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Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype–phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23–45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents.

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Purpose of review The multisystemic involvement of myotonic dystrophies (DMs) intricates disease monitoring, patients' care and trial design. This update of the multifaceted comorbidities observed in DMs aims to assist neurologists in the complex management of patients and to encourage further studies for still under-investigated aspects of the disease. Recent findings We reviewed the most recent studies covering pathogenesis and clinical aspects of extra-muscular involvement in DM1 and DM2. The largest body of evidence regards the cardiac and respiratory features, for which experts' recommendations have been produced. Gastrointestinal symptoms emerge as one of the most prevalent complaints in DMs. The alteration of insulin signaling pathways, involved in gastrointestinal manifestations, carcinogenesis, muscle function, cognitive and endocrinological aspects, gain further relevance in the light of recent evidence of metformin efficacy in DM1. Still, too few studies are performed on large DM2 cohorts, so that current recommendations mainly rely on data gathered in DM1 that cannot be fully translated to DM2. Summary Extra-muscular manifestations greatly contribute to the overall disease burden. A multidisciplinary approach is the key for the management of patients. Consensus-based recommendations for DM1 and DM2 allow high standards of care but further evidence are needed to implement these recommendations.

Background Late-onset Pompe disease (LOPD) is a rare autosomal recessive disorder caused by mutations in the GAA gene, leading to progressive weakness of locomotor and respiratory muscles. Enzyme replacement therapy (ERT), administered every second week, has been proven to slow down disease progression and stabilize pulmonary function. Due to the COVID-19 pandemic in Germany, ERT was interrupted at our centre for 29 days. As reports on ERT discontinuation in LOPD are rare, our study aimed to analyse the impact of ERT interruption on the change in clinical outcome. Methods We performed a prospective cohort study in 12 LOPD patients. Clinical assessments were performed after ERT interruption and after the next three consecutive infusions. We assessed motor function by muscle strength testing, a 6-minute-walk-test, pulmonary function tests, and adverse events. For statistical analysis, an estimated baseline was calculated based on the individual yearly decline. Results The mean time of ERT interruption was 49.42 days (SD ± 12.54). During ERT interruption, seven patients reported 14 adverse events and two of them were severe. Frequent symptoms were reduced muscle endurance/increased muscle fatigability and shortness of breath/worsening of breathing impairment. After ERT interruption, significant deterioration was found for MIP%pred (p = 0.026) and MRC%pred, as well as a trend to clinical deterioration in FVC%pred and the 6MWT%pred. Conclusion Interruption of ERT was associated with a deterioration in the core clinical outcome measures. Therefore, an interruption of ERT should be kept as short as possible.

More than 80 genes are known to be associated with Charcot-Marie-Tooth disease (CMT). Mutations of LRSAM1 were identified as a rare cause and define the subgroup of axonal neuropathy CMT2P. We identified additional 14 patients out of 12 families. Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment. The patients harbored ten different variants in LRSAM1, seven of which were novel. Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging. The majority follows dominant inheritance, whereas recessive inheritance has been described for one variant. Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance. Our data emphasize the importance of the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein. In conclusion, CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy. ACMG (American College of Medical Genetics and genomics) criteria should be carefully applied in variant interpretation, with special attention to premature termination codon-introducing variants and their location within the gene.

Introduction Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort. Methods We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy. Results 70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient’s perceived efficacy were mexiletine and lamotrigine. Conclusion This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.

Myotonic dystrophy type 2 (DM2) lacks validated patients´ reported outcomes (PROs). This represents a limit for monitoring disease progression and perceived efficacy of symptomatic treatments. Our aim was to investigate whether PROs for activities of daily living designed for other neuromuscular diseases could be used in DM2. Sixty-six DM2 patients completed the following PROs: DM1-Activ-c, Rasch-built Pompe-specific activity (R-PAct) scale, McGill-pain questionnaire, fatigue and daytime sleepiness scale and Beck depression inventory (BDI-II). Clinical data and motor outcome measures (6-minutes walking test - 6MWT, manual muscle testing, quick motor function test and myotonia behavior scale) were collected as well. Patients underwent one visit at baseline and one after 10 months. Ceiling/flooring effects, criterion validity and discriminant validity were calculated. DM1-activ-c and R-PAct showed acceptable ceiling effects despite being built for myotonic dystrophy type 1 and Pompe disease, respectively. The difficulty hierarchy of the single items was better preserved in R-PAct than in DM1-Activ-c. Both tests showed excellent criterion validity highly correlating with 6MWT, quick motor function test, myalgia and disease duration. They could partially discriminate patients with different disability grades. These results suggest that DM1-Activ-c, slightly better than R-PAct, might be adopted for monitoring activities of daily living also in DM2, at least until disease-specific PROs will be available.

