Myotonia congenita in a Greek cohort: Genotype spectrum and impact of the CLCN1:c.501C > G variant as a genetic modifier.

INTRODUCTION/AIMS: Myotonia congenita (MC) is the most common hereditary channelopathy in humans. Characterized by muscle stiffness, MC may be transmitted as either an autosomal dominant (Thomsen) or a recessive (Becker) disorder. MC is caused by variants in the voltage-gated chloride channel 1 (CLCN1) gene, important for the normal repolarization of the muscle action potential. More than 250 disease-causing variants in the CLCN1 gene have been reported. This study provides an MC genotype-phenotype spectrum in a large cohort of Greek patients and focuses on novel variants and disease epidemiology, including additional insights for the variant CLCN1:c.501C > G. METHODS: Sanger sequencing for the entire coding region of the CLCN1 gene was performed. Targeted segregation analysis of likely candidate variants in additional family members was performed. Variant classification was based on American College of Medical Genetics (ACMG) guidelines. RESULTS: Sixty-one patients from 47 unrelated families were identified, consisting of 51 probands with Becker MC (84%) and 10 with Thomsen MC (16%). Among the different variants detected, 11 were novel and 16 were previously reported. The three most prevalent variants were c.501C > G, c.2680C > T, and c.1649C > G. Additionally, c.501C > G was detected in seven Becker cases in-cis with the c.1649C > G. DISCUSSION: The large number of patients in whom a diagnosis was established allowed the characterization of genotype-phenotype correlations with respect to both previously reported and novel findings. For the c.501C > G (p.Phe167Leu) variant a likely nonpathogenic property is suggested, as it only seems to act as an aggravating modifying factor in cases in which a pathogenic variant triggers phenotypic expression.

Effect of air-abrasion pretreatment with three desensitizing agents on efficacy of in-office tooth bleaching.

OBJECTIVE: To evaluate the influence of air-abrasion of enamel with three different desensitizing powders on the whitening effect of a bleaching gel containing 40% H2O2, which was used for in-office tooth bleaching. MATERIALS AND METHODS: Forty human incisors, extracted and prepared, were acquired for this study and subsequently randomized into four groups (n = 10). The control group specimens underwent no pretreatment prior to the bleaching procedure, whereas the remaining three groups underwent air abrasion using distinct desensitizing powders; (a) Sylc, which contains bioglass 45S5; (b) BioMinF, which contains calcium phospho-fluoro-silicate glass; and (c) MI Pearls, which contains nano-hydroxyapatite, 1 h preceding the Opalescence Boost PF 40% bleaching procedure. Color measurements were conducted using a double-beam UV-Vis spectrophotometer at four distinct time points (prior to bleaching, 24 h, 15 days, and 30 days post-bleaching). RESULTS: Tooth color change outcomes revealed that there were no statistically significant results with respect to the interaction of the two criteria (treatments and time) (p = 0.990). Additionally, there were no statistically significant results with respect to the main effects of treatments (p = 0.385), while there were statistically significant effects with respect to the time criterion (p = 0.013). CONCLUSIONS: The use of the tested desensitizing powders prior the bleaching procedure did not affect the tooth color change induced by the tested bleaching agent. CLINICAL SIGNIFICANCE: Tooth color change and whiteness are not affected by air-abrasion desensitizing treatments when applied prior to in-office bleaching procedures.

Skeletal muscle and erythrocyte redox status is associated with dietary cysteine intake and physical fitness in healthy young physically active men.

