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Background and purpose: Late onset Pompe disease (LOPD) is a rare neuromuscular disorder caused by a deficit in acid alpha‐glucosidase. Macroglossia and swallowing disorders have already been reported, but no study has focused yet on its frequency and functional impact on patients' daily life. Methods: We reviewed 100 adult LOPD patients followed in 17 hospitals in France included in the French national Pompe disease registry. The Swallowing Quality of Life Questionnaire and the Sydney Swallow Questionnaire were completed by patients, and a specialist carried out a medical examination focused on swallowing and assigned a Salassa score to each patient. Respiratory and motor functions were also recorded. Subgroup analysis compared patients with and without swallowing difficulties based on Salassa score. Results: Thirty‐two percent of patients presented with swallowing difficulties, often mild but sometimes severe enough to require percutaneous endoscopic gastrostomy (1%). Daily dysphagia was reported for 20% of our patients and aspirations for 18%; 9.5% were unable to eat away from home. Macroglossia was described in 18% of our patients, and 11% had lingual atrophy. Only 15% of patients presenting with swallowing disorders were followed by a speech therapist. Swallowing difficulties were significantly associated with macroglossia (p = 0.015), longer duration of illness (p = 0.032), and a lower body mass index (p = 0.047). Conclusions: Swallowing difficulties in LOPD are common and have significant functional impact. Increased awareness by physicians of these symptoms with systematic examination of the tongue and questions about swallowing can lead to appropriate multidisciplinary care with a speech therapist and dietitian if needed. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common genetically inherited myopathies in adults. It is characterized by incomplete penetrance and variable expressivity. Typically, FSHD patients display asymmetric weakness of facial, scapular, and humeral muscles that may progress to other muscle groups, particularly the abdominal and lower limb muscles. Early-onset patients display more severe muscle weakness and atrophy, resulting in a higher frequency of associated skeletal abnormalities. In these patients, multisystem involvement, including respiratory, ocular, and auditory, is more frequent and severe and may include the central nervous system. Adult-onset FSHD patients may also display some degree of multisystem involvement which mainly remains subclinical. In 95% of cases, FSHD patients carry a pathogenic contraction of the D4Z4 repeat units (RUs) in the subtelomeric region of chromosome 4 (4q35), which leads to the expression of DUX4 retrogene, toxic for muscles (FSHD1). Five percent of patients display the same clinical phenotype in association with a mutation in the SMCHD1 gene located in chromosome 18, inducing epigenetic modifications of the 4q D4Z4 repeated region and expression of DUX4 retrogene. This review highlights the complexities and challenges of diagnosing and managing FSHD, underscoring the importance of standardized approaches for optimal patient outcomes. It emphasizes the critical role of multidisciplinary care in addressing the diverse manifestations of FSHD across different age groups, from skeletal abnormalities in early-onset cases to the often-subclinical multisystem involvement in adults. With no current cure, the focus on alleviating symptoms and slowing disease progression through coordinated care is paramount. [ABSTRACT FROM AUTHOR]

Introduction: Late‐onset Pompe disease (LOPD) is characterized by a progressive myopathy resulting from a deficiency of acid α‐glucosidase enzyme activity. Enzyme replacement therapy has been shown to be effective, but long‐term treatment results vary. Avalglucosidase alfa demonstrated non‐inferiority to alglucosidase alfa in a phase 3 study, allowing in France compassionate access for advanced LOPD patients unresponsive to alglucosidase alfa. Methods: Data from the French Pompe registry were analyzed for patients who benefited from a switch to avalglucosidase alfa with at least 1 year of follow‐up. Respiratory (forced vital capacity [FVC]) and motor functions (Six‐Minute Walk Test [6MWT]) were assessed before and 1 year after switching. Individual changes in FVC and 6MWT were expressed as slopes and statistical analyses were performed to compare values. Results: Twenty‐nine patients were included (mean age 56 years, 11 years of prior treatment). The FVC and 6MWT values remained stable. The individual analyses showed a stabilization of motor worsening: –1 m/year on the 6MWT after the switch versus –63 m/year the year before the switch (i.e., a worsening of 33%/year before vs. an improvement of 3%/year later). Respiratory data were not statistically different. Discussion: At the group level, gait parameters improved slightly with a stabilization of previous worsening, but respiratory parameters showed limited changes. At the individual level, results were discordant, with some patients with a good motor or respiratory response and some with further worsening. Conclusion: Switching to avalglucosidase alfa demonstrated varied responses in advanced LOPD patients with failing alglucosidase alfa therapy, with a general improvement in motor stabilization. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin amyloidosis (ATTRv) is an adult-onset autosomal dominant disease resulting from TTR gene pathogenic variants. ATTRv often presents as a progressive polyneuropathy, and effective ATTRv treatments are available. In this 5 year-long (2017–2021) nationwide prospective study, we systematically analysed the TTR gene in French patients with age >50 years with a progressive idiopathic polyneuropathy. 553 patients (70% males) with a mean age of 70 years were included. A TTR gene pathogenic variant was found in 15 patients (2.7%), including the Val30Met TTR variation in 10 cases. In comparison with patients with no TTR gene pathogenic variants (n = 538), patients with TTR pathogenic variants more often presented with orthostatic hypotension (53 vs. 21%, p =.007), significant weight loss (33 vs 11%, p =.024) and rapidly deteriorating nerve conduction studies (26 vs. 8%, p =.03). ATTRv diagnosis led to amyloid cardiomyopathy diagnosis in 11 cases, ATTRv specific treatment in all cases and identification of 15 additional ATTRv cases among relatives. In this nationwide prospective study, we found ATTRv in 2.7% of patients with age >50 years with a progressive polyneuropathy. These results are highly important for the early identification of patients in need of disease-modifying treatments. [ABSTRACT FROM AUTHOR]

