Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines.

The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South-Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed-field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre-implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial-readiness for FSHD.

Recurrent de-novo gain-of-function mutation in SPTLC2 confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific gain-of-function mutations in SPTLC1 were identified in patients with juvenile form of ALS. SPTLC2 encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex. METHODS: We used the GENESIS platform to screen 700 ALS whole-genome and whole-exome data sets for variants in SPTLC2. The de-novo status was confirmed by Sanger sequencing. Sphingolipidomics was performed using liquid chromatography and high-resolution mass spectrometry. RESULTS: Two unrelated patients presented with early-onset progressive proximal and distal muscle weakness, oral fasciculations, and pyramidal signs. Both patients carried the novel de-novo SPTLC2 mutation, c.203T>G, p.Met68Arg. This variant lies within a single short transmembrane domain of SPTLC2, suggesting that the mutation renders the SPT complex irresponsive to regulation through ORMDL3. Confirming this hypothesis, ceramide and complex sphingolipid levels were significantly increased in patient plasma. Accordingly, excessive sphingolipid production was shown in mutant-expressing human embryonic kindney (HEK) cells. CONCLUSIONS: Specific gain-of-function mutations in both core subunits affect the homoeostatic control of SPT. SPTLC2 represents a new Mendelian ALS gene, highlighting a key role of dysregulated sphingolipid synthesis in the pathogenesis of juvenile ALS. Given the direct interaction of SPTLC1 and SPTLC2, this knowledge might open new therapeutic avenues for motor neuron diseases.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database.

The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with ~70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well-established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome-wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease-associated candidates, points to a significant enrichment for cell cycle- and division-related genes. Within this network, literature text-mining highlights DECR1, ATL1, HDAC2, GEMIN4, and HNRNPA3 as important genes. Finally, information on ALS-related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser (www.gendal.org).

Clinical exome sequencing in neuromuscular diseases: an experience from Turkey.

Neuromuscular diseases (NMDs) encompass a variety of ailments from muscular dystrophies to ataxias, in the course of which the functioning of the muscles is eventually either directly or indirectly impaired. The clinical diagnosis of a particular NMD is not always straightforward due to the clinical and genetic heterogeneity of the disorders under investigation. Traditional diagnostic tools such as electrophysiological tests and muscle biopsies are both invasive and painful methods, causing the patients to be reluctant. Next-generation sequencing, on the other hand, emerged as an alternative method for the diagnosis of NMDs, both with its minimally invasive nature and fast processing period. In this study, clinical exome sequencing (CES) was applied to a cohort of 70 probands in Turkey, 44 of whom received a final diagnosis, representing a diagnostic rate of 62.9%. Out of the 50 mutations identified to be causal, 26 were novel in the known 27 NMD genes. Two probands had complex/blended phenotypes. Molecular confirmation of clinical diagnosis of NMDs has a major prognostic impact and is crucial for the management and the possibility of alternative reproductive options. CES, which has been increasingly adopted to diagnose single-gene disorders, is also a powerful tool for revealing the etiopathogenesis in complex/blended phenotypes, as observed in two probands of the cohort.

A multidisciplinary clinical approach to facioscapulohumeral muscular dystrophy.

BACKGROUND AND PURPOSE: Impaired shoulder function is the most disabling problem for daily life of Fascioscapulohumeral muscular dystrophy (FSHD) patients. Scapulothoracic arthrodesis can give a high impact to the functionality of patients. Here we report our experience with scapulothoracic arthrodesis and spinal stenosis surgery in FSHD patients. METHODS: 32 FSHD patients were collected between 2015-2016. Demographical and clinical features were documented. All the patients were neurologically examined. The Medical Research Council (MRC) and the FSHD evaluation scale was used to assess muscle involvement1. Scapulothoracic arthrodesis and spinal stenosis surgeries were performed in eligible patients. RESULTS: There were 16 male and 16 female (mean age 34.4 years; range 12-73) patients. 6 shoulders of 4 patients aged between 2132 years underwent scapulothoracic arthrodesis (two bilateral, one left and one right sided). Only one 63 years old female patient with severe hyperlordosis had spinal fusion surgery. All of the patients undergoing these corrective surgeries have better functionality in daily life, as well as superior shoulder elevation. CONCLUSION: Until the emergence and clinical use of novel therapeutics, surgical interventions are indicated in carefully selected patients with FSHD to improve arm movements, the posture and the quality of life of patients in general. Scapulothorosic arthrodesis is a management with good clinical results and patient satisfaction. In selected cases other corrective orthopedic surgeries like spinal fusion may also be considered.

