Search

Background: Variants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1-related malignant hyperthermia (MH) susceptibility. Objective: To provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for of MH susceptible patients. Methods: We performed a prospective cross-sectional observational muscle ultrasound study in patients with a history of RYR1-related MH susceptibility (n = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders. Results: A total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P < 0.001), biceps femoris (z = 0.43; P = 0.002), deltoid (z = 0.31; P = 0.009), trapezius (z = 0.38; P = 0.010) and the sum of all muscles (z = 0.40; P < 0.001) were significantly higher compared to 0, indicating hypertrophy. Conclusions: Patients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and increased echogenicity.

Background and ObjectivesFacioscapulohumeral muscular dystrophy (FSHD) is a rare, debilitating disease characterized by progressive muscle weakness. MRI is a sensitive assessment of disease severity and progression. We developed a quantitative whole-body (WB) musculoskeletal MRI (WB-MSK-MRI) protocol analyzing muscles in their entirety. This study aimed to assess WB-MSK-MRI as a potential imaging biomarker providing reliable measurements of muscle health that capture disease heterogeneity and clinically meaningful composite assessments correlating with severity and more responsive to change in clinical trials.MethodsParticipants aged 18–65 years, with genetically confirmed FSHD1, clinical severity 2 to 4 (Ricci scale, range 0–5), and ≥1 short tau inversion recovery–positive lower extremity muscle eligible for needle biopsy, enrolled at 6 sites and were imaged twice 4–12 weeks apart. Volumetric analysis of muscle fat infiltration (MFI), muscle fat fraction (MFF), and lean muscle volume (LMV) in 18 (36 total) muscles from bilateral shoulder, proximal arm, trunk, and legs was performed after automated atlas-based segmentation, followed by manual verification. A WB composite score, including muscles at highest risk for progression, and functional cross-sectional composites for correlation with relevant functional outcomes including timed up and go (TUG), FSHD-TUG, and reachable workspace (RWS), were developed.ResultsSeventeen participants enrolled in this study; 16 follow-up MRIs were performed at 52 days (range 36–85 days). Functional cross-sectional composites (MFF and MFI) showed moderate to strong correlations: TUG (ρ = 0.71, ρ = 0.83), FSHD-TUG (ρ = 0.73, ρ = 0.73), and RWS (left arm: ρ = −0.71, ρ = −0.53; right arm: ρ = −0.61, ρ = −0.65). WB composite variability: LMVtot, coefficient of variation (CV) 1.9% and 3.4%; MFFtot, within-subject SD (Sw) 0.5% and 1.5%; and MFItot (Sw), 0.3% and 0.4% for normal and intermediate muscles, respectively. CV and Sw were higher in intermediate (MFI ≥0.10; MFF DiscussionWe developed a WB-MSK-MRI protocol and composite measures that capture disease heterogeneity and assess muscle involvement as it correlates with FSHD-relevant clinical endpoints. Functional composites robustly correlate with functional assessments. Stability of the WB composite shows that it could be an assessment of change in therapeutic clinical trials.Classification of EvidenceThis study provides Class II evidence that quantitative WB-MSK-MRI findings associate with FSHD1 severity measured using established functional assessments.

Item does not contain fulltext Muscle cramps are painful, sudden, involuntary muscle contractions that are generally self-limiting. They are often part of the spectrum of normal human physiology and can be associated with a wide range of acquired and inherited causes. Cramps are only infrequently due to progressive systemic or neuromuscular diseases. Contractures can mimic cramps and are defined as shortenings of the muscle resulting in an inability of the muscle to relax normally, and are generally myogenic. General practitioners and neurologists frequently encounter patients with muscle cramps but more rarely those with contractures. The main questions for clinicians are: (1) Is this a muscle cramp, a contracture or a mimic? (2) Are the cramps exercise induced, idiopathic or symptomatic? (3) What is/are the presumed cause(s) of symptomatic muscle cramps or contractures? (4) What should be the diagnostic approach? and (5) How should we advise and treat patients with muscle cramps or contractures? We consider these questions and present a practical approach to muscle cramps and contractures, including their causes, pathophysiology and treatment options. 01 februari 2023

Despite the growing knowledge on the (epi)genetic background of facioscapulohumeral muscular dystrophy (FSHD), the substantial variability in disease severity that exists between FSHD patients is not fully understood. We hypothesized that smoking and alcohol consumption are disease modifiers in FSHD and contribute to the variability in disease severity, because they are both associated with higher levels of oxidative stress in muscle tissue. Oxidative stress is known to influence FSHD muscle tissue. One hundred and ninety-eight genetically confirmed FSHD patients completed a questionnaire from which the number of packyears of smoking and the lifetime cumulative alcohol units consumed were calculated. Disease severity was determined by the FSDH evaluation score. Multiple linear regression analyses showed that both the number of packyears and the amount of alcohol consumption did not influence disease severity (respectively B = 0.025, ΔR2=0.006, p = 0.231; and B = 0.000, ΔR2=0.004, p = 0.406). Although smoking and excessive alcohol consumption are unhealthy habits which should be discouraged, these results show that smoking and alcohol consumption have no clinically meaningful modifying effect on disease severity in FSHD patients. However, prospective data should show whether alcohol consumption and smoking influence disease progression rate.

Introduction: Chronic hypercapnic respiratory failure induces considerable morbidity and mortality in patients with myotonic dystrophy type 1 (DM1). This study systematically reviews the effects of noninvasive home mechanical ventilation (HMV) on gas exchange, quality of life, survival, and compliance in DM1 patients. Methods: A systematic Medline and Embase search was performed (January 1995 to January 2020). Records were screened for eligibility criteria, data were extracted from included studies, and risk of bias was assessed. We present findings mainly using a narrative synthesis. Results: Twenty-eight relevant full-text articles were screened for eligibility criteria. Nine studies were included. Randomized controlled trials were not found. Studies had either an observational (n = 8) or interventional (n = 1) design. In the pooled data analysis, HMV showed to improve mean oxygen saturation with 4.8% and decreased mean carbon dioxide values with 3 mm Hg. Compliance varied widely between studies, from no use to more than 12 h per day. Quality of life was not studied extensively, but some studies reported positive effects of HMV on symptoms of chronic respiratory failure. HMV may improve survival in DM1 patients with chronic hypercapnic respiratory failure. Conclusion: This review shows that HMV can improve gas exchange and relieve symptoms with a possible survival benefit in DM1 patients with chronic hypercapnic respiratory failure. Future studies should focus on developing strategies to optimize the timing of HMV initiation and to promote compliance.

BackgroundSELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in theLAMA2gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness.MethodsLAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age ≥ 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All examinations are adapted to the patient’s age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed.DiscussionOur study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up.ConclusionOur natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD.Trial registrationThis study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017–3911) and is registered atClinicalTrial.gov(NCT04478981).

Background and objectives Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient‐reported Rasch‐built interval scale on activity and participation for FSHD. Methods A pre‐phase FSHD‐Rasch‐built overall disability scale (pre‐FSHD‐RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease‐related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2–4 weeks; reliability studies). The pre‐FSHD‐RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure. Results The pre‐FSHD‐RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38‐inquiry (originating from 32 items; six items split) FSHD‐RODS was constructed achieving Rasch model expectations. Adequate test‐retest reliability and (cross‐cultural and external) validity scores were obtained. Conclusions The FSHD‐RODS is a disease‐specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD., This paper presents the development and validation of a patient‐reported Rasch‐built interval scale on activity and participation for facioscapulohumeral muscular dystrophy (FSHD‐RODS). The final 38‐inquiry scale met Rasch model expectations and showed adequate discriminative power, test‐retest reliability and validity. The use of this scale is recommended in the near future to determine the functional deterioration slope in facioscapulohumeral muscular dystrophy (FSHD) per year as a preparation for the upcoming clinical intervention trials in FSHD.

Contains fulltext : 232905.pdf (Publisher’s version ) (Open Access) Brain involvement in myotonic dystrophy type 1 (DM1) is characterized by heterogeneous cognitive, behavioral, and affective symptoms and imaging alterations indicative of widespread grey and white matter involvement. The aim of the present study was to systematically review the literature on brain pathology in DM1. We conducted a structured search in EMBASE (index period 1974-2017) and MEDLINE (index period 1887-2017) on December 11, 2017, using free text and index search terms related to myotonic dystrophy type 1 and brain structures or regions. Eligible studies were full-text studies reporting on microscopic brain pathology of DM1 patients without potentially interfering comorbidity. We discussed the findings based on the anatomical region and the nature of the anomaly. Neuropathological findings in DM1 can be classified as follows: (1) protein and nucleotide deposits; (2) changes in neurons and glial cells; and (3) white matter alterations. Most findings are unspecific to DM1 and may occur with physiological aging, albeit to a lesser degree. There are similarities and contrasts with Alzheimer's disease; both show the appearance of neurofibrillary tangles in the limbic system without plaque occurrence. Likewise, there is myelin loss and gliosis, and there are dilated perivascular spaces in the white matter resemblant of cerebral small vessel disease. However, we did not find evidence of lacunar infarction or microbleeding. The various neuropathological findings in DM1 are reflective of the heterogeneous clinical and neuroimaging features of the disease. The strength of conclusions from this study's findings is bounded by limited numbers of participants in studies, methodological constraints, and lack of assessed associations between histopathology and clinical or neuroimaging findings.

Background: Non-invasive home mechanical ventilation (HMV) is a complex treatment in myotonic dystrophy type 1 (DM1) patients, due to a presumed poor adherence, variable symptom improvement, and uncertainty regarding survival benefits. Objectives: We aimed to investigate indications, adherence to HMV and its effects on mortality in a large cohort of DM1 patients. Methods: In this retrospective cohort study, we evaluated 224 DM1 patients. Different groups based on hypercapnia and HMV treatment were compared. Cox regression analyses were performed to compare mortality between different defined groups. Results: 224 patients were analysed of whom 111 started non-invasive HMV. Indications were daytime hypercapnia (n = 75), only nocturnal hypercapnia (n = 33), or other reasons (n = 3). Adequate adherence (≥4 h/night) was found in 84.9% of patients. Adequate ventilation was reached in 86.5% of patients. In 33 patients (29.7%), HMV was stopped prematurely due to not reaching patients’ expectations on symptom relief or treatment burden (n = 22), or intolerance (n = 8), or other reasons (n = 3). HMV did not improve survival in daytime hypercapnic patients (p = 0.61) nor in nocturnal hypercapnia patients compared to daytime hypercapnia (p = 0.21). Significant survival benefits after starting HMV were found for patients with HMV adherence ≥5 h/24 h compared to patients who used HMV less. Conclusion: In this large cohort, daytime hypercapnia is the main reason for starting HMV, which is well tolerated and used. Mortality is not associated with the reason why HMV was started, but once started, patients with ≥5 h/24 h adherence have significantly better survival compared to patients who use it less.

Rasch analysis is a popular statistical tool for developing and validating instruments that aim to measure human performance, attitudes and perceptions. Despite the availability of various software packages, constructing a good instrument based on Rasch analysis is still considered to be a complex, labor-intensive task, requiring human expertise and bares the possibility results in different but equally suited instruments. In this paper, we propose a semi-automated method for Rasch analysis based on first principles that reduces the need for human input. To this end, we introduce a novel criterion, called in-plus-out-of-questionnaire log-likelihood (IPOQ-LL). On artificial datasets, we confirm that optimization of IPOQ-LL leads to the desired behavior in the case of multi-dimensional and inhomogeneous surveys. On three publicly available real-world datasets, our method leads to instruments that have, for all practical purposes, similar clinimetrical properties as those obtained by Rasch analysis experts through a manual procedure.

Contains fulltext : 241356.pdf (Publisher’s version ) (Open Access) Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.