Background Cognitive 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. Methods We 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. Results Fifty-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. Conclusion The 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.

Introduction: Myotonic dystrophies (DMs) are the most frequent autosomal dominant neuromuscular disorders in adults. Our objective was to evaluate the utility of an online survey in a rare disease as well as to assess and compare the onset and the progression of clinical symptoms in patients with myotonic dystrophy types 1 (DM1) and 2 (DM2). Methods: We conducted a patient’s reported online survey assessing demographics, disease-related symptoms (age of onset, first symptom, time of diagnosis, current symptoms, inheritance, and family history) combined with capturing current symptoms by validated questionnaires. The questionnaire consisted of open, closed, single- and multiple-choice questions. Multiple answers were possible in some cases. Patients with genetically confirmed DM1 or DM2 who were registered in the German DM registry or the Deutsche Gesellschaft für Muskelkranke e.V. – Diagnostic Group for DMs were invited to participate in this online survey. We calculated descriptive and exploratory analysis, where applicable. Results: Out of 677 data sets from respondents, 394 were suitable for final analysis, containing completed questionnaires from 207 DM1 (56% female) and 187 DM2 patients (71% female). The median age of onset was 28 years for DM1 and 35 years for DM2. Muscular symptoms were most frequently reported as the first symptom. The onset of myotonia was earlier than the onset of muscle weakness in both DM1 and DM2. Forty-four percent of patients with DM1 and one-third of patients with DM2 indicated muscle weakness as the first symptom. Patients with DM1 were significantly younger when experiencing muscle weakness as first symptom. Fatigue was only mentioned by a small fraction of patients as a first symptom but increased significantly in the course of the disease. There was no statistically significant difference in the incidence of cataracts, cardiac symptoms, and gastrointestinal symptoms between DM1 and DM2. Falls were reported almost equally in both groups, and most of the patients reported 2–3 falls within the past year. Discussion: Overall, as our results are consistent with the results of clinical studies and online registries, it can be assumed that this type of systematic gathering of data from patients with rare diseases is useful and provides realistic and appropriate results. Due to the nature of online surveys and the absence of an assessor, some uncertainty remains. Furthermore, survey frauds cannot be completely excluded. An additional clinical assessment could confirm the given information and will improve the utility and validity of reported symptoms participants provide in online surveys. Therefore, we recommend a combination of data collecting by online surveys and clinical assessments.

Genetic diagnosis of facioscapulohumeral muscular dystrophy (FSHD) remains a challenge in clinical practice as it cannot be detected by standard sequencing methods despite being the third most common muscular dystrophy. The conventional diagnostic strategy addresses the known genetic parameters of FSHD: the required presence of a permissive haplotype, a size reduction of the D4Z4 repeat of chromosome 4q35 (defining FSHD1) or a pathogenic variant in an epigenetic suppressor gene (consistent with FSHD2). Incomplete penetrance and epistatic effects of the underlying genetic parameters as well as epigenetic parameters (D4Z4 methylation) pose challenges to diagnostic accuracy and hinder prediction of clinical severity. In order to circumvent the known limitations of conventional diagnostics and to complement genetic parameters with epigenetic ones, we developed and validated a multistage diagnostic workflow that consists of a haplotype analysis and a high-throughput methylation profile analysis (FSHD-MPA). FSHD-MPA determines the average global methylation level of the D4Z4 repeat array as well as the regional methylation of the most distal repeat unit by combining bisulphite conversion with next-generation sequencing and a bioinformatics pipeline and uses these as diagnostic parameters. We applied the diagnostic workflow to a cohort of 148 patients and compared the epigenetic parameters based on FSHD-MPA to genetic parameters of conventional genetic testing. In addition, we studied the correlation of repeat length and methylation level within the most distal repeat unit with age-corrected clinical severity and age at disease onset in FSHD patients. The results of our study show that FSHD-MPA is a powerful tool to accurately determine the epigenetic parameters of FSHD, allowing discrimination between FSHD patients and healthy individuals, while simultaneously distinguishing FSHD1 and FSHD2. The strong correlation between methylation level and clinical severity indicates that the methylation level determined by FSHD-MPA accounts for differences in disease severity among individuals with similar genetic parameters. Thus, our findings further confirm that epigenetic parameters rather than genetic parameters represent FSHD disease status and may serve as a valuable biomarker for disease status.