To date, little is known about the usefulness of ultra-high frequency ultrasound (UHF-US, 50–70 MHz) in clinical practice for the diagnosis of dysimmune neuropathies. We present a prospective study aimed at comparing UHF-US alterations of nerves and fascicles in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), distal CIDP (d-CIDP) and anti-MAG neuropathy and their relationships with clinical and electrodiagnostic (EDX) features. 28 patients were included (twelve CIDP, 6 d-CIDP and 10 anti-MAG) and ten healthy controls. Each patient underwent neurological examination, EDX and UHF-US study of median and ulnar nerves bilaterally. UHF-US was reliable in differentiating immune neuropathies from controls when using mean and/or segmental nerve and/or fascicle cross-sectional area (CSA); furthermore, fascicle ratio (fascicle/nerve CSA) was a reliable factor for differentiating d-CIDP from other types of polyneuropathies. The fascicle CSA appears to be more increased in CIDP and its variant than in anti-MAG neuropathy. UHF-US offers information beyond simple nerve CSA and allows for a better characterization of the different forms of dysimmune neuropathies. [ABSTRACT FROM AUTHOR]

Background: In 2017, a new treatment by nusinersen, an antisense oligonucleotide delivered by repeated intrathecal injections, became available for patients with spinal muscular atrophy (SMA), whereas clinical trials had mainly involved children. Since 2020, the oral, selective SMN2-splicing modifier risdiplam has been available with restrictions evolving with time. In this peculiar context of lack of data regarding adult patients, many questions were raised to define the indications of treatment and the appropriate follow-up in this population. To homogenize access to treatment in France, a national multidisciplinary team meeting dedicated to adult SMA patients, named SMA multidisciplinary team meeting, (SMDTs) was created in 2018. Our objective was to analyze the value of SMDTs in the decision-making process in SMA adult patients and to provide guidelines about treatment. Methods: From October 2020 to September 2021, data extracted from the SMDT reports were collected. The primary outcome was the percentage of cases in which recommendations on validating treatment plans were given. The secondary outcomes were type of treatment requested, description of expectations regarding treatment and description of recommendations or follow-up and discontinuation. Data were analyzed using descriptive statistics. Comparisons between the type of treatment requested were performed using Mann–Whitney test or the Student t test for quantitative data and the Fisher's exact test or the χ2 test for qualitative data. Results: Cases of 107 patients were discussed at the SMDTs with a mean age of 35.3 (16–62). Forty-seven were SMA type 2, and 57 SMA type 3. Twelve cases were presented twice. Out of 122 presentations to the SMDTs, most of requests related to the initiation of a treatment (nusinersen (n = 46), risdiplam (n = 54), treatment without mentioning preferred choice (n = 5)) or a switch of treatment (n = 12). Risdiplam requests concerned significantly older patients (p = 0.002), mostly SMA type 2 (p < 0.0001), with greater disease severity in terms of motor and respiratory function compared to requests for nusinersen. In the year prior to presentation to the SMDTs, most of the patients experienced worsening of motor weakness assessed by functional tests as MFM32 or other meaningful scales for the most severe patients. Only 12% of the patients discussed had a stable condition. Only 49/122 patients (40.1%) expressed clear expectations regarding treatment. The treatment requested was approved by the SMDTs in 72 patients (67.2%). The most common reasons to decline treatment were lack of objective data on the disease course prior discussion to the SMDTs or inappropriate patient's expectations. Treatment requests were more likely to be validated by the SMDTs if sufficient pre-therapeutic functional assessment had been performed to assess the natural history (55% vs. 32%) and if the patient had worsening rather than stable motor function (p = 0.029). In patients with approved treatment, a-priori criteria to define a further ineffectiveness of treatment (usually after 14 months of treatment) were proposed for 67/72 patients. Conclusions: In the context of costly treatments with few controlled studies in adults with SMA, in whom assessment of efficacy can be complex, SMDTs are 'real-world observatories' of great interest to establish national recommendations about indications of treatment and follow-up. [ABSTRACT FROM AUTHOR]