PURPOSE: To investigate the association between redox status in erythrocytes and skeletal muscle with dietary nutrient intake and markers of physical fitness and habitual physical activity (PA). METHODS: Forty-five young physically active men were assessed for body composition, dietary nutrient intake, muscle strength, cardiorespiratory capacity and habitual PA. Blood and muscle samples were collected to estimate selected redox biomarkers. Partial correlation analysis was used to evaluate the independent relationship of each factor with redox biomarkers. RESULTS: Dietary cysteine intake was positively correlated (p < 0.001) with both erythrocyte (r = 0.697) and muscle GSH (0.654, p < 0.001), erythrocyte reduced/oxidized glutathione ratio (GSH/GSSG) (r = 0.530, p = 0.001) and glutathione reductase (GR) activity (r = 0.352, p = 0.030) and inversely correlated with erythrocyte protein carbonyls (PC) levels (r = - 0.325; p = 0.046). Knee extensors eccentric peak torque was positively correlated with GR activity (r = 0.355; p = 0.031) while, one-repetition maximum in back squat exercise was positively correlated with erythrocyte GSH/GSSG ratio (r = 0.401; p = 0.014) and inversely correlated with erythrocyte GSSG and PC (r = - 0.441, p = 0.006; r = - 0.413, p = 0.011 respectively). Glutathione peroxidase (GPx) activity was positively correlated with step count (r = 0.520; p < 0.001), light (r = 0.406; p = 0.008), moderate (r = 0.417; p = 0.006), moderate-to-vigorous (r = 0.475; p = 0.001), vigorous (r = 0.352; p = 0.022) and very vigorous (r = 0.326; p = 0.035) PA. Muscle GSSG inversely correlated with light PA (r = - 0.353; p = 0.022). CONCLUSION: These results indicate that dietary cysteine intake may be a critical element for the regulation of glutathione metabolism and redox status in two different tissues pinpointing the independent significance of cysteine for optimal redox regulation. Musculoskeletal fitness and PA levels may be predictors of skeletal muscle, but not erythrocyte, antioxidant capacity. TRIAL REGISTRATION: Registry: ClinicalTrials.gov, identifier: NCT03711838, date of registration: October 19, 2018.

Skeletal muscle fiber composition may modify the effect of nutrition on body composition in young females.

BACKGROUND AND AIM: The aim of this study was to investigate the hypothesis that healthy, normal-weight females with greater proportions and sizes of the oxidative muscle fibers would also be characterized by a healthier body composition compared with individuals with increased glycolytic fibers, even if both follow similar nutritional plans. METHODS AND RESULTS: Vastus lateralis muscle fiber-type composition, body composition through dual-energy X-ray absorptiometry, and dietary intakes through questionnaire were evaluated in twenty-two young, healthy, non-obese females (age: 21.3±1.8yrs, body mass: 67.5±6.2 kg, body height: 1.66±0.05m, body mass index (BMI): 24.2±2.6  kg m-2). The participants were allocated into two groups according to their type I muscle fibers percentage [high (HI) and low (LI)]. The participants of the LI group were characterized by significantly higher body mass, fat mass, BMI, and cross-sectional and percentage cross-sectional area (%CSA) of type IIx muscle fibers compared with participants of the HI group (p < 0.021). In contrast, the HI group was characterized by higher cross-sectional and %CSA of type I muscle fibers compared with the LI group (p < 0.038). Significant correlations were observed between body fat mass, lean body mass, total energy intake, fat energy intake, and %CSAs of type I and IIx muscle fibers (r: -0.505 to 0.685; p < 0.05). CONCLUSION: In conclusion, this study suggests that muscle fiber composition is an important factor that at least partly could explain the observed differential inter-individual responses of the body composition to nutrition in female individuals. Increased %CSAs of type I muscle fibers seem to act as a protective mechanism against obesity and favor a healthier body composition, neutralizing the negative effect of increased caloric fats intake on body composition, probably because of their greater oxidative metabolic properties and fat utilization capacities. In contrast, female individuals with low type I and high type IIx %CSAs of type I seem to be more metabolically inflexible and dietinduced obesity prone, even if they consume fewer total daily calories and fats.

Effect of tooth brushing simulation on the surface properties of various resin-matrix computer-aided design/computer-aided manufacturing ceramics.

PURPOSE: The purpose was to investigate the alterations in surface properties of different resin-matrix CAD/CAM ceramics following tooth brushing simulation (TBS) and compare them with a direct resin composite and a glass ceramic CAD/CAM material. MATERIALS AND METHODS: Four resin-based CAD/CAM restoratives (Brilliant Crios-BR, Lava™ Ultimate-LV, Grandio Blocs-GR and Shofu Block HC-SH), a leucite-reinforced glass ceramic (IPS Empress® CAD-EC) and a resin composite (Filtek™ Z250-FZ) for direct restorations were tested. In particular, surface loss, hardness, roughness and morphology were investigated utilizing confocal microscopy, scanning electron microscopy and nanoindentation tester. TBS was conducted for 4 × 15 min on the surface of the samples and then the changes in their surface properties were evaluated. RESULTS: After TBS, all the experimental groups exhibited surface loss to different extent. FZ and BR presented the highest surface loss, while EC and GR the lowest (p < 0.05). Regarding surface roughness, all the tested materials exhibited increase after TBS (p < 0.05), except LV (p = 0.099). EC presented the lowest Sa values, while FZ and BR the highest (p < 0.05). Changes in surface morphology were in compliance with the results of surface roughness and also surface hardness was correlated with surface loss. CONCLUSIONS: The tested resin-matrix CAD/CAM ceramic restorative materials showed a competent behavior against abrasive forces applied during TBS. Surface loss and roughness changes were material dependent and superior compared to a resin composite for direct restorations, while in comparison with a leucite-reinforced glass ceramic exhibited inferior properties. CLINICAL SIGNIFICANCE: Tooth brushing affected differently the surface of the tested restorative materials. However, the abrasive wear that was induced was negligible. Clinical studies are necessary to ascertain if there is clinical significance of these surface alterations that may demand repair of such restorations.

