Historic characteristics and mortality of patients in the Swiss Amyloidosis Registry.

AIMS OF THE STUDY: Systemic amyloidoses are rare protein-folding diseases with heterogeneous, often nonspecific clinical presentations. To better understand systemic amyloidoses and to apply state-of-the-art diagnostic pathways and treatment, the interdisciplinary Amyloidosis Network was founded in 2013 at University Hospital Zurich. In this respect, a registry was implemented to study the characteristics and life expectancy of patients with amyloidosis within the area covered by the network. Patient data were collected retrospectively for the period 2005-2014 and prospectively from 2015 onwards. METHODS: Patients aged 18 years or older diagnosed with any subtype of systemic amyloidosis were eligible for inclusion if they were treated in one of the four referring centres (Zurich, Chur, St Gallen, Bellinzona). Baseline data were captured at the time of diagnosis. Follow-up data were assessed half-yearly for the first two years, then annually. RESULTS: Between January 2005 and March 2020, 247 patients were screened, and 155 patients with confirmed systemic amyloidosis were included in the present analysis. The most common amyloidosis type was light-chain (49.7%, n = 77), followed by transthyretin amyloidosis (40%, n = 62) and amyloid A amyloidosis (5.2%, n = 8). Most patients (61.9%, n = 96) presented with multiorgan involvement. Nevertheless, single organ involvement was seen in all types of amyloidosis, most commonly in amyloid A amyloidosis (75%, n = 6). The median observation time of the surviving patients was calculated by the reverse Kaplan-Meier method and was 3.29 years (95% confidence interval [CI] 2.33-4.87); it was 4.87 years (95% CI 3.14-7.22) in light-chain amyloidosis patients and 1.85 years (95% CI 1.48-3.66) in transthyretin amyloidosis patients, respectively. The 1-, 3- and 5-year survival rates were 87.0% (95% CI 79.4-95.3%), 68.5% (95% CI 57.4-81.7%) and 66.0% (95% CI 54.6-79.9%) respectively for light-chain amyloidosis patients and 91.2% (95% CI 83.2-99.8%), 77.0% (95% CI 63.4-93.7%) and 50.6% (95% CI 31.8-80.3%) respectively for transthyretin amyloidosis patients. There was no significant difference between the two groups (p = 0.81). CONCLUSION: During registry set-up, a more comprehensive work-up of our patients suffering mainly from light-chain amyloidosis and transthyretin amyloidosis was implemented. Survival rates were remarkably high and similar between light-chain amyloidosis and transthyretin amyloidosis, a finding which was noted in similar historic registries of international centres. However, further studies are needed to depict morbidity and mortality as the amyloidosis landscape is changing rapidly.

Rapid Review on the Concept of Positive Health and Its Implementation in Practice.

Positive health (PH) has been described as a promising transformative innovation to address the challenges of promoting well-being and reducing the burden of disease. For this study, we conducted a scientific literature review of the current state of knowledge about PH as introduced by Huber and colleagues, following the Cochrane Rapid Review recommendations. Three databases were searched (PubMed, Google Scholar, and CINAHL). Data were extracted and synthesised using a narrative approach. A total of 55 articles were included. The initial evaluation revealed promising results at both the individual and collective levels. However, several articles gave reason for further refinement of the conceptualisation of PH and of ways to measure the effects of PH interventions in greater detail. Professionals also expressed a desire for a more informed application and elaboration of the PH method, in various settings and populations, to increase its effectiveness in practice. The results from the rapid review highlight the transformative potential of PH in shifting from a disease-oriented to a health-oriented paradigm of healthcare. This underlines the need for continued research regarding further development of the concept and its practical method, along with the necessity for methodological innovation.

Assessment of Fitbit Charge 4 for sleep stage and heart rate monitoring against polysomnography and during home monitoring in Huntington's disease.