Background and Aims: ADVANCE‐CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. Methods: ADVANCE‐CIDP 1 was a phase 3, double‐blind, placebo‐controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0–7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre‐randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1‐point increase in adjusted INCAT score from pre‐subcutaneous treatment baseline) in the modified intention‐to‐treat population. Secondary outcomes included time to relapse and safety endpoints. Results: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: −21.8% [−34.5%, −7.9%], p =.0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p =.002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. Interpretation: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment. [ABSTRACT FROM AUTHOR]

Background: The European registry for individuals with GSD5 and other muscle glycogenosis (EUROMAC) was launched to register rare muscle glycogenosis in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases. A network of twenty collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. Methods: Following the initial report on demographics, neuromuscular features and comorbidity (2020), we here present the data on social participation, previous and current treatments (medication, supplements, diet and rehabilitation) and limitations. Furthermore, the following questionnaires were used: Fatigue severity scale (FSS), WHO Disability Assessment Scale (DAS 2.0), health related quality of life (SF36) and International Physical Activity Questionnaire (IPAQ). Results: Of 282 participants with confirmed diagnoses of muscle glycogenosis, 269 had GSD5. Of them 196 (73%) completed all questionnaires; for the others, the data were incomplete. The majority, 180 (67%) were currently working. Previous medical treatments included pain medication (23%) and rehabilitation treatment (60%). The carbohydrate-rich diet was reported to be beneficial for 68%, the low sucrose diet for 76% and the ketogenic diet for 88%. Almost all participants (93%) reported difficulties climbing stairs. The median FSS score was 5.22, indicating severe fatigue. The data from the WHODAS and IPAQ was not of sufficient quality to be interpreted. Conclusions: The EUROMAC registry have provided insight into the functional and social status of participants with GSD5: most participants are socially active despite limitations in physical and daily life activities. Regular physical activity and different dietary approaches may alleviate fatigue and pain. [ABSTRACT FROM AUTHOR]

Telomeric repeat binding factor 2 (TRF2) binds to telomeres and protects chromosome ends against the DNA damage response and senescence. Although the expression of TRF2 is downregulated upon cellular senescence and in various aging tissues, including skeletal muscle tissues, very little is known about the contribution of this decline to aging. We previously showed that TRF2 loss in myofibers does not trigger telomere deprotection but mitochondrial dysfunction leading to an increased level of reactive oxygen species. We show here that this oxidative stress triggers the binding of FOXO3a to telomeres where it protects against ATM activation, revealing a previously unrecognized telomere protective function of FOXO3a, to the best of our knowledge. We further showed in transformed fibroblasts and myotubes that the telomere properties of FOXO3a are dependent on the C-terminal segment of its CR2 domain (CR2C) but independent of its Forkhead DNA binding domain and of its CR3 transactivation domain. We propose that these non-canonical properties of FOXO3a at telomeres play a role downstream of the mitochondrial signaling induced by TRF2 downregulation to regulate skeletal muscle homeostasis and aging. Loss of the telomeric repeat binding factor 2 (TRF2) and its resulting oxidative stress leads to FOXO3a binding to telomeres, which protects against activation of ATM to maintain skeletal muscle homeostasis. [ABSTRACT FROM AUTHOR]

Background and purpose: Although myasthenia gravis (MG) is recognized as an immunoglobulin G autoantibody‐mediated disease, the relationship between autoantibody levels and disease activity in MG is unclear. We sought to evaluate this landscape through systematically assessing the evidence, testing the impact of predefined variables on any relationship, and augmenting with expert opinion. Methods: In October 2020, a forum of leading clinicians and researchers in neurology from across Europe (Expert Forum for Rare Autoantibodies in Neurology in Myasthenia Gravis) participated in a series of virtual meetings that took place alongside the conduct of a systematic literature review (SLR). Results: Forty‐two studies were identified meeting inclusion criteria. Of these, 10 reported some correlation between a patient's autoantibody level and disease severity. Generally, decreased autoantibody levels (acetylcholine receptor, muscle‐specific kinase, and titin) were positively and significantly correlated with improvements in disease severity (Quantitative Myasthenia Gravis score, Myasthenia Gravis Composite score, Myasthenia Gravis Activities of Daily Living score, Myasthenia Gravis Foundation of America classification). Given the limited evidence, testing the impact of predefined variables was not feasible. Conclusions: This first SLR to assess whether a correlation exists between autoantibody levels and disease activity in patients with MG has indicated a potential positive correlation, which could have clinical implications in guiding treatment decisions. However, in light of the limited and variable evidence, we cannot currently recommend routine clinical use of autoantibody level testing in this context. For now, patient's characteristics, clinical disease course, and laboratory data (e.g., autoantibody status, thymus histology) should inform management, alongside patient‐reported outcomes. We highlight the need for future studies to reach more definitive conclusions on this relationship. [ABSTRACT FROM AUTHOR]