The intrinsic regenerative capacity of skeletal muscle makes it an excellent target for cell therapy. However, the potential of muscle tissue to renew is typically exhausted and insufficient in muscular dystrophies (MDs), a large group of heterogeneous genetic disorders showing progressive loss of skeletal muscle fibers. Cell therapy for MDs has to rely on suppletion with donor cells with high myogenic regenerative capacity. Here, we provide an overview on stem cell lineages employed for strategies in MDs, with a focus on adult stem cells and progenitor cells resident in skeletal muscle. In the early days, the potential of myoblasts and satellite cells was explored, but after disappointing clinical results the field moved to other muscle progenitor cells, each with its own advantages and disadvantages. Most recently, mesoangioblasts and pericytes have been pursued for muscle cell therapy, leading to a handful of preclinical studies and a clinical trial. The current status of (pre)clinical work for the most common forms of MD illustrates the existing challenges and bottlenecks. Besides the intrinsic properties of transplantable cells, we discuss issues relating to cell expansion and cell viability after transplantation, optimal dosage, and route and timing of administration. Since MDs are genetic conditions, autologous cell therapy and gene therapy will need to go hand-in-hand, bringing in additional complications. Finally, we discuss determinants for optimization of future clinical trials for muscle cell therapy. Joined research efforts bring hope that effective therapies for MDs are on the horizon to fulfil the unmet clinical need in patients. Graphical abstract

Rasch analysis is a procedure to develop and validate instruments that aim to measure a person’s traits. However, manual Rasch analysis is a complex and time-consuming task, even more so when the possibility of differential item functioning (DIF) is taken into consideration. Furthermore, manual Rasch analysis by construction relies on a modeler’s subjective choices. As an alternative approach, we introduce a semi-automated procedure that is based on the optimization of a new criterion, called in-plus-out-of-questionnaire log likelihood with differential item functioning (IPOQ-LL-DIF), which extends our previous criterion. We illustrate our procedure on artificially generated data as well as on several real-world datasets containing potential DIF items. On these real-world datasets, our procedure found instruments with similar clinimetric properties as those suggested by experts through manual analyses.

Contains fulltext : 236035.pdf (Publisher’s version ) (Open Access) Some patients with Oculopharyngeal Muscular Dystrophy (OPMD) develop frontotemporal dementia (FTD). The prevalence and clinical correlates of behavioural impairment, including FTD, is unknown in OPMD. 24 OPMD patients and their proxies completed a questionnaire concerning behavioural impairment (ALS-FTD-Q). We examined proportions with mild or severe behavioural changes, according to validated cut-off proxy scores. We examined correlations with the Hospital Anxiety and Depression Scale (HADS), the Short Form Health Survey (SF-36), motor symptoms, genotype and disease duration. In this small patient sample, behavioural impairment was present in 29%of OPMD patients; in 17%the severity of symptoms was compatible with bvFTD. Correlations were small to medium. 7 p.

Background and ObjectivesTo perform a systematic review of published N-of-1 trials (e.g., single patient crossover trials) in neurologic disorders, including an assessment of methodologic quality and reporting.MethodsWe searched PubMed, MEDLINE, and Embase from inception date to the December 1, 2019, for reports on N-of-1 trials in neurologic disorders. Basic trial information on design, disease, intervention, analysis, and treatment success was extracted. Strengths and weaknesses of the N-of-1 trials were assessed with the Consolidated Standards of Reporting Trials extension for N-of-1 trials (CENT) 2015 criteria checklist and the Jadad score as measures of quality and reporting.ResultsWe retrieved 40 reports of N-of-1 trials in neurologic disorders (19 individual N-of-1 trials, 21 series of N-of-1 trials). Most N-of-1 trials were performed in neuromuscular and neurodegenerative/movement disorders. Unlike the majority of trials that studied the main symptom(s) of a chronic stable condition, 9 N-of-1 trials studied a stable chronic symptom of a progressive or acute neurologic disorder. Besides pharmacologic interventions, electric stimulation protocols and nutritional products were studied. A mean total CENT score of 20.88 (SD 9.10, range 0–43) and mean total Jadad score of 2.90 (SD 2.15, range 0–5) were found as methodologic measures of quality and reporting across all N-of-1 trials.DiscussionN-of-1 trials have been reported in numerous neurologic disorders, not only in chronic stable disorders, but also in progressive or acute disorders with a stable symptom. This indicates the emerging therapeutic area of N-of-1 trials in neurology. Methodologic quality and reporting of N-of-1 trials were found to be suboptimal and can easily be improved in future trials by appropriately describing the methods of blinding and randomization and following CENT guidelines. Because most N-of-1 trials remain unreported in medical literature, this systematic review probably represents only the tip of the iceberg of conducted N-of-1 trials in neurologic disorders. In addition to conventional trial designs, N-of-1 trials can help to bridge the gap between research and clinical care by providing an alternative, personalized level 1 evidence base for suitable treatments.

BackgroundFacioscapulohumeral dystrophy (FSHD) is an inherited muscular dystrophy clinically characterised by muscle weakness starting with the facial and upper extremity muscles. A disease model has been developed that postulates that failure in somatic repression of the transcription factor DUX4 embedded in the D4Z4 repeat on chromosome 4q causes FSHD. However, due to the position of the D4Z4 repeat close to the telomere and the complex genetic and epigenetic aetiology of FSHD, there is ongoing debate about the transcriptional deregulation of closely linked genes and their involvement in FSHD.MethodDetailed genetic characterisation and gene expression analysis of patients with clinically confirmed FSHD and control individuals.ResultsIdentification of two FSHD families in which the disease is caused by repeat contraction and DUX4 expression from chromosome 10 due to a de novo D4Z4 repeat exchange between chromosomes 4 and 10. We show that the genetic lesion causal to FSHD in these families is physically separated from other candidate genes on chromosome 4. We demonstrate that muscle cell cultures from affected family members exhibit the characteristic molecular features of FSHD, including DUX4 and DUX4 target gene expression, without showing evidence for transcriptional deregulation of other chromosome 4-specific candidate genes.ConclusionThis study shows that in rare situations, FSHD can occur on chromosome 10 due to an interchromosomal rearrangement with the FSHD locus on chromosome 4q. These findings provide further evidence that DUX4 derepression is the dominant disease pathway for FSHD. Hence, therapeutic strategies should focus on DUX4 as the primary target.