Genetic heterogeneity within the HLA region in three distinct clinical subgroups of myasthenia gravis.

This study aims to investigate genetic susceptibility to early-onset and late-onset anti-acetylcholine receptor antibody positive myasthenia gravis (EOMG and LOMG) and anti-muscle specific kinase antibody positive MG (MuSK-MG) at genome-wide level in a single population. Using a custom-designed array and imputing additional variants and the classical HLA alleles in 398 patients, we detected distinct associations. In EOMG, rs113519545 in the HLA class I region (OR=5.71 [3.77-8.66], P=2.24×10(-16)), HLA-B*08:01 (OR=7.04 [3.95-12.52], P=3.34×10(-11)) and HLA-C*07:01 (OR=2.74 [1.97-3.81], P=2.07(-9)), in LOMG, rs111256513 in the HLA class II region (OR=2.22 [1.59-3.09], P=2.48×10(-6)) and in MuSK-MG, an intronic variant within HLA-DQB1 (rs68081734, OR=5.86, P=2.25×10(-14)) and HLA-DQB1*05:02 (OR=8.56, P=6.88×10(-13)) revealed the most significant associations for genome-wide significance. Differential genetic susceptibility within the HLA to EOMG, LOMG and MuSK-MG has been established in a population from Turkey.

Inspiratory Muscle Training in Late-Onset Pompe Disease: The Effects on Pulmonary Function Tests, Quality of Life, and Sleep Quality.

INTRODUCTION: Late-onset Pompe disease (LOPD) is characterized by progressive skeletal and respiratory muscle weakness. Little is known about the effect of inspiratory muscle training (IMT) on pulmonary function in subjects with LOPD. The aim of the present study was to investigate the effect of an 8-week IMT program on pulmonary function tests, quality of life, and sleep quality in eight patients with LOPD who were receiving enzyme replacement therapy (ERT). METHODS: Before and after the IMT program, spirometric measurements in sitting and supine positions, and measurements of maximum inspiratory and expiratory pressures, peak cough flow, quality of life (assessed using the Nottingham Health Profile), and sleep quality (assessed using the Pittsburgh sleep quality index) were performed. RESULTS: A significant increase in maximum inspiratory pressure (cmH2O and % predicted) (median [interquartile range]: 30.0 cmH2O [21.5-48] versus 39 cmH2O [31.2-56.5] and 38.3 % [28.1-48.4] versus 50.5 % [37.7-54.9]) was observed after training (p = 0.01). There were no significant changes in the other pulmonary function measurements. With the exception of the social isolation subscore (p = 0.02), quality of life subscores did not change after IMT (p > 0.05). Sleep quality subscores and total scores were similar before and after IMT. CONCLUSION: These results suggest that IMT has a positive effect on maximum inspiratory pressure in subjects with LOPD who are under ERT.

The TREAT-NMD Duchenne muscular dystrophy registries: conception, design, and utilization by industry and academia.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

A frameshift mutation of ERLIN2 in recessive intellectual disability, motor dysfunction and multiple joint contractures.

We present a family afflicted with a novel autosomal recessive disease characterized by progressive intellectual disability, motor dysfunction and multiple joint contractures. No pathology was found by cranial imaging, electromyography and muscle biopsy, but electron microscopy in leukocytes revealed large vacuoles containing flocculent material. We mapped the disease gene by SNP genome scan and linkage analysis to an ∼0.80 cM and 1 Mb region at 8p11.23 with a multipoint logarithm of odds (LOD) score of 12. By candidate gene approach, we identified a homozygous two-nucleotide insertion in ERLIN2, predicted to lead to the truncation of the protein by about 20%. The gene encodes endoplasmic reticulum (ER) lipid raft-associated protein 2 that mediates the ER-associated degradation of activated inositol 1,4,5-trisphosphate receptors and other substrates.

Coexistence of Guillain-Barré syndrome and Behçet's disease.

Behçet's disease (BD) is a multisystemic, recurrent and inflammatory disorder. Neurological involvement is rare and affects mainly the central nervous system (CNS) in the form of brainstem meningoencephalitis or dural sinus thrombosis. Peripheral neuropathy is usually not observed during the course of BD but some reports have shown electrophysiologic evidence of subclinical neuropathy, mononeuritis multiplex and cranial neuropathy in BD patients. The co-occurrence of Guillain-Barré syndrome (GBS), an acute inflammatory demyelinating neuropathy, with other autoimmune or systemic diseases is rare. We present a case of BD with clinical and electrophysiological diagnosis of GBS. The findings of the patient were discussed with reference to literature.