Introduction: Lambert–Eaton myasthenic syndrome (LEMS) is characterized by autoantibodies against voltage-gated calcium channels (VGCC) at the neuromuscular junction causing proximal muscle weakness, decreased tendon reflexes, and autonomic changes. The European LEMS registry aimed to collate observational safety data for 3,4-diaminopyridine phosphate (3,4-DAPP) and examine long-term outcomes for patients with LEMS. Methods: Thirty centers across four countries participated in the non-interventional European LEMS registry. Any patients diagnosed with LEMS by means of clinical assessment and abnormal neurophysiological testing, or clinical assessment and positive for VGCC antibodies were eligible to participate. Patients were monitored using standard assessments for LEMS-related clinical manifestations. Results: Among 96 evaluable participants, 50 (52.1%) were being treated with 3,4-DAPP, 21 (21.9%) with 3,4-diaminopyridine (3,4-DAP), and 25 (26.0%) with other treatments (e.g., pyridostigmine, corticosteroids, immunoglobulins, and azathioprine); 74 participants (77.1%) were exposed to 3,4-DAPP at any time. Quantitative myasthenia gravis scores were similar across treatment groups. Muscle strength was generally good and maintained during follow-up. Cerebellar ataxia, defined as a negative Romberg's test and at least one other positive ataxia test, was observed in 30 (56.6%) patients. Most participants had reduced reflex tone and limited functioning. Sustained or improved functioning was observed in participants administered 3,4-DAPP. Inconsistent and sporadic functional improvement and regression was observed with 3,4-DAP and other treatments. Fifty-five treatment-related adverse events (AEs) were reported by 32 (33.3%) participants. Eight (8.3%) participants reported nine treatment-related serious AEs. No new safety signals were identified. Conclusion: No new safety signals were observed following long-term management of LEMS with 3,4-DAPP. [ABSTRACT FROM AUTHOR]

Background and purpose: Andersen–Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by KCNJ2 mutations, characterized by a clinical triad of periodic paralysis, cardiac arrhythmias and dysmorphism. The muscle phenotype, particularly the atypical forms with prominent permanent weakness or predominantly painful symptoms, remains incompletely characterized. Methods: A retrospective clinical, histological, electroneuromyography (ENMG) and genetic analysis of molecularly confirmed ATS patients, diagnosed and followed up at neuromuscular reference centers in France, was conducted. Results: Thirty‐five patients from 27 unrelated families carrying 17 different missense KCNJ2 mutations (four novel mutations) and a heterozygous KCNJ2 duplication are reported. The typical triad was observed in 42.9% of patients. Cardiac abnormalities were observed in 65.7%: 56.5% asymptomatic and 39.1% requiring antiarrhythmic drugs. 71.4% of patients exhibited dysmorphic features. Muscle symptoms were reported in 85.7%, amongst whom 13.3% had no cardiopathy and 33.3% no dysmorphic features. Periodic paralysis was present in 80% and was significantly more frequent in men. Common triggers were exercise, immobility and carbohydrate‐rich diet. Ictal serum potassium concentrations were low in 53.6%. Of the 35 patients, 45.7% had permanent weakness affecting proximal muscles, which was mild and stable or slowly progressive over several decades. Four patients presented with exercise‐induced pain and myalgia attacks. Diagnostic delay was 14.4 ± 9.5 years. ENMG long‐exercise test performed in 25 patients (71.4%) showed in all a decremental response up to 40%. Muscle biopsy performed in 12 patients revealed tubular aggregates in six patients (associated in two of them with vacuolar lesions), dystrophic features in one patient and non‐specific myopathic features in one patient; it was normal in four patients. Discussion: Recognition of atypical features (exercise‐induced pain or myalgia and permanent weakness) along with any of the elements of the triad should arouse suspicion. The ENMG long‐exercise test has a high diagnostic yield and should be performed. Early diagnosis is of utmost importance to improve disease prognosis. [ABSTRACT FROM AUTHOR]

Particularly in highly active disease courses, we urgently need blood-based biomarkers for therapy guidance, which could include autoantibody levels, taking into account individual therapy. For example, treatment of AChR autoantibody-positive generalized MG with neonatal Fc receptor inhibitors reveals a strong correlation between clinical severity and AChR autoantibodies, as well as total immunoglobulin G (IgG) levels. Keywords: activity; autoantibody level; biomarker; myasthenia gravis EN activity autoantibody level biomarker myasthenia gravis 1162 1164 3 03/08/23 20230401 NES 230401 Dear Editor, We appreciate the comments from Li et al. [[1]] on aspects of our article entitled "Role of Autoantibody Levels as Biomarkers in the Management of Patients With Myasthenia Gravis: A Systematic Review and Expert Appraisal.". [Extracted from the article]

