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BackgroundCognitive impairments in patients with myotonic dystrophy type 1 (DM1) have often been described, however, there are only few studies differentiating between partial performance disorders and mental retardation in common. This study focused on the evaluation of reading performance and the frequency of dyslexia in adult DM1 patients.MethodsWe performed a prospective cohort study including genetically confirmed adult DM1 patients registered in the DM registry of Germany or the internal database of the Friedrich-Baur-Institute, Munich, Germany. For the assessment of the patients’ reading and spelling performance, we used the standardized and validated test ‚Salzburger Lese- und Rechtschreibtest‘ (SLRT II). The ‚CFT-20 R Grundintelligenztest Skala 2‘ in revised (\"R\") version (CFT 20-R), determining the intelligence level, was appropriate to differentiate between dyslexia and general mental retardation. The diagnosis of dyslexia, the combined reading and spelling disorder, was based on the guidelines for diagnosis and therapy of children and adolescents with dyslexia 2015 (S3-guideline) providing (1) the criterion of the divergence from age level and (2) the criterion of IQ-divergence. ResultsFifty-seven DM1 patients participated in our study. Evaluating the reading performance, 16 patients fulfilled the divergence criteria of the age level and 2 patients the IQ-divergence criteria. In total, the diagnosis of a reading disorder was given in 18 DM1 patients (31.6 %). In 11 out of these 18 patients with a reading disorder, a relevant impairment of spelling performance was observed with at least three spelling errors. As there are no normative values for adults in spelling performance, we assume a combined reading disorder and dyslexia, in those 11 DM1 patients (19.3 %). Regarding the separate analyses of the test procedures, in the SLRT II the performance was below average in 40.4 % of all patients for ‘word reading’ and in 61.4 % of all patients for ‘pseudoword reading’. There was a significant positive correlation between the CTG expansion size and a reading disorder (p=0.027). The average IQ of 17 examined DM1 patients was in the lower normal range (86.1 ± 19.1). 54.5 % of patients with reading disorder had a normal IQ. ConclusionThe calculated prevalence of dyslexia in the DM1 study cohort was 19.3 % and thus considerably increased compared to the normal German population. As dyslexia is not equivalent to a general cognitive impairment, it is important not to miss dyslexic features in cognitive inconspicuous DM1 patients. Case-by-case one should consider a differential diagnostic approach, as individualized therapies can be offered to support dyslexic patients in their performance.

Recent epidemiological studies on the general population reveal that up to 1.3% have oligo/asymptomatic hyperCKemia. This guideline aims to provide updated, evidence-based recommendations on investigating persons older than 18 years. The guideline followed EAN standard operating procedures and was developed according to the GRADE methodology. Fourteen neuromuscular experts from the EAN neuromuscular group were joined by a methodologist and a patient representative. There are two types of recommendations: evidence-based recommendations, based on published studies, and consensus statements if the quality of evidence is poor. We recommend that: (1) Persistent oligo/asymptomatic hyperCKemia with a CK > 1.5 ULN be investigated (Consensus statement); (2) Neurogenic and non-neuromuscular causes of hyperCKemia be excluded (Expert opinion); (3) A Dried Blood Spot (DBS) be done (Strong recommendation); (4) A NCS/EMG to identify whether there is a myopathy or neuropathy be performed (Weak recommendation); (5) A resting lactate and fasting acyl-carnitine assays, if a metabolic myopathy is suspected, be done (Consensus statement); (6) A skeletal muscle MRI be performed to guide/interpret genetic testing (Strong recommendation); (7) NGS is recommended over sequential gene testing (Consensus statement); (8) NGS is recommended over muscle biopsy (Strong recommendation); (9) A muscle biopsy may be offered, if genetic testing is uninformative and one or more applies: a genetic variant of unknown significance (VUS), suspected metabolic myopathy, suspected inflammatory myopathy, abnormal muscle MRI, a CK ≥ 3 ULN, a family history of muscle disease or age, less than 25 years (Expert opinion). An evidence-based guideline is suggested for when and how to investigate adults with oligo/asymptomatic hyperCKemia.