Pathophysiology of protein aggregation and extended phenotyping in filaminopathy.

Mutations in FLNC cause two distinct types of myopathy. Disease associated with mutations in filamin C rod domain leading to expression of a toxic protein presents with progressive proximal muscle weakness and shows focal destructive lesions of polymorphous aggregates containing desmin, myotilin and other proteins in the affected myofibres; these features correspond to the profile of myofibrillar myopathy. The second variant associated with mutations in the actin-binding domain of filamin C is characterized by weakness of distal muscles and morphologically by non-specific myopathic features. A frameshift mutation in the filamin C rod domain causing haploinsufficiency was also found responsible for distal myopathy with some myofibrillar changes but no protein aggregation typical of myofibrillar myopathies. Controversial data accumulating in the literature require re-evaluation and comparative analysis of phenotypes associated with the position of the FLNC mutation and investigation of the underlying disease mechanisms. This is relevant and necessary for the refinement of diagnostic criteria and developing therapeutic approaches. We identified a p.W2710X mutation in families originating from ethnically diverse populations and re-evaluated a family with a p.V930_T933del mutation. Analysis of the expanded database allows us to refine clinical and myopathological characteristics of myofibrillar myopathy caused by mutations in the rod domain of filamin C. Biophysical and biochemical studies indicate that certain pathogenic mutations in FLNC cause protein misfolding, which triggers aggregation of the mutant filamin C protein and subsequently involves several other proteins. Immunofluorescence analyses using markers for the ubiquitin-proteasome system and autophagy reveal that the affected muscle fibres react to protein aggregate formation with a highly increased expression of chaperones and proteins involved in proteasomal protein degradation and autophagy. However, there is a noticeably diminished efficiency of both the ubiquitin-proteasome system and autophagy that impairs the muscle capacity to prevent the formation or mediate the degradation of aggregates. Transfection studies of cultured muscle cells imitate events observed in the patient's affected muscle and therefore provide a helpful model for testing future therapeutic strategies.

Lumbar Spinal Stenosis: A Rare Presentation of Hereditary Transthyretin Amyloidosis.

Hereditary transthyretin amyloidosis (hATTR) is caused by the mutations of the transthyretin (TTR) gene. Length dependent sensory-motor neuropathy with autonomic involvement is the hallmark of the disease. However, it can manifest with unusual phenotypes. A 53-year-old man presented with progressive weakness in lower limbs and operated for lumbar spinal stenosis. The progression of weakness restarted after two years with the addition of symptoms related to polyneuropathy. Electrodiagnostic studies revealed sensorimotor polyneuropathy with autonomic involvement. Sural nerve biopsy disclosed amyloid deposits. Genetic testing of TTR gene identified Glu89Gln mutation. Two years after the diagnosis, he had another decompressive surgery for lumbar spinal stenosis. Histopathological examination of ligamentum flavum specimens revealed amyloid deposits. During the follow up, he was diagnosed with laryngeal amyloidosis, which is an unusual manifestation. Seven years after the diagnosis, he died due to cardiac complications. Our patient suggested that hATTR with Glu89Gln may present with atypical symptoms. Clinicians should carefully look for hATTR in recurrent lumbar stenosis.

Clinical and genetic characteristics of Emery-Dreifuss muscular dystrophy patients from Turkey: 30 years longitudinal follow-up study.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare inherited disorder usually presenting in childhood with early contractures, slowly progressive scapulohumeroperoneal weakness/atrophy and potentially fatal dilated cardiomyopathy with conduction defects. We evaluated clinical and genetic findings of 32 patients with EDMD phenotype from 14 unrelated families, diagnosed at the Department of Neurology, Istanbul Faculty of Medicine between 1989 and 2022. Twenty-three patients from 8 unrelated families were diagnosed with EDMD1 (58%), 5 patients from 3 families with EDMD2 (21%), and 2 patients from 1 family with the rare EDMD3 (7%). Genetic diagnosis was achieved in 12 unrelated kinships with classical EDMD phenotype (86%) by applying panel testing, but no mutation could be determined in 2 patients with classical EDMD phenotype from 2 unrelated families (14%). Three novel pathogenic variants (c.19delC, c.416_417delTT, c.123C > G) in EMD, and a novel (c.1441dupT) heterozygous likely pathogenic variant in LMNA gene were found. This is the largest cohort from Turkey, expanding the genetic spectrum of EDMD, and providing clues for genetic testing of EDMD in Turkey.