Background: Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies and currently has no treatment. Clinical and genetic heterogeneity are the main challenges to a full comprehension of the physiopathological mechanism. Improving our knowledge of FSHD is crucial to the development of future therapeutic trials and standards of care. National FSHD registries have been set up to this end. The French National Registry of FSHD combines a clinical evaluation form (CEF) and a self-report questionnaire (SRQ), filled out by a physician with expertise in neuromuscular dystrophies and by the patient, respectively. Aside from favoring recruitment, our strategy was devised to improve data quality. Indeed, the pairwise comparison of data from 281 patients for 39 items allowed for evaluating data accuracy. Kappa or intra-class coefficient (ICC) values were calculated to determine the correlation between answers provided in both the CEF and SRQ.Results: Patients and physicians agreed on a majority of questions common to the SRQ and CEF (24 out of 39). Demographic, diagnosis- and care-related questions were generally answered consistently by the patient and the medical practitioner (kappa or ICC values of most items in these groups were greater than 0.8). Muscle function-related items, i.e. FSHD-specific signs, showed an overall medium to poor correlation between data provided in the two forms; the distribution of agreements in this section was markedly spread out and ranged from poor to good. In particular, there was very little agreement regarding the assessment of facial motricity and the presence of a winged scapula. However, patients and physicians agreed very well on the Vignos and Brooke scores. The report of symptoms not specific to FSHD showed general poor consistency.Conclusions: Patient and physician answers are largely concordant when addressing quantitative and objective items. Consequently, we updated collection forms by relying more on patient-reported data where appropriate. We hope the revised forms will reduce data collection time while ensuring the same quality standard. With the advent of artificial intelligence and automated decision-making, high-quality and reliable data are critical to develop top-performing algorithms to improve diagnosis, care, and evaluate the efficiency of upcoming treatments. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) is the second most common genetic myopathy, characterized by slowly progressing and highly heterogeneous muscle wasting with a typical onset in the late teens/early adulthood [1]. Although the etiology of the disease for both FSHD type 1 and type 2 has been attributed to gain-of-toxic function stemming from aberrant DUX4 expression, the exact pathogenic mechanisms involved in muscle wasting have yet to be elucidated [2–4]. The 2021 FSHD International Research Congress, held virtually on June 24–25, convened over 350 researchers and clinicians to share the most recent advances in the understanding of the disease mechanism, discuss the proliferation of interventional strategies and refinement of clinical outcome measures, including results from the ReDUX4 trial, a phase 2b clinical trial of losmapimod in FSHD [NCT04003974]. [ABSTRACT FROM AUTHOR]

The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy. [ABSTRACT FROM AUTHOR]

Background and purpose: Preparations for clinical trials of unfolded protein response (UPR) inhibitors (such as Sephin1) that target the upregulated UPR in patients with Charcot–Marie–Tooth disease (CMT) carrying MPZ mutations are currently underway. The inclusion criteria for these trials are still being formulated. Our objective was to characterize the relation between genotypes and phenotypes in patients with CMT caused by MPZ mutations, and to refine the inclusion criteria for future trials. Methods: Clinical and neurophysiological data of CMT patients with MPZ mutations were retrospectively collected at 11 French reference centers. Results: Forty‐four mutations in MPZ were identified in 91 patients from 61 families. There was considerable heterogeneity. The same mutation was found to cause either axonal or demyelinating neuropathy. Three groups were identified according to the age at disease onset. CMT Examination Score (CMTES) tended to be higher in the early (≤22 years) and adult (23–47 years) onset groups (mean CMTESv2 = 10.4 and 10.0, respectively) than in the late onset group (>47 years, mean CMTESv2 = 8.6, p = 0.47). There was a significant positive correlation between CMTESv2 and the age of patients in Groups I (p = 0.027) and II (p = 0.023), indicating that clinical severity progressed with age in these patients. Conclusions: To optimize the selection of CMT patients carrying MPZ mutations for the upcoming trials, inclusion criteria should take into account the pathophysiology of the disease (upregulated UPR). Recruited patients should have a mild to moderate disease severity and a disease onset at between 18 and 50 years, as these patients exhibit significant disease progression over time. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Mutations in the GNE gene have been so far described as predominantly associated with distal lower‐limb myopathies. Recent reports describe mutations in this gene in patients with peripheral neuropathy and motor neuron disease. Methods: We describe three patients displaying motor neuropathy in association with GNE mutations. Clinical, electrophysiological, imaging, pathological, and genetic data are presented in a retrospective manner. Results: The three patients had different phenotypes, ranging from mildly progressive lower limb weakness to a rapidly progressive 4‐limb weakness. Genetic testing revealed GNE gene mutations in all patients; of those mutations, p.(His186Arg) has not been previously reported. All patients showed evidence of axonal motor nerve involvement on electrodiagnostic examination and/or muscle biopsy. Conclusions: Nerve involvement associated with GNE gene mutations may be an underdiagnosed pathology and may influence clinical presentation and disease progression. [ABSTRACT FROM AUTHOR]