Background: Neuralgic amyotrophy (NA) is a common peripheral nerve disorder caused by auto-immune inflammation of nerves in the brachial plexus territory, characterized by acute pain and weakness of the shoulder muscles, followed by motor impairment. Recent work has confirmed that NA patients with residual motor dysfunction have abnormal cerebral sensorimotor representations of their affected upper extremity. Objective: To determine whether abnormal cerebral sensorimotor representations associated with NA can be altered by specialized, multidisciplinary outpatient rehabilitation focused on relearning motor control. Methods: 27 NA patients with residual lateralized symptoms in the right upper extremity participated in a randomized controlled trial, comparing 17 weeks of multidisciplinary rehabilitation ( n = 16) to usual care ( n = 11). We used task-based functional MRI and a hand laterality judgment task, which involves motor imagery and is sensitive to altered cerebral sensorimotor representations of the upper extremity. Results: Change in task performance and related brain activity did not differ significantly between the multidisciplinary rehabilitation and usual care groups, whereas the multidisciplinary rehabilitation group showed significantly greater clinical improvement on the Shoulder Rating Questionnaire. Both groups, however, showed a significant improvement in task performance from baseline to follow-up, and significantly increased activity in visuomotor occipito-parietal brain areas, both specific to their affected upper extremity. Conclusions: Abnormal cerebral sensorimotor representations of the upper extremity after peripheral nerve damage in NA can recover toward normality. As adaptations occurred in visuomotor brain areas, multidisciplinary rehabilitation after peripheral nerve damage may be further optimized by applying visuomotor strategies. This study is registered at ClinicalTrials.gov (NCT03441347).

This study focuses on the functional and psychosocial consequences of facial weakness of patients with facioscapulohumeral muscular dystrophy (FSHD) and how they manage their daily lives. We conducted a qualitative study. Sixteen FSHD patients with varying degrees of facial weakness were interviewed using a semi-structured interview guide. Data were analyzed using the constant comparison approach based on the Straussian Grounded Theory. Reduced facial expression affected different aspects of a participant’s life, which is reinforced by fatigue. Particularly the younger participants described the confrontation with reduced facial expression as upsetting. The unpredictability of the progression of facial weakness makes many participants insecure and concerned. They generally tend to avoid discussing facial weakness with loved ones as well as with strangers. Patients would like the expert teams to shed more light on effective skill training and psychosocial support, especially for the younger patient group. A multidisciplinary approach is needed in addition to programs focusing on the individual aspects of facial weakness. As the experienced psychosocial effect is not commonly equal to the objective degree of facial weakness, we recommend a tailored approach. Finally, these programs should point out the importance of the patient’s own ingenuity.Implications for RehabilitationFacial weakness affects both activities and social participation in patients with facioscapulohumeral muscular dystrophy (FSHD), which is reinforced by fatigue.Many participants try to stay down to earth and focus on their ability to self-manage their obstacles regarding facial weakness.Thus, future treatment programs should have a multidisciplinary approach and should point out the importance of the patient’s own ingenuity. Facial weakness affects both activities and social participation in patients with facioscapulohumeral muscular dystrophy (FSHD), which is reinforced by fatigue. Many participants try to stay down to earth and focus on their ability to self-manage their obstacles regarding facial weakness. Thus, future treatment programs should have a multidisciplinary approach and should point out the importance of the patient’s own ingenuity.

Contains fulltext : 248862.pdf (Publisher’s version ) (Closed access) Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy clinically characterized by weakness in the facial, shoulder girdle and upper a muscles. FSHD is caused by chromatin relaxation of the D4Z4 macrosatellite repeat, mostly by a repeat contraction, facilitating ectopic expression of DUX4 in skeletal muscle. Genetic diagnosis for FSHD is generally based on the sizing and haplotyping of the D4Z4 repeat on chromosome 4 by Southern blotting (SB), molecular combing or single-molecule optical mapping, which is usually straight forward but can be complicated by atypical rearrangements of the D4Z4 repeat. One of these rearrangements is a D4Z4 proximally extended deletion (DPED) allele, where not only the D4Z4 repeat is partially deleted, but also sequences immediately proximal to the repeat are lost, which can impede accurate diagnosis in all genetic methods. Previously, we identified several DPED alleles in FSHD and estimated the size of the proximal deletions by a complex pulsed-field gel electrophoresis and SB strategy. Here, using the next-generation sequencing, we have defined the breakpoint junctions of these DPED alleles at the base pair resolution in 12 FSHD families and 4 control individuals facilitating a PCR-based diagnosis of these DPED alleles. Our resultsshow that half of the DPED alleles are derivates of an ancient founder allele. For some DPED alleles, we found that genetic elements are deleted such as DUX4c, FRG2, DBE-T and myogenic enhancers necessitating re-evaluation of their role in FSHD pathogenesis.

Contains fulltext : 248860.pdf (Publisher’s version ) (Open Access) Reproductive counseling in facioscapulohumeral muscular dystrophy (FSHD) can be challenging due to the complexity of its underlying genetic mechanisms and due to incomplete penetrance of the disease. Full understanding of the genetic causes and potential inheritance patterns of both distinct FSHD types is essential: FSHD1 is an autosomal dominantly inherited repeat disorder, whereas FSHD2 is a digenic disorder. This has become even more relevant now that prenatal diagnosis and preimplantation genetic diagnosis options are available for FSHD1. Pregnancy and delivery outcomes in FSHD are usually favorable, but clinicians should be aware of the risks. We aim to provide clinicians with case-based strategies for reproductive counseling in FSHD, as well as recommendations for pregnancy and delivery.

Contains fulltext : 226018.pdf (Publisher’s version ) (Open Access) BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late onset progressive neuromuscular disorder. Although dysphagia is a pivotal sign in OPMD it is still not completely understood. OBJECTIVE: The aim of this study was to systematically investigate oropharyngeal functioning in a large OPMD population. METHODS: Forty-eight genetically confirmed OPMD patients completed questionnaires, performed clinical tests on swallowing, chewing, speaking, tongue strength and bite force, and underwent videofluoroscopy of swallowing. Descriptive statistics was used for all outcomes and logistic regression to investigate predictors of abnormal swallowing. RESULTS: Eighty-two percent reported difficulties with swallowing, 27% with chewing and 67% with speaking. Patients performed significantly worse on all oropharyngeal tests compared to age-matched controls except for bite force. Also asymptomatic carriers performed worse than controls: on chewing time, swallowing speed and articulation rate. During videofluoroscopy, all patients (except one asymptomatic) had abnormal residue and 19% aspirated. Independent predictors of abnormal residue were reduced swallowing capacity for thin liquids (OR 10 mL = 0.93; 20 mL = 0.95) and reduced tongue strength for thick liquids (OR 10 mL = 0.95); 20 mL = 0.90). Aspiration of thin liquids was predicted by disease duration (OR = 1.11) and post-swallow residue with 20 mL (OR = 4.03). CONCLUSION: Next to pharyngeal dysphagia, chewing and speaking are also frequently affected in OPMD patients, even in asymptomatic carriers. Residue after swallowing is a very early sign, while aspiration is a later sign in OPMD. For clinical follow-up monitoring of subjective complaints, swallowing capacity and tongue strength seems relevant.