The main pathologies in the muscles of patients with neuromuscular diseases (NMD) are fatty infiltration and edema. Recently, quantitative magnetic resonance (MR) imaging for determination of the MR biomarkers proton density fat fraction (PDFF) and water Tsub2/sub(Tsub2w/sub) has been advanced. Biophysical effects or pathology can have different effects on MR biomarkers. Thus, for heterogeneously affected muscles, the routinely performed mean or median value analyses of MR biomarkers are questionable. Our work presents a voxel-based histogram analysis of PDFF and Tsub2w/subimages to point out potential quantification errors. In 12 patients with NMD, chemical-shift encoding-based water-fat imaging for PDFF and Tsub2/submapping with spectral adiabatic inversion recovery (SPAIR) for Tsub2w/subdetermination was performed. Segmentation of nine thigh muscles was performed bilaterally (n = 216). PDFF and Tsub2/submaps were coregistered. A voxel-based comparison of PDFF and Tsub2w/subshowed a decreased Tsub2w/subwith increasing PDFF. Mean Tsub2w/suband mean Tsub2w/subsupwithout fatty voxels/sup(PDFFlt; 10%) show good agreement, whereas standard deviation (σ) Tsub2w/suband σ Tsub2w/subsupwithout fatty voxels/supshow increasing difference with increasing values of σ. Thereby two subgroups can be observed, referring to muscles in which the exclusion of fatty voxels has a negligible influence versus muscles in which a strong dependency of the Tsub2w/subvalue distribution on the exclusion of fatty voxels is present. Because of the two opposite effects that influence Tsub2w/subin a voxel, namely, (i) a pathophysiologically increased water mobility leading to Tsub2w/subelevation, and (ii) a dependency of Tsub2w/subon the PDFF leading to decreased Tsub2w/sub, the Tsub2w/subdistribution within a muscle might be heterogenous and the routine mean or median analysis can lead to a misinterpretation of the muscle health. It was concluded that muscle Tsub2w/submean values can wrongly suggest healthy muscle tissue. A deeper analysis of the underlying value distribution is necessary. Therefore, a quantitative analysis of Tsub2w/subhistograms is a potential alternative.

Background McLeod syndrome (MLS) is an ultra-rare neurodegenerative X-linked disease caused by mutations in the XK gene, classified as one of the core neuroacanthocytosis syndromes. Together with the clinically very similar chorea-acanthocytosis it belongs to the heterogeneous group of ‘Huntington’s disease (HD) phenocopies’. Aims To characterize a cohort of HD phenocopies with the genetically confirmed diagnosis of McLeod syndrome. Methods This is a retrospective and prospective analysis of genotype and phenotype of sixteen McLeod cases. Results We longitudinally characterized the second largest cohort known to date. We identified novel XK mutations as well as deletions that extend into the PRRG1 gene (novel) and describe two contiguous gene deletion cases of MLS with X-linked chronic granulomatous disease (deletion also effecting the CYBB gene). This study confirms core features of MLS such as late onset hyperkinetic movements in association with neuro/myopathy, neuropsychiatric impairment, cardiac involvement, hyperCKemia. Novel aspects in this MLS series seem obstructive sleep apnea and epileptic seizure onset in childhood. Conclusions Our study expands the limited knowledge on the variable course, the various clinical manifestations and the genetic spectrum of a hereditary HD phenocopy syndrome.

Purpose of the review Myotonic dystrophy types 1 and 2 are frequent forms of muscular dystrophies in adulthood. Their clinical differences need to be taken into account for the most appropriate treatment of patients. The aim of this article is to provide an overview on the current and upcoming therapeutic options for patients with myotonic dystrophy type 2 (DM2). Recent findings At the moment, no disease-modifying therapies are available for DM2; next-generation therapies may however be available in the near future. In the meanwhile, the symptomatic management of patients has greatly improved, thank to the production of consensus-based standards of care and the growing evidence of efficacy of anti-myotonic drugs, promising employment of cannabinoids for symptom’s relief, regular monitoring, and early detection of treatable extra-muscular manifestations. Summary The treatment of DM2 is currently symptomatic and relies on the coordinated intervention of a multidisciplinary team. It remains to be determined whether upcoming causal therapies for myotonic dystrophy type 1 will be applicable also in DM2.