STUDY OBJECTIVES: Wearable devices, monitoring sleep stages and heart rate (HR), bring the potential for longitudinal sleep monitoring in patients with neurodegenerative diseases. Sleep quality reduces with disease progression in Huntington's disease (HD). However, the involuntary movements characteristic of HD may affect the accuracy of wrist-worn devices. This study compares sleep stage and heart rate data from the Fitbit Charge 4 (FB) against polysomnography (PSG) in participants with HD. METHODS: Ten participants with manifest HD wore a FB during overnight hospital-based PSG, and for nine of these participants continued to wear the FB for seven nights at home. Sleep stages (30s epochs) and minute-by-minute HR were extracted and compared against PSG data. RESULTS: FB-estimated total sleep and wake times, and sleep stage times were in good agreement with PSG, with intra-class correlations 0.79-0.96. However, poor agreement was observed for Wake After Sleep Onset, and the number of awakenings. FB detected wake with 68.6±15.5% sensitivity and 93.7±2.5% specificity, rapid eye movement (REM) sleep with high sensitivity and specificity (78.7±31.9%, 95.6±2.3%), and deep sleep with lower sensitivity but high specificity (56.4±28.8%, 95.0±4.8%). FB HR was strongly correlated with PSG, and the mean absolute error between FB and PSG HR data was 1.16 ± 0.42 bpm. At home, longer sleep and shorter wake times were observed compared to hospital data, while percentage sleep stage times were consistent with hospital data. CONCLUSIONS: Results suggest the potential for long-term monitoring of sleep patterns using wrist-worn wearable devices as part of symptom management in HD.

Neurologic involvement in cystinosis: Focus on brain lesions and new evidence of four-repeat (4R-) Tau immunoreactivity.

Nephropathic cystinosis is a rare autosomal recessive storage disorder caused by CTNS gene mutations, leading to autophagy-lysosomal pathway impairment and cystine crystals accumulation. Neurologic involvement is highly variable and includes both neurodevelopmental and neurodegenerative disturbances, as well as focal neurologic deficits. By presenting longitudinal data of a 28-year-old patient with a large infratentorial lesion, we summarized the pathology, clinical and imaging features of neurological involvement in cystinosis patients. Brain damage in form of cystinosis-related cerebral lesions occurs in advanced disease phases and is characterized by the accumulation of cystine crystals, subsequent inflammation with vasculitis-like features, necrosis, and calcification. Epilepsy is a frequent comorbidity in affected individuals. Steroids might play a role in the symptomatic treatment of "stroke-like" episodes due to edematous-inflammatory lesions, but probably do not change the overall prognosis. Lifelong compliance to depleting therapy with cysteamine still represents the main therapeutic option. However, consequences of CTNS gene defects are not restricted to cystine accumulation. New evidence of four-repeat (4R-) Tau immunoreactivity suggests concurrent progressive neurodegeneration in cystinosis patients, highlighting the need of innovative therapeutic strategies, and shedding light on the crosstalk between proteinopathies and autophagy-lysosomal system defects. Eventually, emerging easily accessible biomarkers such as serum neurofilament light chains (NfL) might detect subclinical neurologic involvement in cystinosis patients.

Neuropathies related to hepatitis E virus infection: A prospective, matched case-control study.

BACKGROUND: Acute hepatitis E virus (HEV) infection has recently emerged as a potential trigger for acute dysimmune neuropathies, but prospective controlled studies are lacking. AIMS: To compare the frequency of concomitant acute HEV infection in patients with neuralgic amyotrophy (NA), Guillain-Barré syndrome (GBS), and Bell's palsy with a matched control population. METHODS: Swiss multicenter, prospective, observational, matched case-control study over 3 years (September 2019-October 2022). Neurological cases with NA, GBS, or Bell's palsy were recruited within 1 month of disease onset. Healthy controls were matched for age, sex, geographical location, and timing of blood collection. Diagnostic criteria for acute hepatitis E were reactive serum anti-HEV IgM and IgG assays (ELISA test) and/or HEV RNA detection in serum by real-time polymerase chain reaction (RT-PCR). RT-PCR was performed on sera to confirm IgM positivity. RESULTS: We included 180 patients (59 GBS, 51 NA, 70 Bell's palsy cases) and corresponding matched controls (blood donors) with median age 51 years for both groups and equal gender distribution. Six IgM+ cases were detected in the NA, two in the GBS, and none in the Bell's palsy group. Two controls were anti-HEV IgM-positive. At disease onset, most cases with acute HEV infection had increased liver enzymes. A moderate association (p = 0.027, Fisher's exact test; Cramér's V = -0.25) was observed only between acute HEV infection and NA. CONCLUSION: This prospective observational study suggests an association between concomitant acute HEV infection and NA, but not with GBS or Bell's palsy.