Contains fulltext : 220627.pdf (Publisher’s version ) (Open Access) Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (FSHD1) or by mutations in D4Z4 chromatin modifiers such as Structural Maintenance of Chromosomes Hinge Domain Containing 1 (FSHD2). These two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the D4Z4 repeat. All together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the DUX4 gene, which is otherwise kept epigenetically silent in skeletal muscle. DUX4 is consistently transcriptionally upregulated in FSHD1 and FSHD2 skeletal muscle cells where it is believed to exercise a toxic effect. Here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of FSHD, with a focus on one of the consequences that these epigenetic changes inflict, the DUX4-induced immune deregulation cascade. Moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the FSHD locus.

Contains fulltext : 218857.pdf (Publisher’s version ) (Closed access)

Brody disease is a rare myopathy characterized by exercise-induced muscle stiffness caused by mutations in the ATP2A1 gene. In the largest cohort of Brody patients to date, Molenaar et al. clarify the phenotype and diagnostic possibilities to help improve understanding and recognition of this distinct myopathy., Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.

We aimed to examine the incidence as well as the circumstances and the consequences of falling in adult patients with myotonic dystrophy type 1 and 2 (DM1/DM2). We performed a prospective cohort study in 209 subjects, of which 102 had DM1, 42 had DM2 and 65 healthy controls. An assessment of their falls was carried out during 100 consecutive days. In addition, falls during the previous year were reported. The primary outcome measure was the number of self-reported falls per participant during these 100 days. The secondary outcome measures included self-reported causes, circumstances and consequences of the falls. Mean (SD) falls per participant in 100 days was seven- to eightfold higher in patients with DM1 (0.74 (0.14)) and DM2 (0.62 (0.20)) compared to the controls (0.09 (0.04); p < 0.001)). Sixteen percent of DM1 and 17% of DM2 patients fell at least twice. Two-thirds of the falls occurred inside. Fifty percent of falls resulted in an injury, including a head trauma in four patients. Compared to non-fallers, those patients who fell were older (DM1/DM2), had a lower DM1-Activ score (DM1), had more muscle weakness (DM1), and reported less confidence in balance (DM1). This study demonstrates a high incidence and clinical relevance of falling in patients with DM1 and DM2. Fall prevention strategies in both DM1 and DM2 should focus on adaptations of the home environment and the patient's interaction in this environment.

Background and ObjectivesOculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Disease progression is known to be slow, but details on the natural history remain unknown. We aimed to examine the natural history of OPMD in a large nationwide cohort to determine clinical outcome measures that capture disease progression and can be used in future clinical trials.MethodsPatients invited by their treating physicians or identified from the national neuromuscular database and invited family members were examined twice 20 months apart with fixed dynamometry; Medical Research Council (MRC) grading; maximum bite force and isometric tongue strength; Motor Function Measure (MFM); 10-step stair test; maximum swallowing, chewing, and speech tasks; and quality of life assessments.ResultsDisease progression was captured by 8 of 18 measures over 20 months in 43 patients with genetically confirmed OPMD. The largest deterioration was seen in deltoid muscle strength (−27% [range −17% to −37%]), followed by the quadriceps (−14% [range −6 to −23%]), iliopsoas (−12.2%), tongue (−9.9%), and MRC sum score (−2.5%). The 10-step stair test (−12.5%), MFM part D1 (−7.1%), and maximum repetition rate of /pa/ (−5.3%) showed a significant decrease as well (all p < 0.05). The Physical Functioning domain of the Short Form-36 Health Survey significantly deteriorated (p = 0.044). No relationship was found between disease progression and genotype or disease duration (p > 0.05).DiscussionDespite the slow disease progression of OPMD, this study showed that several outcome measures detected progression within 20 months. Deltoid muscle strength, measured by fixed dynamometry, showed the greatest decline. These longitudinal data provide clinical outcome measures that can be used as biomarkers in future clinical trials.

Aims Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD). Methods This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C: FSHD subjects received open-label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging-normal appearing (Part B) and affected muscle identified by abnormal short-tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol-stimulated blood. Results PK profiles were similar between healthy volunteers and FSHD subjects, with mean Cmax and AUC0-12 for 15 mg in FSHD subjects (Part B) of 85.0 ± 16.7 ng*h/mL and 410 ± 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose-dependent concentrations in muscle (42.1 ± 10.5 ng/g [7.5 mg] to 97.2 ± 22.4 ng/g [15 mg]) were observed, with plasma-to-muscle ratio from ~0.67 to ~1 at estimated tmax of 3.5 hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self-limited. Conclusion Losmapimod was well tolerated, with no serious AEs. Dose-dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD. Clinical trial registration Clinical trial identifier ToetsingOnline: NL68539.056.18 Nederlands Trials Register NL8000.

Summary Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7–9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1·4 (95% CI 0·6–3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13–24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products.

ObjectivesTo describe the combination of spinocerebellar ataxia (SCA) types 3 and 6 and sporadic inclusion body myositis (IBM).MethodsA description of five patients with SCA type 3 and 6 who were diagnosed with IBM. We explore possible mechanisms explaining the coexistence of both diseases.ResultsThe patients with SCA-3 (n=4) and SCA-6 (n=1) developed asymmetric muscle weakness in a pattern suggestive of IBM in the course of their disease. Based on findings of neurological examination and additional investigations (muscle ultrasound, muscle biopsy), the diagnosis of IBM was made in all patients.ConclusionWe report on five patients with concomitant SCA and IBM. Our cases may merely illustrate coincidental co-occurrence of IBM and SCA-3/SCA-6. However, the presence of SCA mutations could predispose to the development of IBM in some SCA patients, or, the presence of toxic aggregates and malfunctioning of cellular quality control processes in both diseases could indicate a convergence of disease mechanisms.