BACKGROUND: Chemical shift encoding-based water-fat magnetic resonance imaging (CSE-MRI) measures a quantitative biomarker: the proton density fat fraction (PDFF). The aim was to assess regional and proximo-distal PDFF variations at the thigh in patients with myotonic dystrophy type 2 (DM2), limb-girdle muscular dystrophy type 2A (LGMD2A), and late-onset Pompe disease (LOPD) as compared to healthy controls. METHODS: Seven patients (n=2 DM2, n=2 LGMD2A, n=3 LOPD) and 20 controls were recruited. A 3D-spoiled gradient echo sequence was used to scan the thigh musculature. Muscles were manually segmented to generate mean muscle PDFF. RESULTS: In all three disease entities, there was an increase in muscle fat replacement compared to healthy controls. However, within each disease group, there were patients with a shorter time since symptom onset that only showed mild PDFF elevation (range, 10% to 20%) compared to controls (P≤0.05), whereas patients with a longer period since symptom onset showed a more severe grade of fat replacement with a range of 50% to 70% (P

(1) Background and Purpose: The skeletal muscles of patients suffering from neuromuscular diseases (NMD) are affected by atrophy, hypertrophy, fatty infiltration, and edematous changes. Magnetic resonance imaging (MRI) is an important tool for diagnosis and monitoring. Concerning fatty infiltration, T1-weighted or T2-weighted DIXON turbo spin echo (TSE) sequences enable a qualitative assessment of muscle involvement. To achieve higher comparability, semi-quantitative grading scales, such as the four-point Mercuri scale, are commonly applied. However, the evaluation remains investigator-dependent. Therefore, effort is being invested to develop quantitative MRI techniques for determination of imaging markers such as the proton density fat fraction (PDFF). The present work aims to assess the diagnostic value of PDFF in correlation to Mercuri grading and clinically determined muscle strength in patients with myotonic dystrophy type 2 (DM2), limb girdle muscular dystrophy type 2A (LGMD2A), and adult Pompe disease. (2) Methods: T2-weighted two-dimensional (2D) DIXON TSE and chemical shift encoding-based water-fat MRI were acquired in 13 patients (DM2: n = 5; LGMD2A: n = 5; Pompe disease: n = 3). Nine different thigh muscles were rated in all patients according to the Mercuri grading and segmented to extract PDFF values. Muscle strength was assessed according to the British Medical Research Council (BMRC) scale. For correlation analyses between Mercuri grading, muscle strength, and PDFF, the Spearman correlation coefficient (rs) was computed. (3) Results: Mean PDFF values ranged from 7% to 37% in adults with Pompe disease and DM2 and up to 79% in LGMD2A patients. In all three groups, a strong correlation of the Mercuri grading and PDFF values was observed for almost all muscles (rs > 0.70, p < 0.05). PDFF values correlated significantly to muscle strength for muscle groups responsible for knee flexion (rs = −0.80, p < 0.01). (4) Conclusion: In the small, investigated patient cohort, PDFF offers similar diagnostic precision as the clinically established Mercuri grading. Based on these preliminary data, PDFF could be further considered as an MRI-based biomarker in the assessment of fatty infiltration of muscle tissue in NMD. Further studies with larger patient cohorts are needed to advance PDFF as an MRI-based biomarker in NMD, with advantages such as its greater dynamic range, enabling the assessment of subtler changes, the amplified objectivity, and the potential of direct correlation to muscle function for selected muscles.

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. 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. 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. 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.

Purpose of reviewMyotonic dystrophy type 2 (DM2) is a rare, progressive multisystem disease particularly affecting the skeletal muscle. A causal therapy is not yet available; however, prompt, appropriate symptomatic treatments are essential to limit disease-related complications. Evidence-based guidelines to assist medical practitioners in the care of DM2 patients do not exist.Recent findingsThe Myotonic Dystrophy Foundation (MDF) previously worked with an international group of 66 clinicians to develop consensus-based care recommendations for myotonic dystrophy type 1. Following a similar approach, the MDF recruited 15 international clinicians with long-standing experience in the care of DM2 patients to develop consensus-based care recommendations. The single text procedure was adopted. This process generated a 4-page Quick Reference Guide and a comprehensive 55-page document that provides care recommendations for DM2 patients.SummaryThe resulting recommendations will help standardize and improve care for DM2 patients and facilitate appropriate management in centers without neuromuscular specialists.

