFD) and muscle fiber cross-sectional area (CSA) were increased in all groups (p = 0.001). Low-volume training induced higher increases in CMJ height/power and early RFD, compared with the moderate- and high-volume training programs (p < 0.001). Significant reductions in type IIx muscle fiber percentages and %CSAs were found after moderate- and high-volume training, with concomitant increases in type IIa fibers (p = 0.001). Significant correlations were found between the changes in type IIa and type IIx percentages, fiber CSA, %CSA, and the changes in performance (r: –0.787 to 0.792; p < 0.05). These results suggest that relatively large eccentric power training volumes may result in detrimental neuromuscular adaptations, minimal changes in early RFD, and a reduction of type IIx muscle fiber percentage. Novelty Low but not high volume of power training maintains type IIx muscle fibers. Early rate of force development increases after a low- or moderate-power training volume, but not after a high-power training volume. Training-induced changes in type IIx muscle fiber percentage is related with changes in early rate of force development.

Cardiac arrhythmias refer to any abnormality or disturbance in the normal activation sequence of the myocardium and may be indicative of structural heart disease and the cause of significant cardiovascular complications and sudden cardiac death. The following review summarizes the current state-of-the-art knowledge on the role of echocardiography in the management of cardiac arrhythmias and focuses on atrial fibrillation and ventricular arrhythmias where echocardiography presents a particular diagnostic and prognostic interest. Moreover, a brief reference is made to the effect of cardiac arrhythmias and conduction abnormalities on echocardiographic examination. Keywords: Atrial fibrillation, Ventricular arrhythmias, Echocardiography

We report the clinical, morphological and molecular features of two patients with autosomal recessive SLC25A4 (ANT1) gene mutations. Furthermore, all previously published cases are reviewed to identify valuable features for future diagnosis. Patients present a common phenotype with exercise intolerance, hyperlactatemia, and hypertrophic cardiomyopathy. Muscle biopsies show wide sub-sarcolemmal mitochondrial aggregates, and increased activities of all respiratory chain complexes. The phenotype of recessive SLC25A4 (ANT1) mutations although rare, is homogenous and easily recognizable and could help orientate the molecular analysis in adults with exercise intolerance associated with hyperlactatemia.

The mitochondrial DNA depletion syndrome (MDDS) is characterized by extensive phenotypic variability and is due to nuclear gene mutations resulting in reduced mtDNA copy number. Thymidine kinase 2 (TK2) mutations are well known to be associated with MDDS. Few severely affected cases carrying the c.416C > T mutation in TK2 gene have been described so far. We describe the case of a 14months boy with the aforementioned TK2 gene pathogenic mutation at a homozygous state, presenting with a mild clinical phenotype. In addition to severe mitochondrial pathology on muscle biopsy, there was also histochemical evidence of adenylate deaminase deficiency. Overall, this report serves to further expand the clinical spectrum of TK2 mutations associated with MDDS.

Myotonic dystrophies (DMs) are hereditary, multisystem, slowly progressive myopathies. One of the systems they affect is the CNS. In contrast to the well-established cognitive profile of myotonic dystrophy type 1 (DM1), only a few studies have investigated cognitive dysfunction in individuals with myotonic dystrophy type 2 (DM2), and their findings have been inconsistent. To identify the most commonly affected cognitive domains in individuals with DM2, we performed a formal comprehensive review of published DM2 studies. Using the terms "myotonic dystrophy type 2" AND "cognitive deficits," "cognitive," "cognition," "neuropsychological," "neurocognitive," and "neurobehavioral" in all fields, we conducted an advanced search on PubMed. We read and evaluated all of the available original research articles (13) and one case study, 14 in total, and included them in our review. Most of the research studies of DM2 reported primary cognitive deficits in executive functions (dysexecutive syndrome), memory (short-term nonverbal, verbal episodic memory), visuospatial/constructive-motor functions, and attention and processing speed; language was rarely reported to be affected. Based on the few neuroimaging and/or multimodal DM2 studies we could find, the cognitive profile of DM2 is associated with brain abnormalities in several secondary and high-order cortical and subcortical regions and associative white matter tracts. The limited sample size of individuals with DM2 was the most prominent limitation of these studies. The multifaceted profile of cognitive deficits found in individuals with DM2 highlights the need for routine neuropsychological assessment at both baseline and follow-up, which could unveil these individuals' cognitive strengths and deficits.