Contains fulltext : 207009.pdf (Publisher’s version ) (Closed access) The diagnosis and classification of idiopathic inflammatory myopathies are based mainly on clinical and histological features. The discovery of myositis-specific and myositis-associated antibodies has simplified the (sub)classification of inflammatory myopathies. Patients suspected of having an idiopathic inflammatory myopathy should undergo routine antibody testing to gain more insight into distinct phenotypes, comorbidities, treatment response and prognosis. Furthermore, autoantibody testing can help in patients with atypical patterns of weakness or with an unresolved limb-girdle myopathic phenotype, or interstitial lung disease. However, some important technical and methodological issues can hamper the interpretation of antibody testing; for example, some antibodies are not included in the widely available line blots. We aim to provide a practical review of the use of autoantibody testing in idiopathic inflammatory myopathies in clinical practice.

Background Adult-onset myotonic dystrophy type 1 (DM1) is a chronic, multisystem disorder that leads to disability and premature death. Objectives The objective of our study was to conduct a systematic literature review of the health-related quality of life (HRQoL) of patients with DM1. Methods We searched Embase, Web of Science, and PubMed for English language full-text articles reporting results from studies of HRQoL in patients with adult-onset DM1 published between 1 January 2000 and 21 February 2018. We excluded reviews, editorials, and studies reporting results for a sample with fewer than five patients (to allow for meaningful inference). Results The search identified 266 unique publications. Of these, 231 were excluded following title and abstract screening and 16 after full-text review, leaving 19 articles for data synthesis. We found 15 articles measuring the HRQoL of patients with adult-onset DM1 using the 36-Item Short Form Health Survey (SF-36), six using the Individualized Neuromuscular Quality of Life Questionnaire (INQoL), and one using Cantril’s Ladder. Available evidence shows that patient HRQoL is impaired in DM1, mainly due to compromised physical health, but also reveals that substantial heterogeneity exists in estimates across studies. Conclusions HRQoL in adult-onset DM1 has been extensively studied using the SF-36 and the INQoL, but current estimates are inconclusive, and little is known of the impact of the disease as measured using other instruments. Our data synthesis should help characterize the patient burden of DM1 and inform future studies of HRQoL in this indication. Electronic supplementary material The online version of this article (10.1007/s40271-019-00357-y) contains supplementary material, which is available to authorized users.

Contains fulltext : 207092.pdf (Publisher’s version ) (Closed access) In the era of patient-centered medicine, shared decision-making (SDM) - in which healthcare professionals and patients exchange information and preferences and jointly reach a decision - has emerged as the gold standard model for the provision of formal healthcare. Indeed, in many geographical settings, patients are frequently invited to participate in choices concerning the design and delivery of their medical management. From a clinical perspective, benefits of this type of patient involvement encompass, for example, enhanced treatment satisfaction, improved medical compliance, better health outcomes, and maintained or promoted quality of life. Yet, although the theory and enactment of SDM in healthcare are well-described in the literature [1-3], comparatively less attention has been devoted to contextualizing questions relating to if, when, and how to include patients in decisions within medical research. In this context, patient involvement would be expected to be potentially relevant for and applicable to a wide range of activities and processes, from the identification of research priorities and development of grant applications, to the design of patient information and consent procedures, formulation of interventions, identification and recruitment of study sample populations, feasibility of a clinical trial, identification, selection, and specification of endpoints and outcomes in clinical trials and observational studies, data collection and analysis, and dissemination of results. To this end, 45 clinicians, healthcare professionals, researchers, patients, caregivers, and representatives from regulatory authorities and pharmaceutical companies from 15 different countries met to discuss the level of involvement of patients with neuromuscular diseases, specifically in the following settings of medical research for neuromuscular diseases: i) registries and biobanks; ii) clinical trials; and iii) regulatory processes. In this report, we present summaries of the talks that were given during the workshop, as well as discussion outcomes from the three topic areas listed above.

Contains fulltext : 205507.pdf (Publisher’s version ) (Open Access) Atrophy and fatty infiltration are important causes of muscle weakness in inclusion body myositis (IBM). Muscle weakness can also be caused by reduced specific force; i.e. the amount of force generated per unit of residual muscle tissue. This study investigates in vivo specific force of the quadriceps and ex vivo specific force of single muscle fibers in patients with IBM. We included 8 participants with IBM and 12 healthy controls, who all underwent quantitative muscle testing, quantitative MRI of the quadriceps and paired muscle biopsies of the quadriceps and tibialis anterior. Single muscle fibers were isolated to measure muscle fiber specific force and contractile properties. Both in vivo quadriceps specific force and ex vivo muscle fiber specific force were reduced. Muscle fiber dysfunction was accompanied by reduced active stiffness, which reflects a decrease in the number of attached actin-myosin cross-bridges during activation. Myosin concentration was reduced in IBM fibers. Because reduced specific force contributes to muscle weakness in patients with IBM, therapeutic strategies that augment muscle fiber strength may provide benefit to patients with IBM.

Pericytes are multipotent, vessel-associated progenitors that exhibit high proliferative capacity, can cross the blood-muscle barrier, and have the ability to home to muscle tissue and contribute to myogenesis. Consequently, pericyte-based therapies hold great promise for muscular dystrophies. A complex multi-system disorder exhibiting muscular dystrophy for which pericytes might be a valuable cell source is myotonic dystrophy type 1 (DM1). DM1 is caused by an unstable (CTG)n repeat in the DMPK gene and characterized by skeletal muscle weakness, muscle wasting, and myotonia. We have successfully isolated alkaline phosphatase-positive pericytes from skeletal muscle of DM1 patients and a transgenic mouse model. Intranuclear (CUG)n RNA foci, a pathogenic DM1 hallmark, were identified in human and mouse pericytes. Notably, pericytes from DM1 patients maintained similar growth parameters and innate myogenic characteristics in vitro compared to cells from unaffected controls. Our in vitro results thus demonstrate the potential of pericytes to ameliorate muscle features in DM1 in a therapeutic setting., Graphical Abstract

ObjectiveTo assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD).MethodsIn this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups.ResultsTwenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, p < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, p < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2–3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8–9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%).ConclusionsPatients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients.