Herein we report on a patient acutely admitted to the emergency room due to malaise and effort intolerance. A heart ultrasound, a cardiovascular MRI and an endomyocardial biopsy were suggestive of myocarditis. With appropriate medications the ejection fraction (EF) slowly improved but follow-up blood examinations revealed a hyperckemia. A neuromuscular examination revealed bilateral atrophy of medial gastrocnemius muscle and absent deep tendon reflexes at lower limbs . Genetic analysis revealed the presence of the hemizygous novel mutation c.757delT (p.Trp253fs) in XK gene thus confirming the diagnosis of McLeod Syndrome (MLS). In this patient an overlap of two conditions, dilative cardiomyopathy (DCMi) due to myocarditis and MLS, might have occurred. Patients with DCMi and hyperckemia should undergo a careful neuromuscular examination as some subclinical signs (calves-hypotrophy, areflexia) might go overlooked. We therefore suggest including the search for acanthocytes in patients with DCMi and hyperCKemia as it is a quick and cheap test that might unravel the MLS diagnosis.

Myotonic syndromes are rare neuromuscular diseases characterized by the clinical or neurophysiological detection of myotonia. The genetic defects involve primarily or secondarily the muscular isoforms of the ion channels. The channel dysfunction consecutively leads to a hyper-excitability of the muscle membrane and the clinical symptom myotonia. Two forms of dystrophic myotonic diseases are currently known: the myotonic dystrophy type 1 (DM1) and the myotonic dystrophy type 2 (DM2). They are multisystemic diseases clinically characterized by a combination of myotonia and other muscular symptoms (muscle weakness, wasting and myalgia) together with the involvement of other organs and systems (cataract, diabetes, heart diseases, hormone dysfunctions). The non-dystrophic myotonic diseases are caused by mutations affecting either the chloride ion channels or the sodium ion channels. The clinical picture is dominated by the presence of myotonia and other minor muscular complaints as mild episodic weakness and muscle hypertrophy. The differential diagnosis among the myotonic syndromes is extremely challenging leading to a significant diagnostic delay. This review will update on the main clinical, diagnostic and therapeutic aspects of myotonic syndromes to guide general neurologists through an earlier diagnosis and better management.

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Myositis-associated antibodies (MAA) and myositis-specific antibodies (MSA) are detected in patients with idiopathic inflammatory myopathies (IIM); their role as diagnostic biomarkers is however still debated. The aim of our study was to assess the utility of MAA/MSA assessed by new line immunoassays in detecting myositis among neuromuscular patients. We retrospectively analysed sera samples obtained from patients tested for myositis antibodies with the “Euroline: Autoimmune Inflammatory Myopathies 16Ag” and “myositis profile 3” kits (Mi-2, TIF1γ, MDA5, NXP2, SAE1, Jo-1, SRP, PL-7/12, EJ, OJ, Ro-52, Ku, PM-Scl75/100). First symptom, CK, EMG, muscle biopsy and diagnosis were also analysed. Using logistic regression analysis, two diagnostic models were built to evaluate the diagnostic power of MAA/MSA in distinguishing myositis patients from controls and other myopathies. 1229 patients were identified. 141 patients had a bioptic confirmed IIM; other diagnoses included: myopathy (n = 357), other neuromuscular diseases (n = 144) and no neuromuscular diseases (n = 587). The specificity was 95% for MSA and 89% for MAA, the sensitivity 20% and 22%, respectively. MAA showed no use in differentiating myositis patients from controls, whereas MSA had limited effect (OR = 5.165), compared to other variables as EMG (OR = 47.755) or CK > 2000 U/L (OR = 45.307). MSA were, however, the most useful parameter differentiating IIM from non-IIM patients (OR = 7.259), better than CK > 2000 U/L (OR = 4.033) and MAA (OR = 2.737). Line immunoassays for myositis antibodies show high specificity but low sensitivity. Their usefulness as diagnostic biomarkers widely depends on the clinical settings. Our study suggests that MSA/MAA should be used for confirmatory and differential diagnosis rather than for screening purposes in inflammatory myopathies.