Neuroacanthocytosis Syndromes: The Clinical Perspective.

The two very rare neurodegenerative diseases historically known as the "neuroacanthocytosis syndromes" are due to mutations of either VPS13A or XK. These are phenotypically similar disorders that affect primarily the basal ganglia and hence result in involuntary abnormal movements as well as neuropsychiatric and cognitive alterations. There are other shared features such as abnormalities of red cell membranes which result in acanthocytes, whose relationship to neurodegeneration is not yet known. Recent insights into the functions of these two proteins suggest dysfunction of lipid processing and trafficking at the subcellular level and may provide a mechanism for neuronal dysfunction and death, and potentially a target for therapeutic interventions.

Symptomatic treatment options for Huntington's disease (guidelines of the German Neurological Society).

INTRODUCTION: Ameliorating symptoms and signs of Huntington's disease (HD) is essential to care but can be challenging and hard to achieve. The pharmacological treatment of motor signs (e.g. chorea) may favorably or unfavorably impact other facets of the disease phenotype (such as mood and cognition). Similarly, pharmacotherapy for behavioral issues may modify the motor phenotype. Sometimes synergistic effects can be achieved. In patients undergoing pragmatic polypharmacological therapy, emerging complaints may stem from the employed medications' side effects, a possibility that needs to be considered. It is recommended to clearly and precisely delineate the targeted signs and symptoms (e.g., chorea, myoclonus, bradykinesia, Parkinsonism, or dystonia). Evidence from randomized controlled trials (RCTs) is limited. Therefore, the guidelines prepared for the German Neurological Society (DGN) for German-speaking countries intentionally extend beyond evidence from RCTs and aim to synthesize evidence from RCTs and recommendations of experienced clinicians. RECOMMENDATIONS: First-line treatment for chorea is critically discussed, and a preference in prescription practice for using tiapride instead of tetrabenazine is noted. In severe chorea, combining two antidopaminergic drugs with a postsynaptic (e.g., tiapride) and presynaptic mode of action (e.g., tetrabenazine) is discussed as a potentially helpful strategy. Sedative side effects of both classes of compounds can be used to improve sleep if the highest dosage of the day is given at night. Risperidone, in some cases, may ameliorate irritability but also chorea and sleep disorders. Olanzapine can be helpful in the treatment of weight loss and chorea, and quetiapine as a mood stabilizer with an antidepressant effect. CONCLUSIONS: Since most HD patients simultaneously suffer from distinct motor signs and distinct psychiatric/behavioral symptoms, treatment should be individually adapted.

Differential diagnosis of chorea (guidelines of the German Neurological Society).

INTRODUCTION: Choreiform movement disorders are characterized by involuntary, rapid, irregular, and unpredictable movements of the limbs, face, neck, and trunk. These movements often initially go unnoticed by the affected individuals and may blend together with seemingly intended, random motions. Choreiform movements can occur both at rest and during voluntary movements. They typically increase in intensity with stress and physical activity and essentially cease during deep sleep stages. In particularly in advanced stages of Huntington disease (HD), choreiform hyperkinesia occurs alongside with dystonic postures of the limbs or trunk before they typically decrease in intensity. The differential diagnosis of HD can be complex. Here, the authors aim to provide guidance for the diagnostic process. This guidance was prepared for the German Neurological Society (DGN) for German-speaking countries. RECOMMENDATIONS: Hereditary (inherited) and non-hereditary (non-inherited) forms of chorea can be distinguished. Therefore, the family history is crucial. However, even in conditions with autosomal-dominant transmission such as HD, unremarkable family histories do not necessarily rule out a hereditary form (e.g., in cases of early deceased or unknown parents, uncertainties in familial relationships, as well as in offspring of parents with CAG repeats in the expandable range (27-35 CAG repeats) which may display expansions into the pathogenic range). CONCLUSIONS: The differential diagnosis of chorea can be challenging. This guidance prepared for the German Neurological Society (DGN) reflects the state of the art as of 2023.

Dementia During the COVID-19 Pandemic: Experiences From Clinicians, Patients, and Caregivers in Switzerland.