Background and purpose The Rasch‐Built Pompe‐Specific Activity (R‐PAct) scale is a patient‐reported outcome measure specifically designed to quantify the effects of Pompe disease on daily life activities, developed for use in Dutch‐ and English‐speaking countries. This study aimed to validate the R‐PAct for use in other countries. Methods Four other language versions (German, French, Italian, and Spanish) of the R‐PAct were created and distributed among Pompe patients (≥16 years old) in Germany, France, Spain, Italy, and Switzerland and pooled with data of newly diagnosed patients from Australia, Belgium, Canada, the Netherlands, New Zealand, the USA, and the UK and the original validation cohort (n = 186). The psychometric properties of the scale were assessed by exploratory factor analysis and Rasch analysis. Results Data for 520 patients were eligible for analysis. Exploratory factor analysis suggested that the items separated into two domains: Activities of Daily Living and Mobility. Both domains independently displayed adequate Rasch model measurement properties, following the removal of one item (\"Are you able to practice a sport?\") from the Mobility domain, and can be added together to form a \"higher order\" factor as well. Differential item functioning (DIF)‐by‐language assessment indicated DIF for several items; however, the impact of accounting for DIF was negligible. We recalibrated the nomogram (raw score interval‐level transformation) for the updated 17‐item R‐PAct scale. The minimal detectable change value was 13.85 for the overall R‐PAct. Conclusions After removing one item, the modified‐R‐PAct scale is a valid disease‐specific patient‐reported outcome measure for patients with Pompe disease across multiple countries.

Background Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase ( DMPK ) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Through a process of reverse engineering, this study aims to identify druggable molecular biomarkers associated with the clinical improvement in the OPTIMISTIC cohort. Methods Based on full blood samples collected during OPTIMISTIC, we performed paired mRNA sequencing for 27 patients before and after the CBT intervention. Linear mixed effect models were used to identify biomarkers associated with the disease-causing CTG expansion and the mean clinical improvement across all clinical outcome measures. Results We identified 608 genes for which their expression was significantly associated with the CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes associated with both returned to more normal levels in patients who benefited the most from CBT. This main finding has been replicated based on an external dataset of mRNA data of DM1 patients and controls, singling these genes out as candidate biomarkers for therapy response. Among these candidate genes were DNAJB12 , HDAC5 , and TRIM8 , each belonging to a protein family that is being studied in the context of neurological disorders or muscular dystrophies. Across the different gene sets, gene pathway enrichment analysis revealed disease-relevant impaired signaling in, among others, insulin-, metabolism-, and immune-related pathways. Furthermore, evidence for shared dysregulations with another neuromuscular disease, Duchenne muscular dystrophy, was found, suggesting a partial overlap in blood-based gene dysregulation. Conclusions DM1-relevant disease signatures can be identified on a molecular level in peripheral blood, opening new avenues for drug discovery and therapy efficacy assessments.

Inflammatory myopathies cover infectious, focal and immunogenic myopathies. This review focuses on the clinical features, diagnostic techniques, pathogenesis and therapy of immunogenic myopathies. Besides myositis associated with other autoimmune disorders, dermatomyositis is the most common immunogenic myopathy. The independent diagnosis of polymyositis has come under debate, since within this group of patients some are now diagnosed as having either hereditary muscular dystrophy with inflammatory signs or inclusion body myositis (IBM). Even more strikingly, patients diagnosed with sporadic IBM may now be diagnosed with either a form of hereditary IBM or with a form belonging to the group of protein aggregate myopathies or myofibrillar myopathies. This re-classification reflects the well-known and clinically evident therapeutic dilemma in many of these patients. Thus the indication for muscle biopsy or rebiopsy requires new consideration and attention.

Introduction Myofibrillar myopathies are characterized by progressive muscle weakness and impressive abnormal protein aggregation in muscle fibers. In about 10 % of patients, the disease is caused by mutations in the MYOT gene encoding myotilin. The aim of our study was to decipher the composition of protein deposits in myotilinopathy to get new information about aggregate pathology. Results Skeletal muscle samples from 15 myotilinopathy patients were included in the study. Aggregate and control samples were collected from muscle sections by laser microdissection and subsequently analyzed by a highly sensitive proteomic approach that enables a relative protein quantification. In total 1002 different proteins were detected. Seventy-six proteins showed a significant over-representation in aggregate samples including 66 newly identified aggregate proteins. Z-disc-associated proteins were the most abundant aggregate components, followed by sarcolemmal and extracellular matrix proteins, proteins involved in protein quality control and degradation, and proteins with a function in actin dynamics or cytoskeletal transport. Forty over-represented proteins were evaluated by immunolocalization studies. These analyses validated our mass spectrometric data and revealed different regions of protein accumulation in abnormal muscle fibers. Comparison of data from our proteomic analysis in myotilinopathy with findings in other myofibrillar myopathy subtypes indicates a characteristic basic pattern of aggregate composition and resulted in identification of a highly sensitive and specific diagnostic marker for myotilinopathy. Conclusions Our findings i) indicate that main protein components of aggregates belong to a network of interacting proteins, ii) provide new insights into the complex regulation of protein degradation in myotilinopathy that may be relevant for new treatment strategies, iii) imply a combination of a toxic gain-of-function leading to myotilin-positive protein aggregates and a loss-of-function caused by a shift in subcellular distribution with a deficiency of myotilin at Z-discs that impairs the integrity of myofibrils, and iv) demonstrate that proteomic analysis can be helpful in differential diagnosis of protein aggregate myopathies.