Introduction: Nerve ultrasound has been used increasingly in clinical practice as a complementary test for diagnostic assessment of neuropathies, but nerve biopsy remains invaluable in certain cases. The aim of this study was to compare ultra-high-frequency ultrasound (UHF-US) to histologic findings in progressive polyneuropathies.Methods: Ten patients with severe, progressive neuropathies underwent ultrasound evaluation of the sural nerve before nerve biopsy. Ultrasound data were compared with histologic results in a retrospective manner.Results: Sural nerves were easily identified on UHF-US. Nerve hyperechogenicity correlated with inflammatory infiltrates on biopsy. Nerve fascicles could be identified and measured on ultrasound in the majority of patients.Discussion: Hyperechogenicity on UHF-US may be a marker of nerve inflammation in neuropathies. Furthermore, the UHF-US probe allows for evaluation of sensory nerves in spite of their small size, providing valuable information on their size and on their internal structure. [ABSTRACT FROM AUTHOR]

Metabolic myopathies comprise a clinically etiological diverse group of disorders caused by defects in cellular energy metabolism including the breakdown of carbohydrates and fatty acids, which include glycogen storage diseases and fatty acid oxidation disorders. Their wide clinical spectrum ranges from infantile severe multisystemic disorders to adult-onset myopathies. To suspect in adults these disorders, clinical features such as exercise intolerance and recurrent myoglobinuria need investigation while another group presents fixed weakness and cardiomyopathy as a clinical pattern. In metabolic myopathies, clinical manifestations are important to guide diagnostic tests used in order to lead to the correct diagnosis. The authors searched in literature the most recent techniques developed. The authors present an overview of the most common phenotypes of Pompe disease and what is currently known about the mechanism of ERT treatment. The most common disorders of lipid metabolism are overviewed, with their possible dietary or supplementary treatments. The clinical suspicion is the clue to conduct in-depth investigations in suspected cases of metabolic myopathies that lead to the final diagnosis with biochemical molecular studies and often nowadays by the use of Next Generation Sequencing (NGS) to determine gene mutations. [ABSTRACT FROM AUTHOR]

Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies were less than 5 years of duration. We report here the findings from 158 treated patients included in the French Pompe Registry, who underwent regular clinical assessments based on commonly used standardized tests (6‐minute walking test, MFM scale, sitting vital capacity, MIP and MEP). For longitudinal analyses, the linear mixed effects models were used to assess trends in primary endpoints over time under ERT. A two‐phase model better described the changes in distance traveled in the 6‐minute walk test and MFM. 6MWT showed an initial significant increase (1.4% ± 0.5/year) followed by a progressive decline (−2.3%/year), with a cut‐off point at 2.2 years. A similar pattern was observed in total MFM score (6.6% ± 2.3/year followed by a − 1.1%/year decline after 0.5 years). A single‐phase decline with a slope of −0.9 ± 0.1%/year (P <.001) was observed for FVC, and MEP remained stable over the all duration of follow‐up. This study provides further evidence that ERT improves walking abilities and likely stabilizes respiratory function in adult patients with Pompe disease, with a ceiling effect for the 6MWT in the first 3 years of treatment. [ABSTRACT FROM AUTHOR]

Background: International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders.Results: Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients.Conclusion: EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level. [ABSTRACT FROM AUTHOR]

Whole mitochondrial DNA (mtDNA) sequencing is now systematically used in clinical laboratories to screen patients with a phenotype suggestive of mitochondrial disease. Next Generation Sequencing (NGS) has significantly increased the number of identified pathogenic mtDNA variants. Simultaneously, the number of variants of unknown significance (VUS) has increased even more, thus challenging their interpretation. Correct classification of the variants' pathogenicity is essential for optimal patient management, including treatment and genetic counseling. Here, we used single muscle fiber studies to characterize eight heteroplasmic mtDNA variants, among which were three novel variants. By applying the pathogenicity scoring system, we classified four variants as "definitely pathogenic" (m.590A>G, m.9166T>C, m.12293G>A, and m.15958A>T). Two variants remain "possibly pathogenic" (m.4327T>C and m.5672T>C) but should these be reported in a different family, they would be reclassified as "definitely pathogenic." We also illustrate the contribution of single‐fiber studies to the diagnostic approach in patients harboring pathogenic variants with low level heteroplasmy. [ABSTRACT FROM AUTHOR]

Telomere shortening follows a developmentally regulated process that leads to replicative senescence of dividing cells. However, whether telomere changes are involved in postmitotic cell function and aging remains elusive. In this study, we discovered that the level of the TRF2 protein, a key telomere‐capping protein, declines in human skeletal muscle over lifetime. In cultured human myotubes, TRF2 downregulation did not trigger telomere dysfunction, but suppressed expression of the mitochondrial Sirtuin 3 gene (SIRT3) leading to mitochondrial respiration dysfunction and increased levels of reactive oxygen species. Importantly, restoring the Sirt3 level in TRF2‐compromised myotubes fully rescued mitochondrial functions. Finally, targeted ablation of the Terf2 gene in mouse skeletal muscle leads to mitochondrial dysfunction and sirt3 downregulation similarly to those of TRF2‐compromised human myotubes. Altogether, these results reveal a TRF2‐SIRT3 axis controlling muscle mitochondrial function. We propose that this axis connects developmentally regulated telomere changes to muscle redox metabolism. [ABSTRACT FROM AUTHOR]