The congenital disorders of glycosylation (CDG) are inborn errors of metabolism with a great genetic heterogeneity. Most CDG are caused by defects in the N-glycan biosynthesis, leading to multisystem phenotypes. However, the occurrence of tissue-restricted clinical symptoms in the various defects in dolichol-phosphate-mannose (DPM) synthesis remains unexplained. To deepen our understanding of the tissue-specific characteristics of defects in the DPM synthesis pathway, we investigated N-glycosylation and O-mannosylation in skeletal muscle of three DPM3-CDG patients presenting with muscle dystrophy and hypo-N-glycosylation of serum transferrin in only two of them. In the three patients, O-mannosylation of alpha-dystroglycan (αDG) was strongly reduced and western blot analysis of beta-dystroglycan (βDG) N-glycosylation revealed a consistent lack of one N-glycan in skeletal muscle. Recently, defective N-glycosylation of βDG has been reported in patients with mutations in guanosine-diphosphate-mannose pyrophosphorylase B (GMPPB). Thus, we suggest that aberrant O-glycosylation of αDG and N-glycosylation of βDG in skeletal muscle is indicative of a defect in the DPM synthesis pathway. Further studies should address to what extent hypo-N-glycosylation of βDG or other skeletal muscle proteins contribute to the phenotype of patients with defects in DPM synthesis. Our findings contribute to our understanding of the tissue-restricted phenotype of DPM3-CDG and other defects in the DPM synthesis pathway.

Polymyositis with mitochondrial pathology (PM-Mito) is a rare form of idiopathic inflammatory myopathy with no definite diagnostic criteria and similarities to both PM and sporadic inclusion body myositis (s-IBM). The aim of this study is to address the dilemma of whether PM-Mito is a subtype of inflammatory myopathy or represents a disease falling into the spectrum of s-IBM. Herein, we report four female patients diagnosed with PM-Mito, highlighting their rather atypical clinical and histopathological characteristics that seem to indicate a diagnosis away from s-IBM. Muscle weakness was rather proximal and symmetrical and lacked the selective pattern observed in s-IBM. Patients had large-scale deletions in mtDNA, reflecting the mitochondrial component in the pathology of the disease. Conclusively, our study adds to the limited data in the literature on whether PM-Mito is a distinct form of myositis or represents a prodromal stage of s-IBM. Although the latter seems to be supported by a substantial body of evidence, there are, however, important differences, such as the different patterns of muscle weakness, and the good response to treatment observed in some patients. Larger-scale studies are certainly needed to clarify pathogenesis and clinical characteristics of PM-Mito patients, especially in therapeutic and prognostic terms.

Background GNE-myopathy is increasingly diagnosed in different ethnicities worldwide. No clear genotype-phenotype correlation has been established to date. Case reports We describe two affected members of the same family from Balkan population carrying an already known homozygous pathogenic mutation in the kinase domain of the UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamime kinase (GNE) gene. The patients presented with severe distal weakness of lower legs combined with rimmed vacuoles in muscle biopsy. However, in contrast to the typical pattern of muscle involvement, one of them showed severe involvement of posterior calf muscles with spared anterior compartment of the lower leg muscles. Conclusions These patients provide evidence for a larger variability and further extend the phenotypic spectrum of GNE-myopathy to include preferential calf involvement.

A 50-year-old man with facioscapulohumeral muscular dystrophy 1 (FSHD1), scapuloperoneal weakness, and bilateral scapular winging presents a downward movement of his umbilicus while attempting to get up from the recumbent position (video 1). Beevor sign, an upward umbilicus deviation when the supine patient is flexing the neck or tries to sit up without the use of the hands, indicates lower abdominal muscle weakness. It is highly sensitive and specific, but not diagnostic, for FSHD1, because it is described in other myopathies.1,2 Beevor sign may be present in this “inverted” form, indicating predominant weakness of upper rectus abdominis muscle.