The treatment of late-onset Pompe disease (LOPD) relies on enzyme replacement therapy (ERT) and physiotherapy but the most appropriate exercise program is not yet established. Whole-body vibration training (WBVT) has showed promising results, improving motor performances in various populations. Our aim is to assess the effects of WBVT performed by two LOPD patients in addition to ERT and physiotherapy. A side-alternating WBVT lasting 2 years; clinical assessments included: manual muscle testing (MRC sumscore), knee extension and arm flection isometric strength (multi-muscle tester M3diagnos), timed function tests (10 m walking, standing-up from chair, ascending 4-steps), 6 min walking (6 MWT), motor disability (Walton Gardner-Medwin scale), pulmonary function. Follow-up evaluations performed for 9 years since ERT start (pre-WBVT and post-WBVT) are reported for comparison. MRC sumscore improved in both patients (Pt.1:41 → 48, Pt.2:42 → 47) as isometric strength of knee extension (Pt.1: + 62 %, Pt.2: + 26 %) and arm flection (Pt.1: + 88 %, Pt.2: + 66 %), 6 MWT improved in Pt.1 (+75 m). Timed function tests did not greatly change. Patients reported no significant CK elevation or WBVT-related complaints. WBVT may be safely used in LOPD and seems to moderately boost muscle strength in patients receiving ERT and physiotherapy for more than 3 years. Larger cohorts should be studied to better assess WBVT potential as adjunctive exercise tool in LOPD.

Hintergrund: Myotone Dystrophien Typ 1 und 2 (DM1 / DM2) sind die haufigsten progressiven, segmental progeroiden, multisystemischen, erblichen Muskelerkrankungen im Erwachsenenalter. Die Storung der Exekutivfunktionen bei DM1-Patienten stellt einen wesentlichen Krankheitsanteil dar. Durch die pathognomonische Facies myopathica wird u. a. ein niedriges Bildungsniveau bei DM1 suggeriert. Detailliertere Untersuchungen zum Bildungsniveau dieser Patientengruppen existieren aber nicht. Methoden: Wir nutzten einen standardisierten strukturierten Fragebogen zur Untersuchung des Bildungsniveaus bei Patienten mit molekulargenetisch gesicherter DM1 und DM2. Inhalte der Untersuchung umfassten das Bildungsniveau, den hochsten erreichten Schulabschluss und die berufliche Qualifikation. Die erhobenen Daten wurden mit vorliegenden Daten zur Bildung der Normalbevolkerung verglichen. Ergebnisse: Aus einem Gesamtkollektiv von 546 DM Patienten nahmen 125 DM1- und 156 DM2-Patienten (51 %) an dieser Studie teil. Fur den hochsten Schulabschluss bestand ein statistisch signifikanter Unterschied zwischen den Kollektiven und der Normalbevolkerung. 50,4 % der DM1- und 48,3 % der DM2-Patienten erreichten die (Fach-)Hochschulreife, wahrend es in der Normalbevolkerung durchschnittlich 29,6 % sind. Fur die weitere berufliche Qualifizierung fanden sich nur geringe Abweichungen zwischen den Kohorten (Fach-/Hochschulabschluss: DM1: 25 %, DM2 23 %; Ausbildung/Lehre: DM1: 61 %, DM2 71 %) und der Normalbevolkerung. Es zeigte sich eine signifikant erhohte Pravalenz von „Rechtschreibproblemen“ (p = 0,039), „Schwierigkeiten beim Kopfrechnen“ (p = 0,043), und Einstufung der Patienten „mit Lernproblemen“ (p = 0,012) bei DM1-Patienten. Diskussion: Die allgemeine klinische Wahrnehmung der DM1-Patienten ist u. a. durch die Facies myopathica determiniert. Mit der Schwache der Gesichtsmuskulatur und dem offenstehenden Mund wird ein kognitives Defizit assoziiert, das diese Patientengruppe stigmatisiert. Die in unserer Studie dargestellten minimalen Abweichungen zwischen den Patientenkollektiven und der Normalbevolkerung weisen darauf hin, dass das erreichbare Bildungsniveau durch die multisystemische Erkrankung nicht wesentlich eingeschrankt wird. Beurteilung: Die im klinischen Alltag vorhandene Fehleinschatzung der kognitiven Leistungsfahigkeit von Erwachsenen mit Myotonen Dystrophien sollte revidiert werden.

Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10 , while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis.