The clinical use of impulse oscillometry in neuromuscular diseases.

BACKGROUND: The patients with neuromuscular diseases (NMD) are very fragile and it is hard to evaluate respiratory involvement of the primary disease in this group. Therefore, our study aimed to reveal the relationship between pulmonary function tests (PFT) and impulse oscillometry (IOS) and their correlation with respiratory clinical findings in NMD. MATERIAL AND METHODS: A total of 86 consecutive patients with NMD were included. The clinical findings of respiratory involvement, PFT, and IOS results of the patients were analyzed. RESULTS: Forty patients out of 86 were female. There were 29 patients with amyotrophic lateral sclerosis, four patients with myasthenia gravis, and 53 patients with muscular dystrophies/myopathies. According to the PFT results, 47 patients had restrictive PFT. However, there was no difference in IOS parameters when we compared the patients according to restrictions in PFT. A positive correlation was found with FVC %pred and X5. PEF %pred values were positively correlated with X10, X15, and X20, and negatively correlated with AX and R5-20. The patients with worse swallowing capability had increased Rrs levels, and more negative Xrs levels. The shortness of breath led to lower FEV1 %pred., higher R5, AX and R5-20, and also more negative X10, X15, and X35. CONCLUSION: Clinically reported dysphagia, a decreased capability of coughing, and shortness of breath in patients with NMD make Rrs increase in general, but Xrs parameters, which mainly express rib cage elasticity, turn more negative. In patients with NMD, IOS monitoring may help in evaluating the regression in respiratory functions, however, future studies are needed to understand more.

Increased complement consumption in MuSK-antibody-positive myasthenia gravis patients.

OBJECTIVE: To investigate the activation of different complement pathways in myasthenia gravis (MG) subtypes. SUBJECTS AND METHODS: Levels of complement breakdown products for different complement pathways were measured using ELISA in sera of acetylcholine receptor antibody (AChR-Ab)-positive (n = 21), muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive (n = 23) and seronegative generalized MG patients (n = 21) and healthy controls (n = 22). Levels of factor Bb (FBb), the breakdown product of factor B, and C4d, the breakdown product of C4, were measured to evaluate the activity of the alternative and classical complement pathways, respectively. Serum iC3b levels were analyzed to assess total complement activity. The results were expressed as OD values. RESULTS: MuSK-Ab-positive MG patients had a significantly higher mean concentration of serum FBb (0.638) than other MG subtypes (0.446 for AChR-Ab-positive, 0.537 for seronegative MG patients) and healthy controls (0.434) (p = 0.045). Mean serum iC3b (1.549-1.780) and C4d (0.364-0.395) levels were comparable among the groups. CONCLUSION: Our results suggest that MuSK-Ab-positive MG patients might have a complement-activating serum factor and the alternative complement pathway might be involved in the pathogenesis of the disease.

Giant cell myositis and myocarditis revisited.

Giant cell myositis (GCMm) and giant cell myocarditis (GCMc) are two rare autoimmune conditions. Among these, GCMc is a life-threatening disease with a 1-year mortality rate of 70%. Lethal ventricular arrhythmias, rapid evolution to heart failure and sudden death risk makes GCMc an emergency condition. It is thought to be mediated by T-cells and characterized by the presence of myofiber necrosis and giant cells in biopsies. Most commonly co-manifesting conditions with GCMm and/or GCMc are thymoma, myasthenia gravis and orbital myositis, all of which are treatable. As suspicion is the key approach in diagnosis, the physician following patients with thymoma with or without myasthenia gravis and with orbital myositis should always be alert. The fatal nature of GCMc associated with these relatively benign diseases deserves a special emergency attention with prompt institution of combined immunosuppressive treatment and very early inclusion of heart failure teams.

Functional Outcomes and Complications Following Scapulothoracic Arthrodesis in Patients with Facioscapulohumeral Dystrophy.

BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant myopathy characterized by facial and shoulder girdle muscle weakness with scapular winging. Scapulothoracic arthrodesis is a successful treatment approach for patients with <90° of shoulder elevation. The purpose of the present study was to assess functional outcomes and complications following scapulothoracic arthrodesis in patients with FSHD. METHODS: We retrospectively reviewed the records of 40 patients (64 shoulders) in whom scapulothoracic arthrodesis was performed. To achieve fusion, multiple multifilament cables were used together with autologous bone and allograft bone. Preoperative and postoperative shoulder elevation and abduction; Disabilities of the Arm, Shoulder and Hand (Quick version, qDASH) scores; and pulmonary function were compared. Recorded complications were classified as pulmonary or scapular. RESULTS: The mean age of the patients at the time of the operation was 25.4 years (range, 15 to 60 years), and the mean duration of follow-up was 71.2 months (range, 12 to 185 months). When the preoperative values were compared with those at the latest follow-up, significant improvement was noted in terms of elevation (from a mean [and standard deviation] of 60.6° ± 17.2° to 123.7° ± 26.7°; p < 0.001), abduction (from 52.7° ± 15.8° to 98.8° ± 20.3°; p < 0.001), and qDASH scores (from 34.7 ± 11.4 to 13.3 ± 13.1; p < 0.001). The overall complication rate was 26.6%. There were 7 pulmonary complications (4 pneumothoraxes, 2 pleural effusions, and 1 major atelectasis), and 5 chest tube placements were required. Ten complications (including 3 rib fractures, 1 brachial plexus palsy, 2 cases of implant irritation, 2 nonunions, 1 delayed union, and 1 scapular fracture) were related to the scapular fixation, and 7 revision procedures were required. Scapulothoracic fusion was achieved in all patients but 1, who had a scapular fracture. Pulmonary function tests were performed for 19 patients, and no difference was observed between preoperative and postoperative results. CONCLUSIONS: Scapulothoracic arthrodesis with use of multifilament cables is a successful surgical technique with high fusion rates and low morbidity. Pulmonary complications are common but resolve with careful attention. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A novel shoulder disability staging system for scapulothoracic arthrodesis in patients with facioscapulohumeral dystrophy.

BACKGROUND: Scapulothoracic arthrodesis (STA) is a well-established surgical technique to provide scapular stabilisation in patients with facioscapulohumeral dystrophy (FSHD). There is no staging or scoring systems available to guide surgical decision. The aim of this study was to develop a staging system to evaluate the shoulder disability in patients with FSHD to guide surgical decision-making and assess its reliability among surgeons. METHODS: Fifty-seven shoulders of 29 patients (15 male, 14 female) with an average age of 34.5 years (13-73) were included. Six stages of the disease were defined to create a system consisting of shoulder elevation, deltoid function and scapular winging. Patients were assessed by two independent orthopaedic surgeons who were blind to each other. Statistical analyses included mean and standard deviation for descriptive variables, Pearson's correlation and Cohen's Kappa for inter- and intraobserver agreement. RESULTS: Measurement of elevation showed excellent correlation in both inter- and intraobserver assessment. There was substantial agreement on deltoid function and moderate agreement on scapular winging. Decisions on stage showed excellent agreement on interobserver and substantial agreement on intraobserver assessment. Surgical decision using the stage showed excellent agreement on both inter- and intraobserver assessment. CONCLUSION: This novel staging system has an excellent inter observer agreement on FSHD patients' shoulder disability. This would provide surgeons a beneficial tool to define patient groups that would have negatively or positively affected from STA.

Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome.

Late-onset myasthenia gravis (LOMG) is a unique MG subgroup. More information is needed on its subgroups such as non-thymomatous generalized LOMG. We evaluated the effect of demographic, clinical, and serological factors as well as different immunosuppressive modalities on outcome in generalized non-thymomatous LOMG with onset ≥ 50 years. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification, MGFA postintervention score (MGFA PIS) and MG Composite scores were obtained to define the severity of disease and clinical outcome. In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive. In those who received immunosuppressives and provided the clinical scores (84 patients), 50 (60%) had favorable outcome (MGFA PIS categories of complete stable remission, pharmacological remission and minimal manifestations) at the end of 3 years. Use of prednisone + azathioprine had significantly positive effect on outcome. The presence of anti-titin antibodies had no significant effect on severity and outcome. Five anti-MuSK-positive patients had favorable outcome. In conclusion, the presence of neither anti-titin nor anti-MuSK antibodies points to unfavorable outcome. Prednisone and azathioprine combination has beneficial effects in non-thymomatous generalized LOMG.