Background Facioscapulohumeral dystrophy (FSHD) is associated with partial chromatin relaxation of the DUX4 retrogene containing D4Z4 macrosatellite repeats on chromosome 4, and transcriptional derepression of DUX4 in skeletal muscle. The common form of FSHD, FSHD1, is caused by a D4Z4 repeat array contraction. The less common form, FSHD2, is generally caused by heterozygous variants in SMCHD1. Methods We employed whole exome sequencing combined with sanger sequencing to screen uncharacterised FSHD2 patients for extra-exonic SMCHD1 mutations. We also used CRISPR-CAS9 genome editing to repair a pathogenic intronic SMCHD1 variant from patient myoblasts. results We identified intronic SMCHD1 variants in two FSHD families. in the first family, an intronic variant resulted in partial intron retention and inclusion of the distal 14 nucleotides of intron 13 into the transcript. in the second family, a deep intronic variant in intron 34 resulted in exonisation of 53 nucleotides of intron 34. in both families, the aberrant transcripts are predicted to be non-functional. Deleting the pseudo-exon by CRISPR-cas9 mediated genome editing in primary and immortalised myoblasts from the index case of the second family restored wild-type SMCHD1 expression to a level that resulted in efficient suppression of DUX4. Conclusions The estimated intronic mutation frequency of almost 2% in FSHD2, as exemplified by the two novel intronic SMCHD1 variants identified here, emphasises the importance of screening for intronic variants in SMCHD1. Furthermore, the efficient suppression of DUX4 after restoring SMCHD1 levels by genome editing of the mutant allele provides further guidance for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background Variants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 (SMCHD1) can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) and the unrelated Bosma arhinia microphthalmia syndrome (BAMS). In FSHD2, pathogenic variants are found anywhere in SMCHD1 while in BAMS, pathogenic variants are restricted to the extended AT Pase domain. Irrespective of the phenotypic outcome, both FSHD2-associated and BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation. We compared FSHD2, BAMS and non-pathogenic SMCHD1 variants to derive genotype-phenotype relationships. Methods Examination of SMCHD1 variants and methylation of the SMCHD1-sensitive FSHD locus DUX4 in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a threedimensional model of the AT Pase domain of SMCHD1. Results DUX4 methylation analysis is essential to establish pathogenicity of SMCHD1 variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire SMCHD1 locus, missense variants are significantly enriched in the extended AT Pase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1. Conclusions The localisation of missense variants within the AT Pase domain of SMCHD1 may contribute to the differences in phenotypic outcome. [ABSTRACT FROM AUTHOR]

Background Subtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of ß-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis-duplication of the distal 4q35 locus identified by molecular combing. Methods Using this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients. Results Our analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before. Conclusion Overall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease. [ABSTRACT FROM AUTHOR]

In the search of a better enzyme therapy in Pompe disease, the conjugation of mannose 6‐phosphonates to the recombinant enzyme appeared as an enhancer of its efficacy. Here, we demonstrated that the increased efficacy of the conjugated enzyme is partly due to a higher intracellular maturation because of its insensitiveness to acid phosphatases during the routing to lysosomes. [ABSTRACT FROM AUTHOR]

Objective: Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B.Methods: We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score.Results: There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations.Interpretation: This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019. [ABSTRACT FROM AUTHOR]

Objective: Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied.Methods: Altogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated.Results: Three families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF.Conclusions: Our collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history. [ABSTRACT FROM AUTHOR]

Abstract: Pompe disease (PD) is caused by a deficiency of lysosomal acid α‐glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype‐phenotype correlations in French late‐onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty‐six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty‐three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in‐frame deletions, and one large deletion. The common c.‐32‐13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.‐32‐13T>G mutation had an older mean age at onset than patients non‐exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late‐onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late‐onset PD patients through a nationwide study covering more than 40 years. [ABSTRACT FROM AUTHOR]

Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years. [ABSTRACT FROM AUTHOR]

Objectives: To describe the combination of spinocerebellar ataxia (SCA) types 3 and 6 and sporadic inclusion body myositis (IBM).Methods: A 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.Results: The 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.Conclusion: We 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. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) has been shown to be related to genetic and epigenetic derepression of DUX4 (mapping to chromosome 4), a gene located within a repeat array of D4Z4 sequences of polymorphic length. FSHD type 1 (FSHD1) is associated with pathogenic D4Z4 repeat array contraction, while FSHD type 2 (FSHD2) is associated with SMCHD1 variants (a chromatin modifier gene that maps to the short arm of chromosome 18). Both FSHD types require permissive polyadenylation signal (4qA) downstream of the D4Z4 array. [ABSTRACT FROM AUTHOR]