To determine how much of the clinical variability in facioscapulohumeral muscular dystrophy type 1 (FSHD1) can be explained by the D4Z4 repeat array size, D4Z4 methylation and familial factors, we included 152 carriers of an FSHD1 allele (23 single cases, 129 familial cases from 37 families) and performed state-of-the-art genetic testing, extensive clinical evaluation and quantitative muscle MRI. Familial factors accounted for 50% of the variance in disease severity (FSHD clinical score). The explained variance by the D4Z4 repeat array size for disease severity was limited (approximately 10%), and varied per body region (facial muscles, upper and lower extremities approximately 30%, 15% and 3%, respectively). Unaffected gene carriers had longer repeat array sizes compared to symptomatic individuals (7.3 vs 6.0 units, P = 0.000) and slightly higher Delta1 methylation levels (D4Z4 methylation corrected for repeat size, 0.96 vs -2.46, P = 0.048). The D4Z4 repeat array size and D4Z4 methylation contribute to variability in disease severity and penetrance, but other disease modifying factors must be involved as well. The larger effect of the D4Z4 repeat array on facial muscle involvement suggests that these muscles are more sensitive to the influence of the FSHD1 locus itself, whereas leg muscle involvement seems highly dependent on modifying factors.

Background Promising genetic therapies are being investigated in facioscapulohumeral muscular dystrophy (FSHD). However, the current cost of illness is largely unknown. Objective This study aimed at determining the socioeconomic burden of FSHD. Methods Adult patients with FSHD from the Dutch FSHD registry were invited to complete a questionnaire on medical consumption, work productivity and health-related quality of life (HR-QoL) using the EQ-5D-5L. Associated costs were calculated from a societal perspective. A generalized linear model was fitted to the data to investigate whether level of mobility was related to annual costs of illness. Results 172 patients with FSHD completed the questionnaire (response rate 65%). The per-patient annual direct medical costs of FSHD were estimated at €12,077, direct non-medical costs at €9179 and indirect costs at €5066, adding up to a total cost of illness of €26,322 per patient per year. The direct costs of illness were €21,256, approximately five times higher than the mean per-capita health expenditures in the Netherlands. Major cost-driving factors were formal home care and informal care. A decreased level of mobility was associated with higher direct costs of illness. HR-QoL was significantly reduced in patients with FSHD with a median health utility value of 0.63. Conclusions We show that FSHD is associated with substantial direct and indirect socioeconomic costs as well as a reduction in HR-QoL. These findings are important for health care decision makers and aids in allocation of research funds and evaluation of the cost-effectiveness of novel therapies.

Background and ObjectivesData on the natural history of facioscapulohumeral dystrophy (FSHD) in childhood are limited and critical for improved patient care and clinical trial readiness. Our objective was to describe the disease course of FSHD in children.MethodsWe performed a nationwide, single-center, prospective cohort study of FSHD in childhood assessing muscle functioning, imaging, and quality of life over 2 years of follow-up.ResultsWe included 20 children with genetically confirmed FSHD who were 2 to 17 years of age. Overall, symptoms were slowly progressive, and the mean FSHD clinical score increased from 2.1 to 2.8 (p = 0.003). The rate of progression was highly variable. At baseline, 16 of 20 symptomatic children had facial weakness; after 2 years, facial weakness was observed in 19 of 20 children. Muscle strength did not change between baseline and follow-up. The most frequently and most severely affected muscles were the trapezius and deltoid. The functional exercise capacity, measured with the 6-minute walk test, improved. Systemic features were infrequent and nonprogressive. Weakness-associated complications such as lumbar hyperlordosis and dysarthria were common, and their prevalence increased during follow-up. Pain and fatigue were frequent complaints in children, and their prevalence also increased during follow-up. Muscle ultrasonography revealed a progressive increase in echogenicity.DiscussionFSHD in childhood has a slowly progressive but variable course over 2 years of follow-up. The most promising outcome measures to detect progression were the FSHD clinical score and muscle ultrasonography. Despite this disease progression, an improvement on functional capacity may still occur as the child grows up. Pain, fatigue, and a decreased quality of life were common symptoms and need to be addressed in the management of childhood FSHD. Our data can be used to counsel patients and as baseline measures for treatment trials in childhood FSHD.

Aims The aim of this study was to determine electrocardiographic (ECG) criteria predicting abnormal infrahissian conduction in patients with myotonic dystrophy type 1 (DM1), as these criteria could be used to identify the need for an electrophysiological study (EPS). Methods and results A retrospective multicentre study was conducted including DM1-affected individuals who underwent EPS between 2007 and 2018. For each individual, EPS indication, His-ventricle (HV) interval, resting ECG parameters prior to EPS, left ventricular ejection fraction (LVEF), neurological status, and DM1 DNA analysis results were collected. Electrocardiographic parameters of patients with a normal HV interval were compared with ECG parameters of patients with a prolonged HV interval. Logistic regression was performed to determine predictors for a prolonged HV interval of ≥70 ms on EPS and diagnostic accuracy of ECG parameters was ascertained. Among 100 DM1-affected individuals undergoing EPS, 47 had a prolonged HV interval. The sole presence of a PR interval >200 ms [odds ratio (OR) 8.45, confidence interval (CI) 2.64–27.04] or a QRS complex >120 ms (OR 9.91, CI 3.53–27.80) on ECG were independent predictors of a prolonged HV interval. The combination of both parameters had a positive predictive value of 78% for delayed infrahissian conduction on EPS. His-ventricle interval was independent of DM1 genetic mutation size, neuromuscular status, and LVEF. Conclusion The combination of a prolonged PR interval and widened QRS complex on ECG accurately predicts abnormal infrahissian conduction on EPS in patients with DM1. These ECG parameters could be used as a screening tool to determine the need for referral to a specialized multidisciplinary neuromuscular team with EPS capacity.

Contains fulltext : 238504.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To assess anti-cytosolic 5'-nucleotidase 1A (anti-cN-1A) autoantibodies in children with juvenile dermatomyositis (DM) and healthy controls, using 3 different methods of antibody detection, as well as verification of the results in an independent cohort. METHODS: Anti-cN-1A reactivity was assessed in 34 Dutch juvenile DM patients and 20 healthy juvenile controls using the following methods: a commercially available full-length cN-1A enzyme-linked immunosorbent assay (ELISA), a synthetic peptide ELISA, and immunoblotting with a lysate from cN-1A-expressing HEK 293 cells. Sera from juvenile DM patients with active disease and those with disease in remission were analyzed. An independent British cohort of 110 juvenile DM patients and 43 healthy juvenile controls was assessed using an in-house full-length cN-1A ELISA. RESULTS: Anti-cN-1A reactivity was not present in sera from juvenile DM patients or healthy controls when tested with the commercially available full-length cN-1A ELISA or by immunoblotting, in either active disease or disease in remission. Additionally, in the British juvenile DM cohort, anti-cN-1A reactivity was not detected. Three Dutch juvenile DM patients had weakly positive results for 1 of 3 synthetic cN-1A peptides measured by ELISA. CONCLUSION: Juvenile DM patients and young healthy individuals did not show anti-cN-1A reactivity as assessed by different antibody detection techniques.