Deep Characterization of a Greek Patient with Desmin-Related Myofibrillar Myopathy and Cardiomyopathy.

Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene (DES) result in a variety of diseases, including cardiomyopathies and myofibrillar myopathy, collectively called desminopathies. Here we describe the clinical, histological and radiological features of a Greek patient with a myofibrillar myopathy and cardiomyopathy linked to the c.734A>G,p.(Glu245Gly) heterozygous variant in the DES gene. Moreover, through ribonucleic acid sequencing analysis in skeletal muscle we show that this variant provokes a defect in exon 3 splicing and thus should be considered clearly pathogenic.

Angiotensin receptor-neprilysin inhibition in patients with acute decompensated heart failure: an expert consensus position paper.

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.

Visual snow: A systematic review and a case series.

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.

Circulating small RNA signatures differentiate accurately the subtypes of muscular dystrophies: small-RNA next-generation sequencing analytics and functional insights.

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.

Executive Dysfunction, Social Cognition Impairment, and Gray Matter Pathology in Myotonic Dystrophy Type 2: A Pilot Study.

BACKGROUND: In contrast to myotonic dystrophy type 1, the cognitive and radiologic profile of myotonic dystrophy type 2 (DM2) is relatively poorly characterized. OBJECTIVE: To conduct a pilot study to systematically evaluate cognitive and radiologic features in a cohort of Greek individuals with DM2. METHOD: 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: PFDR < 0.05 and Bayes factor (BF 10 ) >10. RESULTS: 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. CONCLUSION: 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.

Body composition and 6 minute walking ability in late-onset pompe disease patients after 9 years of enzyme replacement therapy.

OBJECTIVE: 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. METHODS: 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). RESULTS: Total body and upper extremities' lean mass remained unchanged (p < 0.05), but it was decreased for the lower extremities (T3:13.06 ± 3.848 kg vs. T9:11.63 ± 3.49 kg, p < 0.05). Lean body mass was not significantly different after 9 years of ERT compared to before the ERT initiation (T0 to T9). Bone mineral density remained unchanged. Percent body fat increased (T0:39.1 ± 10.3%, vs. T9:43.1 ± 10.4%, p < 0.05). Six minute walking distance tended to increase after 3 years of ERT and decreased gradually thereafter, with no difference between T0-T9. Lean mass of the lower extremities adjusted for body weight was significantly correlated with 6 min walking distance (r = 0.712, p < 0.05). CONCLUSION: The current data show that enzyme replacement therapy may preserve lean body mass, bone mineral density and walking capacity in LOPD patients.

A Greek National Cross-Sectional Study on Myotonic Dystrophies.

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.

Preserved eye movements in adults with spinal muscular atrophy.

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.

Effect of exercise training on functional capacity and body composition in myotonic dystrophy type 2 patients.

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.

Neuropsychological Assessment Should Always be Considered in Myotonic Dystrophy Type 2.

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.

Effect of Concurrent Power Training and High-Intensity Interval Cycling on Muscle Morphology and Performance.

ABSTRACT: 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.

Incidence and predictors of total mortality in 267 adults presenting with mitochondrial diseases.

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.

Update on Congenital Myopathies in Adulthood.

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.

Toward understanding tissue-specific symptoms in dolichol-phosphate-mannose synthesis disorders; insight from DPM3-CDG.

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 (ßDG) N-glycosylation revealed a consistent lack of one N-glycan in skeletal muscle. Recently, defective N-glycosylation of ßDG 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 ßDG in skeletal muscle is indicative of a defect in the DPM synthesis pathway. Further studies should address to what extent hypo-N-glycosylation of ßDG 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 or atypical form of sporadic inclusion body myositis: case series and review of the literature.

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.