Background: The COVID-19 pandemic had a significant impact on the Swiss health care system, affecting especially vulnerable people, such as patients suffering from dementia. The purpose of this study was to investigate the challenges experienced by dementia patients, their carers, and clinicians during the pandemic in Switzerland. Methods: An online survey was sent to all memory clinics in the German speaking part of Switzerland. Patients diagnosed with dementia and their carers were recruited for semi-structured telephone interviews at the memory clinic of the University Hospital Zurich. Results: A total of 28 clinicians, 17 carers, and seven patients participated in this study. According to the clinicians, all aspects of clinical work were affected by the pandemic. Carers did not perceive a significant role of the pandemic in the disease progression of the patients, despite many challenges faced. Patients described a high level of conscientiousness during the pandemic. Recommendations for future scenarios were provided from all groups. Conclusion: In order to increase the systemic resilience of the Swiss health care system, it is important to consider the experiences and recommendations of vulnerable groups and health care professionals for future public health measures and policies.

Cobalt intoxication: mitochondrial features and condition.

Cobalt intoxication is a rare complication of joint arthroplasty with a metal-on-metal prothesis or metal implants after broken ceramic implants. Patients with metal components should be monitored closely for complications. The awareness for the wide range of clinical pictures of this cobalt intoxication should be increased. We here describe the clinical presentation, diagnostic and therapeutic work-up of a 70-year-old patient with a cobalt metallosis. The patient presented with a progressive deterioration of vision and hearing, axonal sensorimotor polyneuropathy and cataract. The extensive work-up resulted in the diagnosis of a cobalt metallosis as a complication of a metal hip prosthesis. Cobalt intoxication, especially after metal-on-metal total joint arthroplasty, is a rare complication; however, there have been several reports of similar cases. It is therefore recommended to avoid the implantation of a metal-on-metal prothesis or metal implants after broken ceramic implants as in this case whenever possible. Patients with exclusively metal components should be monitored closely for complications.

Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T.

BACKGROUND: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). METHODS: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. RESULTS: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, PWald<0.001); the expression correlated with pathological disease activity (R=0.59, Pt-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, Pt-statistic=0.031). CONCLUSIONS: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03660969.

Evaluation of real-life outcome data of patients with spinal muscular atrophy treated with nusinersen in Switzerland.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder causing progressive proximal muscular, respiratory, and bulbar weakness. We present outcome data on motor function, ventilation, nutrition, and language development of SMA patients treated with nusinersen in Switzerland. This multicenter, observational study included 44 patients. At treatment initiation, after 2 months and then every 4 months we assessed motor function with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale expanded (HFMSE) and 6-Minute Walk Test (6MWT). At treatment initiation, patients were 0.1-44.6 years old, treatment duration ranged from 6 to 41 months. All 11 SMA type 1 children achieved higher CHOP-INTEND scores at the last assessment compared to treatment initiation, 4 acquired stable sitting. Six type 1 children were <18 months-old at treatment initiation. Two of them did not need ventilation or nutritional support at the last assessment; three had delayed language development and 3 articulation difficulties. 5/21 SMA type 2 patients achieved higher HFMSE scores. All ambulant type 3 patients showed a gain in the 6MWT. Nusinersen is an effective treatment, with gains in motor function occurring particularly in children and SMA type 1, but also in type 2 and 3, adolescents and adults.

Comparison of electrodiagnosis, neurosonography and MR neurography in localization of ulnar neuropathy at the elbow.

INTRODUCTION: In patients with ulnar neuropathy at the elbow (UNE) the precise determination of the site of lesion is important for subsequent differential diagnostic considerations and therapeutic management. Due to a paucity of comparable data, to better define the role of different diagnostic tests, we performed the first prospective study comparing the diagnostic accuracy of short segment nerve stimulation, nerve ultrasonography, MR neurography (MRN), and diffusion tensor imaging (DTI) in patients with UNE. METHODS: UNE was clinically diagnosed in 17 patients with 18 affected elbows. For all 18 affected elbows in patients and 20 elbows in 10 healthy volunteers, measurements of all different diagnostic tests were performed at six anatomical positions across the elbow with measuring points from distal (D4) to proximal (P6) in relation to the medial epicondyle (P0). Additional qualitative assessment regarding structural changes of surrounding nerve anatomy was conducted. RESULTS: The difference between affected arms of patients and healthy control arms were most frequently the largest at measure intervals D2 to P0 and P0 to P2 for electrophysiological testing, or measure points P0 and P2 for all other devices, respectively. At both levels P0 and at P2, T2 contrast-to-noise ratio (CNR) of MRN and mean diffusivity (MD) of DTI-based MRN showed best accuracies. DISCUSSION: This study revealed differences in diagnostic performance of tests concerning a specific location of UNE, with better results for T2 contrast to noise ratio (CNR) in MRN and mean diffusivity of DTI-based MRN. Additional testing with MRN and nerve ultrasonography is recommended to uncover anatomical changes.