Congenital myopathies (CMs) constitute a group of heterogenous rare inherited muscle diseases with different incidences. They are traditionally grouped based on characteristic histopathological findings revealed on muscle biopsy. In recent decades, the ever-increasing application of modern genetic technologies has not just improved our understanding of their pathophysiology, but also expanded their phenotypic spectrum and contributed to a more genetically based approach for their classification. Later onset forms of CMs are increasingly recognised. They are often considered milder with slower progression, variable clinical presentations and different modes of inheritance. We reviewed the key features and genetic basis of late onset CMs with a special emphasis on those forms that may first manifest in adulthood.

The development of chronic, low-grade systemic inflammation in the elderly (inflammaging) has been associated with increased incidence of chronic diseases, geriatric syndromes, and functional impairments. The aim of this study was to examine differences in habitual physical activity (PA), dietary intake patterns, and musculoskeletal performance among community-dwelling elderly men with low and elevated systemic inflammation. Nonsarcopenic older men free of chronic diseases were grouped as ‘low’ (LSI: n = 17; 68.2 ± 2.6 years; hs-CRP: 1 mg/L) systemic inflammation according to their serum levels of high-sensitivity CRP (hs-CRP). All participants were assessed for body composition via Dual Emission X-ray Absorptiometry (DEXA), physical performance using the Short Physical Performance Battery (SPPB) and handgrip strength, daily PA using accelerometry, and daily macro- and micronutrient intake. ESI was characterized by a 2-fold greater hs-CRP value than LSI (p < 0.01). The two groups were comparable in terms of body composition, but LSI displayed higher physical performance (p < 0.05), daily PA (step count/day and time at moderate-to-vigorous PA (MVPA) were greater by 30% and 42%, respectively, p < 0.05), and daily intake of the antioxidant vitamins A (6590.7 vs. 4701.8 IU/day, p < 0.05), C (120.0 vs. 77.3 mg/day, p < 0.05), and E (10.0 vs. 7.5 mg/day, p < 0.05) compared to ESI. Moreover, daily intake of vitamin A was inversely correlated with levels of hs-CRP (r = −0.39, p = 0.035). These results provide evidence that elderly men characterized by low levels of systemic inflammation are more physically active, spend more time in MVPA, and receive higher amounts of antioxidant vitamins compared to those with increased systemic inflammation.

Background The efficacy of enzyme replacement therapy (ERT) in patients at an advanced stage of Pompe disease has only been addressed in a few studies. Our objective was to assess the long term effects of ERT in a cohort of patients with severe Pompe disease. Methods We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT. Patients' medical records were collected and reviewed and respiratory and motor functions, before ERT initiation and upon last evaluation were compared. Results Twelve patients (7 males) were identified. Median age at symptom onset was 24 years [IQR = 15.5; 36.0]. At baseline ventilation was invasive in 11 patients and noninvasive in one, with a median ventilation time of 24 h [IQR = 21.88; 24.00] (min 20; max 24). ERT was initiated at a median age of 52.5 years [IQR = 35.75; 66.50]. Median treatment duration was 55 months [IQR = 39.5; 81.0]. During observational period no adverse reaction to ERT was recorded, five patients (41.67%) died, three decreased their ventilation time by 30, 60 and 90 min and two increased their assisted walking distance, by 80 and 20 m. Conclusion Some patients at a very advanced stage of Pompe disease may show a mild benefit from ERT, in terms of increased time of autonomous ventilation and of enlarged distance in assisted walk. ERT can be initiated in these patients in order to retain their current level of independence and ability to perform daily life activities.