Pompe disease is a rare metabolic disorder due to lysosomal alpha-glucosidase (GAA) deficiency. It is considered as a multi-systemic disease since, although glycogen accumulation is largely prominent in heart, skeletal and respiratory muscles, other organs can also be affected. As regards the vascular system, few reports have documented cerebrovascular malformations in Pompe patients. The aim of this study was to define the presence and type of intracranial arterial abnormalities in a cohort of late onset Pompe disease (LOPD) patients.We have studied 21 LOPD patients with cerebral CT angiography (CTA), using maximum intensity projection and volume rendering technique for 3D-image reconstruction.We found intracranial arterial abnormalities in 13/21 patients (62 %), of whom: 2/21 patients (9.5 %) showed an unruptured intracranial aneurysm (respectively 2 and 4 mm), 10/21 (47 %) had a vertebrobasilar dolichoectasia (VBD) and 1/21 a basilar artery fenestration. Signs of lacunar encephalopathy (insular, capsular and frontal subcortical lesions) were detected in 13/21 patients (62 %) and this correlated with the presence of respiratory impairment (p = 0.017).These findings differ from what has been previously observed in healthy, aged-matched populations and confirm that cerebral arteries abnormalities, mainly involving the posterior circle, are not so rare in LOPD patients and are often accompanied by a lacunar encephalopathy that might represent a hypoxic-ischemic origin. A CTA or an MRA is recommended, in LOPD patients, for early detection of cerebrovascular malformations as they could lead to life-threatening events such as sub-arachnoid haemorrhage or brainstem compression.

Myotone Dystrophien sind genetisch bedingte Formen der Muskeldystrophie. Diese konnen in allen Altersstufen auftreten und ausern sich durch muskulare, zerebrale und extramuskulare Symptome. Die Variabilitat der Symptomatik macht eine multimodale Untersuchung zur Diagnosestellung und Behandlung notig.

BACKGROUND/AIM Pulmonary function tests are used for screening respiratory insufficiency in patients with myotonic dystrophy (DM). We analysed the agreement between two different approaches in assessment of abnormal findings of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP), in DM patients. METHODS We used Cohen's \textgreekk- and Bangdiwala's B- statistic to compare the agreement between different cut-off values recommended by experts (ENMC) and the cut-off values based on the reference range (RR). We further analysed their sensitivity (Sn) and specificity (Sp) in detecting symptoms associated with respiratory insufficiency. RESULTS The observed agreement was: 1) for FVC: \textgreekk= -0.002, B = 0.406; 2) for FEV1: \textgreekk= 0.944, B = 0.946; 3) for MIP: \textgreekk= 0.625, B = 0.674; and 4) for MEP: \textgreekk= 0.241, B = 0.373. Overall, RR cut-off values showed higher sensitivity, whereas the ENMC values showed higher specificity in detecting symptoms of respiratory involvement. CONCLUSIONS The two approaches showed perfect agreement in assessment of FEV1, substantial agreement for MIP, and weak agreement for FVC and MEP. RR is an established method of assessment for spirometry and should be favoured because it takes variability within the population into account. Further development and validation of regression equations for RR calculations of predicted maximal respiratory pressures, with corresponding lower limits of normal, is required.The B statistic is more robust in assessing agreement between two diagnostic methods, resolving the issue of the \textgreekk paradox.

PURPOSE OF REVIEW Myotonic dystrophies are the most frequent muscular dystrophies in adulthood; however, myotonic dystrophy type 2 (DM2) is by far less prevalent than myotonic dystrophy type 1 (DM1). Consequently, studies on large cohorts are lacking and disease-specific outcome measures have not been developed (see video abstract, Supplemental Digital Content 1, http://links.lww.com/CONR/A44).The aim of this review is to systematically evaluate the outcome measures applied in patients with DM2 and to identify tests adopted from other neuromuscular disorders potentially suitable for DM2.A systematic review of functional tests and patient reported outcomes (PROs) previously used in DM2 has been performed. In addition, we reviewed functional tests and PROs previously used in neuromuscular diseases (NMDs). Based on this approach, we propose a battery of tests to be validated in DM2. RECENT FINDINGS No outcome measures or PROs have been validated in DM2. The most used PROs in DM2 were INQoL, SF-36, MPQ, and BPI. It is not clear whether it is better to use MMT or QMT to assess muscle strength. The algometer seems to be a useful tool to assess myalgia. No currently adopted tests or PROs seem effective to assess the mild myotonia of DM2. Several outcome measures used in other NMDs (e.g. 6MWT, QMFT, GSGC) might be suitable for DM2; however, their disease-specific validity needs to be explored. SUMMARY Although DM2 has a milder and more heterogeneous phenotype than DM1, there is an urgent need to develop validated outcome measures in DM2. The current lack of validated DM2 tests will delay the start of therapeutic trials.