BackgroundThe European OPTIMISTIC clinical trial has demonstrated a significant, yet heterogenous effect of Cognitive Behavioural Therapy (CBT) for Myotonic Dystrophy type 1 (DM1) patients. One of its remaining aims was the assessment of efficacy and adequacy of clinical outcome measures, including the relatively novel primary trial outcome, the DM1-Activ-c questionnaire.ObjectivesAssessment of the relationship between the Rasch-built DM1-Activ-c questionnaire and 26 commonly used clinical outcome measurements. Identification of variables associated with CBT response in DM1 patients.MethodsRetrospective analysis of the to date largest clinical trial in DM1 (OPTIMISTIC), comprising of 255 genetically confirmed DM1 patients randomized to either standard care or CBT with optionally graded exercise therapy. Correlations of 27 different outcome measures were calculated at baseline (cross-sectional) and of their respective intervention induced changes (longitudinal). Bootstrap enhanced Elastic-Net (BeEN) regression was validated and implemented to select variables associated with CBT response.ResultsIn cross-sectional data, DM1-Activ-c correlated significantly with the majority of other outcome measures, including Six Minute Walk Test and Myotonic Dystrophy Health Index. Fewer and weaker significant longitudinal correlations were observed. Nine variables potentially associated with CBT response were identified, including measures of disease severity, executive cognitive functioning and perceived social support.ConclusionsThe DM1-Activ-c questionnaire appears to be a well suited cross-sectional instrument to assess a variety of clinically relevant dimensions in DM1. Yet, apathy and experienced social support measures were less well captured. CBT response was heterogenous, requiring careful selection of outcome measures for different disease aspects.

Background: FSHD is caused by specific genetic mutations resulting in activation of the Double Homeobox 4 gene (DUX4). DUX4 targets hundreds of downstream genes eventually leading to muscle atrophy, oxidative stress, abnormal myogenesis, and muscle inflammation. We hypothesized that DUX4-induced aberrant expression of genes triggers a sustained autoimmune response against skeletal muscle cells. Objective: This study aimed at the identification of autoantibodies directed against muscle antigens in FSHD. Moreover, a possible relationship between serum antibody reactivity and DUX4 expression was also investigated. Methods: FSHD sera (N = 138, 48±16 years, 48% male) and healthy control sera (N = 20, 47±14 years, 50% male) were analyzed by immunoblotting for antibodies against several skeletal muscle protein extracts: healthy muscle, FSHD muscle, healthy and FSHD myotubes, and inducible DUX4 expressing myoblasts. In addition, DUX4 expressing myoblasts were analyzed by immunofluorescence with FSHD and healthy control sera. Results: The results showed that the reactivity of FSHD sera did not significantly differ from that of healthy controls, with all the tested muscle antigen extracts. Besides, the immunofluorescent staining of DUX4-expressing myoblasts was not different when incubated with either FSHD or healthy control sera. Conclusion: Since the methodology used did not lead to the identification of disease-specific autoantibodies in the FSHD cohort, we suggest that autoantibody-mediated pathology may not be an important disease mechanism in FSHD. Nevertheless, it is crucial to further unravel if and which role the immune system plays in FSHD pathogenesis. Other innate as well as adaptive immune players could be involved in the complex DUX4 cascade of events and could become appealing druggable targets.

Contains fulltext : 232919.pdf (Publisher’s version ) (Closed access) Nemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.

Contains fulltext : 229514.pdf (Publisher’s version ) (Open Access) BACKGROUND: Specific force, that is the amount of force generated per unit of muscle tissue, is reduced in patients with facioscapulohumeral muscular dystrophy (FSHD). The causes of reduced specific force and its relation with FSHD disease severity are unknown. METHODS: Quantitative muscle magnetic resonance imaging (MRI), measurement of voluntary maximum force generation and quadriceps force-frequency relationship, and vastus lateralis muscle biopsies were performed in 12 genetically confirmed patients with FSHD and 12 controls. RESULTS: Specific force was reduced by ~33% in all FSHD patients independent of disease severity. Quadriceps force-frequency relationship shifted to the right in severe FSHD compared to controls. Fiber type distribution in vastus lateralis muscle biopsies did not differ between groups. CONCLUSIONS: Reduced quadriceps specific force is present in all FSHD patients regardless of disease severity or fatty infiltration. Early myopathic changes, including fibrosis, and non-muscle factors, such as physical fatigue and musculoskeletal pain, may contribute to reduced specific force.

Contains fulltext : 235675.pdf (Publisher’s version ) (Open Access) Patient-relevant outcome measures for facioscapulohumeral muscular dystrophy (FSHD) are needed. The motor function measure (MFM) is an ordinal-based outcome measure for neuromuscular disorders, but its suitability to measure FSHD patients is questionable. Here, we performed Rasch analyses on MFM data from 194 FSHD patients to assess clinimetric properties in this patient group. Both the total scale and its three domains were analyzed (D1: standing position and transfers; D2: axial and proximal motor function; D3: distal motor function). Fit to the Rasch model, sample-item targeting, individual item fit, threshold ordering, sex- and age-based differential item functioning, response dependency and unidimensionality were assessed. Rasch analysis revealed multiple limitations of the MFM for FSHD, the most important being a large ceiling effect and suboptimal sample-item targeting, which were most pronounced for domains D2 and D3. There were disordered thresholds for most items, often resulting in items functioning in a dichotomous fashion. It was not possible to remodel the MFM into a Rasch-built interval scale. Remodeling of domain D1 into an interval scale with adequate fit statistics was achieved, but sample-item targeting remained suboptimal. Therefore, the MFM should be used with caution in FSHD patients, as it is not optimally suited to measure functional abilities in this patient group.