Based on previous reports the frequency of co-segregating recessive chloride channel ( CLCN1 ) mutations in families with myotonic dystrophy type 2 (DM2) was suspected to be increased. We have studied the frequency of CLCN1 mutations in two separate patient and control cohorts from Germany and Finland, and for comparison in a German myotonic dystrophy type 1 (DM1) patient cohort. The frequency of heterozygous recessive chloride channel ( CLCN1 ) mutations is disproportionally higher (5 %) in currently diagnosed DM2 patients compared to 1.6 % in the control population ( p = 0.037), while the frequency in DM1 patients was the same as in the controls. Because the two genes segregate independently, the prevalence of CLCN1 mutations in the total DM2 patient population is, by definition, the same as in the control population. Our findings are, however, not based on the total DM2 population but on the currently diagnosed DM2 patients and indicate a selection bias in molecular diagnostic referrals. DM2 patients with co-segregating CLCN1 mutation have an increased likelihood to be referred for molecular diagnostic testing compared to DM2 patients without co-segregating CLCN1 mutation.

Abstract ObjectiveThe connectivity between somatosensory evoked potentials (SEPs) and cortical plasticity remains elusive due to a lack of supporting data. This study investigates changes in pathological latencies and amplitudes of SEPs caused by an acute stroke after 2 weeks of rehabilitation with functional electrical stimulation (FES). Furthermore, changes in SEPs and the efficacy of FES against foot drop (FD) stroke symptoms were correlated using the 10-m walk test and foot–ankle strength.MethodsA randomised controlled two-period crossover design plus a control group (group C) was designed. Group A (n = 16) was directly treated with FES, while group B (n = 16) was treated after 2 weeks. The untreated control group of 20 healthy adults underwent repeated SEP measurements for evaluation only.ResultsThe repeated-measures ANOVA showed a decrease in tibial nerve (TN) P40 and N50 latencies in group A after the intervention, followed by a decline in non-paretic TN SEP in latency N50 (p < 0.05). Moreover, compared to groups B and C from baseline to 4 weeks, group A showed a decrease in paretic TN latency P40 and N50 (p < 0.05). An increase in FD strength and a reduction in step cadence in group B (p < 0.05) and a positive tendency in FD strength (p = 0.12) and step cadence (p = 0.08) in group A were observed after the treatment time. The data showed a moderate (r = 0.50–0.70) correlation between non-paretic TN latency N50 and step cadence in groups A and B after the intervention time.ConclusionThe FES intervention modified the pathological gait in association with improved SEP afferent feedback.Registered on 25 February 2021 on ClinicalTrials.gov under identifier number: NCT04767360.

Background The symptomatic treatment of myotonia and myalgia in patients with dystrophic and non-dystrophic myotonias is often not satisfactory. Some patients anecdotally report symptoms’ relief through consumption of cannabis. Methods A combination of cannabidiol and tetrahydrocannabinol (CBD/THC) was prescribed as compassionate use to six patients (four patients with myotonic dystrophy types 1 and 2, and 2 patients with CLCN1-myotonia) with therapy-resistant myotonia and myalgia. CBD/THC oil was administered on a low dose in the first 2 weeks and adjusted to a higher dose in the following 2 weeks. Myotonia behaviour scale (MBS), hand-opening time, visual analogue scales (VAS) for myalgia and myotonia, and fatigue and daytime sleepiness severity scale (FSS, ESS) were performed weekly to monitor treatment response. Results All patients reported an improvement of myotonia especially in weeks 3 and 4 of treatment: MBS improved of at least 2 points in all patients, the hand-opening time variously improved in 5 out of 6 patients. Chronic myalgia was reported by both DM2 patients at baseline, one of them experienced a significant improvement of myalgia under treatment. Some gastrointestinal complaints, as abdominal pain and diarrhoea, improved in 3 patients; however, 4 out of 6 patients reported new-onset constipation. No other relevant side effect was noticed. Conclusions These first empirical results suggest a potentially beneficial role of CBD/THC in alleviating myotonia and should encourage further research in this field including a randomized-controlled trial on larger cohorts.