Pompe disease is an autosomal recessive disorder caused by the deficiency of acid α-glucosidase resulting in lysosomal accumulation of glycogen and abnormal autophagic function. The late-onset form of the disease is characterized by progressive skeletal and respiratory muscle dysfunction. Enzyme replacement therapy (ERT, Genzyme Corporation, Cambridge, MA, USA) was recently introduced and resulted in significant prolongation of the life expectancy of the patients with the infantile form while the results were less significant for the late-onset form. It has been postulated that the weak influence of ERT in late-onset patients might be due to a non-effective delivery of the recombinant enzyme to the skeletal muscles perhaps due to the relatively low blood flow to the resting skeletal muscles during infusion. Exercise training acutely increases the blood flow to the exercising muscles. Thus, it was hypothesized that exercise training during enzyme infusion might increase the effectiveness of the ERT therapy. Five late-onset Pompe disease patients receiving ERT and following regular exercise training for approximately 10 months, followed a 6-month period of exercise training during infusion of the recombinant enzyme. Before and after this period, body composition, isometric strength and 6 minute walking distance were determined. Analysis of the results revealed that none of these parameters changed significantly after the 6-month intervention period (e.g. 6 minute walking distance before: 532 ± 31 m, vs. after: 527 ± 29 m, P = 0.246). These results suggest that exercise training during infusion may not add significant functional changes in late-onset Pompe patients receiving ERT and undergoing regular exercise training.

Patients with anoctamin-5 (ANO5) mutations may present not only with limb-girdle muscular dystrophy type 2L or adult-onset Miyoshi-type myopathy but also with asymptomatic hyperCKemia, exercise intolerance, or rhabdomyolysis.Data from 38 patients in France with ANO5 mutations with and without muscle weakness on first examination were compared.Twenty patients presented without muscle weakness. Median age at symptom onset or discovery of hyperCKemia was 23 years. Creatine kinase levels ranged from 200 to 40,000 U/L. Electromyography showed a myopathic pattern in 5 patients, and muscle imaging showed involvement of posterior calf muscles in 10 patients. Mild cardiac involvement was observed in 2 patients. Sixteen patients remain free of weakness after a median follow-up period of 5 years.Asymptomatic, sometimes mild hyperCKemia or exercise intolerance is a presentation of ANO5-related myopathy and may remain isolated or precede muscle weakness by many years. Muscle Nerve 56: 1096-1100, 2017.

Background:We tried to determine the prevalence of carotid sinus hypersensitivity (CSH) in patients with hip fractures with and without a clear history of an accidental fall. Methods:We studied 51 patients hospitalized for a hip fracture and 51 matched controls from our outpatients department. All patients were subjected to a carotid sinus massage in the supine and upright position. Patients were categorized in accidental (Group A) and unexplained (Group B) fallers. Results:Six of 33 (18.2%) patients in Group A and 12 of 18 (66.7%) patients in Group B (P < 0.001) had a positive response to the carotid sinus massage. Nine controls (17.6%) also demonstrated CSH. Patients in Group B were older (A: 75.5 ± 8.5 years vs B: 80.1 ± 5.9 years, P =0.029) and were more likely to have a history of unexplained falls or syncope in the past (A: 0% vs B: 66.7%, P < 0.0001) than individuals in group A. Vasodepressor/mixed forms accounted for the majority of CSH responses in Group B (75%). When compared with the control group, CSH was still more common in Group B (B: 66.7% vs control: 17.6%, P < 0.0001) but not in Group A (A: 18.2% vs control: 17.6%, P =1.000). Conclusions:The prevalence of CSH is increased in elderly patients with hip fractures, only in those who present with an unexplained fall and report a history of syncope or unexplained falls in the past. The vasodepressor/mixed forms account for the majority of CSH responses in the group of unexplained fallers.