Myotonic syndromes are rare neuromuscular diseases characterized by the clinical or neurophysiological detection of myotonia. The genetic defects involve primarily or secondarily the muscular isoforms of the ion channels. The channel dysfunction consecutively leads to a hyper-excitability of the muscle membrane and the clinical symptom myotonia. Two forms of dystrophic myotonic diseases are currently known: the myotonic dystrophy type 1 (DM1) and the myotonic dystrophy type 2 (DM2). They are multisystemic diseases clinically characterized by a combination of myotonia and other muscular symptoms (muscle weakness, wasting and myalgia) together with the involvement of other organs and systems (cataract, diabetes, heart diseases, hormone dysfunctions). The non-dystrophic myotonic diseases are caused by mutations affecting either the chloride ion channels or the sodium ion channels. The clinical picture is dominated by the presence of myotonia and other minor muscular complaints as mild episodic weakness and muscle hypertrophy. The differential diagnosis among the myotonic syndromes is extremely challenging leading to a significant diagnostic delay. This review will update on the main clinical, diagnostic and therapeutic aspects of myotonic syndromes to guide general neurologists through an earlier diagnosis and better management.Myotone Syndrome sind seltene Erkrankungen der Skelettmuskulatur die mit einer klinischen und elektrischen Myotonie einhergehen. Die genetischen Defekte betreffen primär oder sekundär muskuläre Ionenkanäle und führen zu einer Übererregbarkeit der muskulären Membran. Zu den dystrophischen Myotonien gehören die myotone Dystrophie Typ 1 (DM1) und die myotone Dystrophie Typ 2 (DM2). Es handelt sich bei beiden um multisystemische Erkrankungen, bei denen neben der Myotonie und dystrophischen Veränderungen der Muskulatur (z. B. Muskelatrophie, Muskelschwäche) auch eine Beteiligung verschiedener anderer Organe (Katarakt, Diabetes, Herzerkrankungen, endokrine Störungen) vorhanden ist. Zu den nicht-dystrophischen Myotonien gehören u. a. die Chlorid- und Natriumkanal-Myotonie. Bei diesen steht das Symptom Myotonie im Vordergrund und gelegentlich werden andere muskuläre Auffälligkeiten (Muskelhypertrophie, transiente Muskelschwäche) beobachtet. Die Differentialdiagnose ist oft eine Herausforderung und die zeitliche Verzögerung bis zur endgültigen Diagnosestellung weiterhin sehr lang. In dieser Übersicht werden Hauptaspekte der klinischen Symptome, der Diagnosestellung und der symptomatischen Therapie der dystrophischen und nicht-dystrophischen Myotonien dargestellt.

Quantitative imaging techniques are emerging in the field of magnetic resonance imaging of neuromuscular diseases (NMD). T

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) represent the most frequent multisystemic muscular dystrophies in adulthood. They are progressive, autosomal dominant diseases caused by an abnormal expansion of an unstable nucleotide repeat located in the non-coding region of their respective genes DMPK for DM1 and CNBP in DM2. Clinically, these multisystemic disorders are characterized by a high variability of muscular and extramuscular symptoms, often causing a delay in diagnosis. For both subtypes, many symptoms overlap, but some differences allow their clinical distinction. This article highlights the clinical core features of myotonic dystrophies, thus facilitating their early recognition and diagnosis. Particular attention will be given to signs and symptoms of muscular involvement, to issues related to respiratory impairment, and to the multiorgan involvement. This article is part of a Special Issue entitled “Beyond Borders: Myotonic Dystrophies – A European Perception”.

Quantitative imaging techniques are emerging in the field of magnetic resonance imaging of neuromuscular diseases (NMD). T2 of water (T2w ) is considered an important imaging marker to assess acute and chronic alterations of the muscle fibers, being generally interpreted as an indicator for "disease activity" in the muscle tissue. To validate the accuracy and robustness of quantitative imaging methods, 1 H magnetic resonance spectroscopy (MRS) can be used as a gold standard. The purpose of the present work was to investigate T2w of remaining muscle tissue in regions of higher proton density fat fraction (PDFF) in 40 patients with defined NMD using multi-TE single-voxel 1 H MRS. Patients underwent MR measurements on a 3 T system to perform a multi-TE single-voxel stimulated echo acquisition method (STEAM) MRS (TE = 11/15/20/25(/35) ms) in regions of healthy, edematous and fatty thigh muscle tissue. Muscle regions for MRS were selected based on T2 -weighted water and fat images of a two-echo 2D Dixon TSE. MRS results were confined to regions with qualitatively defined remaining muscle tissue without edema and high fat content, based on visual grading of the imaging data. The results showed decreased T2w values with increasing PDFF with R2 = 0.45 (p