Management of transthyretin amyloidosis.

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts.

[Smarter Medicine in Headache Care - presentation and discussion of 5 recommendations]. / Smarter Medicine in Diagnose und Behandlung von Kopfschmerzen.

Smarter Medicine in Headache Care - presentation and discussion of 5 recommendations Abstract. An unequivocal headache diagnosis cannot always be made. The lack of diagnostic tests able to prove primary headaches often prompts physicians to perform unnecessary examinations to reduce their uncertainty. When setting out the therapeutic strategy, again, insecurity often leads to mendable choices. In this Delphi study, members of the therapy commission of the Swiss Headache Society collected, rated, and re-rated doubtful and questionable procedures. Five recommendations that resulted from this survey are presented and reviewed in this article. The recommendations are: (A) no repeated cerebral imaging in headaches with unchanged phenotype; (B) no computed tomography in the work-up of non-acute headaches; (C) no tooth extraction to treat persistent idiopathic facial pain, (D) no migraine surgery; (E) no removal of amalgam fillings to treat headache disorders.

Single-cell profiling of myasthenia gravis identifies a pathogenic T cell signature.

Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neuromuscular signaling due to autoantibodies targeting the acetylcholine receptor. Although its auto-antigens and effector mechanisms are well defined, the cellular and molecular drivers underpinning MG remain elusive. Here, we employed high-dimensional single-cell mass and spectral cytometry of blood and thymus samples from MG patients in combination with supervised and unsupervised machine-learning tools to gain insight into the immune dysregulation underlying MG. By creating a comprehensive immune map, we identified two dysregulated subsets of inflammatory circulating memory T helper (Th) cells. These signature ThCD103 and ThGM cells populated the diseased thymus, were reduced in the blood of MG patients, and were inversely correlated with disease severity. Both signature Th subsets rebounded in the blood of MG patients after surgical thymus removal, indicative of their role as cellular markers of disease activity. Together, this in-depth analysis of the immune landscape of MG provides valuable insight into disease pathogenesis, suggests novel biomarkers and identifies new potential therapeutic targets for treatment.

Anti-IgLON5 Disease: A New Bulbar-Onset Motor Neuron Mimic Syndrome.

OBJECTIVE: To expand the spectrum of anti-IgLON5 disease by adding 5 novel anti-IgLON5-seropositive cases with bulbar motor neuron disease-like phenotype. METHODS: We characterized the clinical course, brain MRI and laboratory findings, and therapy response in these 5 patients. RESULTS: Patients were severely affected by bulbar impairment and its respiratory consequences. Sleep-related breathing disorders and parasomnias were common. All patients showed clinical or electrophysiologic signs of motor neuron disease without fulfilling the diagnostic criteria for amyotrophic lateral sclerosis. One patient regained autonomy in swallowing and eating, possibly related to immunotherapy. CONCLUSION: IgLON5 disease is an important differential diagnosis to evaluate in patients with bulbar motor neuron disease-like phenotype and sleep disorders. There is need for a deeper understanding of the underlying pathobiology to determine whether IgLON5 disease is an immunotherapy-responsive condition.

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

Collagen VI-Related Myopathy Caused by Compound Heterozygous Mutations of COL6A3 in a Consanguineous Kurdish Family.

ABSTRACT: Collagen VI-related myopathies are caused by mutations of COL6A1, COL6A2, and COL6A3 and present with a wide phenotypic spectrum ranging from severe Ulrich congenital muscular dystrophy to mild Bethlem myopathy. Here, we report a consanguineous Kurdish family with 3 siblings affected by autosomal-recessive Bethlem myopathy caused by compound heterozygous mutations of COL6A3. We found the previously described missense mutation c.7447A > G/p.(Lys2483Glu) and a novel large deletion encompassing the exon 1-39 of the COL6A3 gene. Apart from the classical clinical symptoms, all patients had keratoconus, which expands the phenotype of the collagen VI-related myopathies.