Levosimendan reduces symptoms and improves hemodynamics in patients with acutely decompensated chronic heart failure (ADCHF). The aim of this study was to investigate (1) the association of changes induced by low-dose dobutamine stress echocardiography in 2-dimensional strain parameters with the corresponding changes in the left ventricular (LV) ejection fraction (EF) and LV outflow tract velocity time integral (VTI) in patients with ADCHF and (2) whether LV contractile reserve assessed by conventional and speckle-tracking echocardiography is associated with clinical and neurohumoral improvement after levosimendan treatment. Twenty-eight consecutive patients with ADCHF (mean age 65 +/- 10 years, mean New York Heart Association class 3.6 +/- 0.3, mean EF 22 +/- 6%) were studied using dobutamine stress echocardiography before 24-hour infusion of levosimendan. The LV EF, VTI, and mean longitudinal, circumferential, and radial strain and strain rate using speckle-tracking imaging were measured. Twenty-one patients (75%) had evidence of contractile reserve (LV EF increase10% and VTI increase20% after peak dobutamine dose). Patients with versus without contractile reserve demonstrated greater improvements in New York Heart Association class (mean change -1.0 +/- 0.5 vs -0.5 +/- 0.3, p = 0.01) and reductions in B-type natriuretic peptide levels (-34 +/- 30% vs +4 +/- 31%, p0.01) 48 hours after treatment. On multivariate analysis, mean longitudinal systolic strain rate reserve (peak longitudinal strain rate minus longitudinal strain rate at rest) was the best predictor of improvement in New York Heart Association class (p = 0.039) and B-type natriuretic peptide level (p = 0.042) after levosimendan among the reserve of LV fractional shortening, the EF, VTI, and longitudinal, circumferential, and radial strain and strain rate. In conclusion, dobutamine-induced changes in longitudinal systolic strain rate are associated with clinical and neurohumoral improvement after levosimendan treatment in patients with ADCHF.

Levosimendan improves central hemodynamics and symptoms in acutely decompensated chronic heart failure (CHF) patients. However, its effects on quality of life, emotional stress and functional capacity of patients with advanced CHF have not been properly investigated.Sixty-three advanced CHF patients (NYHA III-IV, LVEF30%) were randomized (2:1) to receive either a 24-h levosimendan infusion of 0.1 mug/kg/min or placebo. Questionnaires addressing quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ), functional and overall, Duke's Activity Status Index (DASI)] and emotional stress [Zung self-rating depression scale (SDS), Beck Depression Inventory (BDI)], as well as plasma BNP and 6-min walking distance (6MWT as a marker of exercise capacity) were assessed before treatment and at hospital discharge. A significant improvement in NYHA class (2.1 +/- 0.7 from 3.3 +/- 0.7, p0.01), 6 MWT (305 +/- 152 from 215 +/- 142 m, p0.01) and plasma BNP (598 +/- 398 from 1,078 +/- 756 pg/ml, p0.01) was observed post-treatment only in levosimendan-treated group. KCCQ functional (45 +/- 19 from 35 +/- 17%, p0.05) and overall (34 +/- 13 from 28 +/- 11%, p0.05), DASI (26 +/- 13 from 22 +/- 12, p0.05), Zung SDS (38 +/- 12 from 42 +/- 13, p0.01) and BDI (11 +/- 6 from 14 +/- 8, p0.05) scores also improved in levosimendan-treated patients, while remained unchanged in the placebo group. The hospital length stay was shorter in levosimendan group compared to placebo (3.2 +/- 1.7 versus 5.8 +/- 2.1 days, p0.01). Levosimendan-induced BNP reduction was significantly correlated with concomitant increase in 6MWT (r = 0.643, p0.001) as well as with the decrease of BDI (r = 0.30, p0.05) and Zung SDS (r = 0.25, p = 0.05).Levosimendan seems to have a beneficial effect on quality of life, physical activity and emotional stress in advanced CHF patients, reducing concurrently hospitalization length.

Introduction: Mutations in the CAV3 gene are usually inherited in an autosomal dominant manner and lead to distinct disorders including limb-girdle muscular dystrophy 1C, rippling muscle disease, and isolated creatine kinase elevation. Patients and Methods: The features of the first patients with caveolin-3 deficiency from Greece are presented. Patients’ phenotypes ranged from asymptomatic creatine kinase elevation to severe weakness of lower extremities. Clinical evaluation disclosed muscle hypertrophy in 2 patients, whereas percussion-induced muscle mounding was a consistent finding in all of them. Muscle histopathology was variable and unrelated with disease severity. The diagnosis was based on the immunohistochemical study of caveolin-3 expression and molecular analysis of the caveolin-3 gene. Conclusions: Clinical manifestations and histochemical findings in caveolinopathy patients may be mild or nonspecific or overlapping with features of other muscular dystrophies. Immunohistochemical study of caveolin-3 expression on muscle biopsy should be routinely performed when investigating isolated hyperCKemia or undetermined myopathy especially in the presence of percussion-induced muscle mounding.