Background 18p deletion syndrome is a rare disorder caused by partial or full monosomy of the short arm of chromosome 18. Clinical symptoms caused by 18p hemizygosity include cognitive impairment, mild facial dysmorphism, strabismus and ptosis. Among other genes, structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is hemizygous in most patients with 18p deletions. Digenic inheritance of a SMCHD1 mutation and a moderately sized D4Z4 repeat on a facioscapulohumeral muscular dystrophy (FSHD) permissive genetic background of chromosome 4 can cause FSHD type 2 (FSHD2). Objectives Since 12% of Caucasian individuals harbour moderately sized D4Z4 repeats on an FSHD permissive background, we tested if people with 18p deletions are at risk of developing FSHD. Methods T o test our hypothesis we studied different cellular systems originating from individuals with 18p deletions not presenting FSHD2 phenotype for transcriptional and epigenetic characteristics of FSHD at D4Z4. Furthermore, individuals with an idiopathic muscle phenotype and an 18p deletion were subjected to neurological examination. Results Primary fibroblasts hemizygous for SMCHD1 have a D4Z4 chromatin structure comparable with FSHD2 concomitant with DUX4 expression after transdifferentiation into myocytes. Neurological examination of 18p deletion individuals from two independent families with a moderately sized D4Z4 repeat identified muscle features compatible with FSHD. Conclusions 18p deletions leading to haploinsufficiency of SMCHD1, together with a moderately sized FSHD permissive D4Z4 allele, can associate with symptoms and molecular features of FSHD. We propose that patients with 18p deletion should be characterised for their D4Z4 repeat size and haplotype and monitored for clinical features of FSHD. [ABSTRACT FROM AUTHOR]

Introduction: Slowly progressive, genetic neuromuscular diseases (gNMDs) often lead to important motor deficiencies and functional limitations. The Quality of Life in Genetic Neuromuscular Disease Questionnaire (QoL-gNMD) is a new health-related quality-of-life questionnaire developed for these patients. The purpose of the present study was to validate the French version of the QoL-gNMD and to calibrate its measurement system.Methods: Both the QoL-gNMD and a validated generic questionnaire (WHOQOL-BREF) were administered to patients. Validation was performed using item response theory. The partial credit model (Rasch) was used to calibrate each domain.Results: Three hundred fifteen adult patients were included. All 3 domains showed adequate psychometric properties (internal consistency: person separation index >0.77; repeatability: test-retest intraclass correlation coefficient >0.75, scalability coefficient >0.38) and fitted the partial credit model. The QoL-gNMD also demonstrated adequate concurrent validity with the WHOQOL-BREF.Discussion: The QoL-gNMD showed adequate psychometric properties and can be used in clinical settings. Although not anchor-based, the minimum detectable change tables help in interpreting score change. Muscle Nerve 56: 1085-1091, 2017. [ABSTRACT FROM AUTHOR]

Introduction: Late-onset Pompe disease (LOPD) is a rare disorder characterized by progressive proximal muscle weakness and early respiratory insufficiency, for which enzyme replacement therapy (ERT) is available.Methods: Having diagnosed a case of LOPD presenting with bent spine syndrome, we conducted a brief survey in the French centers involved in management of Pompe disease, from which we collected data on 3 other cases.Results: The patients (3 women and 1 man) had a mean age of 64 years (range 51-77 years) and a delay in diagnosis of approximately 10 years (range 8-42 years). At diagnosis, 3 patients already had respiratory symptoms. All had normal or very mildly raised creatine kinase levels and magnetic resonance imaging abnormalities in the paraspinal muscles. They exhibited the most frequent mutation in Pompe disease (c.-32-13 T>G).Conclusion: Clinicians should be aware of this atypical presentation of LOPD to enable earlier diagnosis and treatment. Muscle Nerve 56: 167-170, 2017. [ABSTRACT FROM AUTHOR]

Introduction: Acyl-coenzyme A dehydrogenase 9 (ACAD9) has a role in mitochondrial complex I (CI) assembly. Only a few patients who carry ACAD9 mutations have been reported. They mainly present with severe hypertrophic cardiomyopathy, although a minority have only mild isolated myopathy. Although the secondary factors influencing disease severity have not been elucidated, conservation of CI assembly and residual enzymatic activity have been suggested as explanations for the mild phenotypes associated with ACAD9 mutations.Methods: We report a novel homozygous ACAD9 mutation (c.1240C>T; p.Arg414Cys) in a 34-year-old woman who presented with non-progressive myopathy.Results: We show that this ACAD9 mutation led to a severe defect in CI assembly in the patient's muscle. Furthermore, the impact of CI deficiency is confirmed by accumulation of mitochondrial DNA deletions.Conclusion: Our data suggest that a major defect of CI assembly is not responsible for a severe phenotype. Muscle Nerve 55: 919-922, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT Next-generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini-exome coupled to read-depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini-exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes ( ATM, NPC1) and mutations in genes very rarely associated with ataxia ( ERCC4, HSD17B4). We show that mini-exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data. [ABSTRACT FROM AUTHOR]