Myotonic dystrophy type 2 (DM2) is an autosomal dominant inherited disorder with (CCTG)n repeat expansion in intron 1 of the CNBP gene.We studied the first 16 Greek DM2 patients who had undergone thorough evaluation.The age at diagnosis ranged from 38 to 69 years. The initial symptoms were proximal weakness, myalgias, and myotonia. Clinical myotonia was elicited in 10 patients, whereas electromyographic myotonic discharges were observed in almost all patients. Subcapsular cataract was frequently present, but cardiac arrhythmias were rare.In this study of Greek DM2 patients, proximal weakness was the most common initial symptom. Myalgias were also reported in a few patients, yet myotonia was not a major complaint. Although DM2 is considered relatively benign, there are patients who may be affected severely. Thus, a high index of suspicion must be maintained to make a timely diagnosis, especially in those of reproductive age.

We describe the case of a patient with a clinical picture of heart failure, which appeared and worsened rapidly following a reported febrile respiratory infection. The echocardiogram and serological tests established the diagnosis of aortic valve disease from Coxiella Burnetii.

To the Editor: We read with great interest the brief report by Wright et al, 1 which emphasizes that high levels of transaminases may be observed early in presymptomatic children with an underlying myopathy and can wrongly raise the suspicion of an underlying liver disease. According to the results of study by Wright et al, the majority of participants turned out to carry a pathogenic mutation in the dystrophin gene. On the basis of these observations, they proposed that measurement of serum creatine kinase should be obtained when clear gastrointestinal symptoms and signs are absent, and they stressed the need to combine the laboratory findings with a neurological examination. This notion may prove to be even more useful in the work-up of asymptomatic or oligosymptomatic adults with a muscle disease who are found during a routine examination to have increased aspartate aminotransferase

Fish oils have shown beneficial effects on various parameters in patients with coronary artery disease (CAD). The purpose of this study was to investigate whether the same effects can be demonstrated with a low dose of fish oil concentrate (FOC).Thirty-nine patients were studied and divided into two groups. Twenty were given 10 g fish oil (group A) and 19 were given 10 g placebo Italian olive oil (group B).Weekly anginal attacks (AA), weekly glyceryl trinitrate consumption (GTN), exercise tolerance time (ETT), serum triglycerides (ST), platelet aggregation ratio (PAR), and β- thromboglobulin were measured at eight and twelve weeks after start of treatment.1. The number of anginal attacks recorded by both groups decreased by 41% in group A reaching statistical significance (P < 0.05). No change was observed in group B.2. GTN consumption decreased in group A (P < 0.05) with no significant change in group B (P: ns).3. ETT increased significantly in group A eight and twelve weeks after start of treatment (20.6% P < 0.01, 22.6% P < 0.01). A smaller but insignificant increase was observed in group B (P: ns).4. ST decreased significantly in group A by 22% eight weeks after start of treatment (P < 0.01) and to a lesser degree (11%) twelve weeks after start of treatment (P: ns). In group B, ST slightly increased (P: ns). (continued on next page)5. No statistically significant change was observed in either group in regard to PAR and β-thromboglobulin (P: ns).These observations suggest that dietary supplementation with a low dose of FOC may have beneficial effects on the clinical status of patients with CAD. It also seems that this low dose has no impact on platelet function.

Pompe disease is a rare autosomal recessive disorder characterized by the deficiency of acid α-glycosidase resulting in lysosomal accumulation of glycogen. The late-onset disease form is characterized by progressive skeletal and respiratory muscle dysfunction. In addition to the recently introduced enzyme replacement therapy (ERT), treatments such as protein-enriched diet and exercise training have been proposed, although little is known about their effectiveness on the physical condition of such patients. Aim of the present study was to investigate the effect of exercise training on muscular strength and body composition in five patients with late-onset Pompe disease receiving ERT. All subjects followed a 20 week lasting program of supervised aerobic and progressive resistance exercise training. Before and after the training period, body composition was determined with dual X-ray absorptiometry and isometric muscular strength was measured with a specialized load transducer. Functional capacity was assessed using the 6-min shuttle walk test. A significant increase in muscular strength (15-50% at various body parts, p