Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies

Background: Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement. Methods: We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms. Results: We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%). Conclusions: We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim

WNT/β-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner

Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors

Pooled retrospective analysis of 70 mg erenumab in episodic and chronic migraine: a two tertiary headache centers experience during clinical practice

Erenumab is a monoclonal antibody, targeted against the calcitonin gene-related peptide (CGRP) receptor. Clinical studies have demonstrated prophylactic efficacy in both episodic (EM) and chronic migraine (CM). The aim of the present study is to evaluate the efficacy of treatment in tertiary headache centers under real-life conditions. In a retrospective analysis, the period of 3 months before and after initiation of erenumab therapy was compared. Relevant parameters (headache days, headache intensity, headache duration, acute medication, previous prophylaxis treatments) were collected from medical charts of all migraine patients (N = 82) who started treatment with erenumab between November 1st 2018 and May 1st 2019 at two tertiary headache centers in Germany. The sample included 68 female (82.9%) and 14 male patients aged between 22 and 78 years (mean 51.1 years, SD 10.5 years). Of these patients, 57.3% met the criteria for CM and 56.9% overused acute medication. Under therapy with erenumab, a significant reduction of headache days was observed from the first month on. The effect was most pronounced in the third month with a decrease in monthly headache days from 16.6 to 11.6 days (p < 0.001). There was also a significant reduction in reported headache intensity (p = 0.004) and average duration of headache attacks (p = 0.016). The 50% responder rate in patients with CM was lower in the first month compared to EM but then increased similarly to EM. Patients with medication overuse (MO) also responded to the therapy. There was a reduction in medication overuse from 57% at baseline to 29% after therapy (p = 0.011). Overall, a positive result of treatment with erenumab can be shown in a highly selected sample with severely affected migraine patients and a refractory course prior to treatment. This re-confirms the clinical trial data also for this highly selected group

Functional characterization of a novel CSF1R mutation causing hereditary diffuse leukoencephalopathy with spheroids

Background Colony‐stimulating factor 1 receptor is a tyrosine kinase transmembrane protein that mediates proliferation, differentiation, and survival of monocytes/macrophages and microglia. CSF1R gene mutations cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an autosomal‐dominantly inherited microgliopathy, leading to early onset dementia with high lethality. Methods By interdisciplinary assessment of a complex neuropsychiatric condition in a 44‐year old female patient, we narrowed down the genetic diagnostic to CSF1R gene sequencing. Flow cytometric analyses of uncultivated peripheral blood monocytes were conducted sequentially to measure the cell surface CSF1 receptor and autophosphorylation levels. Monocyte subpopulations were monitored during disease progression. Results We identified a novel heterozygous deletion–insertion mutation c.2527_2530delinsGGCA, p.(Ile843_Leu844delinsGlyIle) in our patient with initial signs of HDLS. Marginally elevated cell surface CSF1 receptor levels with increased Tyr723 autophosphorylation suggest an enhanced receptor activity. Furthermore, we observed a shift in monocyte subpopulations during disease course. Conclusion Our data indicate a mutation‐related CSF1R gain‐of‐function, accompanied by an altered composition of the peripheral innate immune cells in our patient with HDLS. Since pharmacological targeting of CSF1R with tyrosine kinase inhibitors prevents disease progression in mouse models of neurodegenerative disorders, a potential pharmacological benefit of CSF1R inhibition remains to be elucidated for patients with HDLS

Telemedizin in der Schlaganfallversorgung: versorgungsrelevant für Deutschland

Background and objective!#!Telemedical stroke networks improve stroke care and provide access to time-dependent acute stroke treatment in predominantly rural regions. The aim is a presentation of data on its utility and regional distribution.!##!Methods!#!The working group on telemedical stroke care of the German Stroke Society performed a survey study among all telestroke networks.!##!Results!#!Currently, 22 telemedical stroke networks including 43 centers (per network: median 1.5, interquartile range, IQR, 1-3) as well as 225 cooperating hospitals (per network: median 9, IQR 4-17) operate in Germany and contribute to acute stroke care delivery to 48 million people. In 2018, 38,211 teleconsultations (per network: median 1340, IQR 319-2758) were performed. The thrombolysis rate was 14.1% (95% confidence interval 13.6-14.7%) and transfer for thrombectomy was initiated in 7.9% (95% confidence interval 7.5-8.4%) of ischemic stroke patients. Financial reimbursement differs regionally with compensation for telemedical stroke care in only three federal states.!##!Conclusion!#!Telemedical stroke care is utilized in about 1 out of 10 stroke patients in Germany. Telemedical stroke networks achieve similar rates of thrombolysis and transfer for thrombectomy compared with neurological stroke units and contribute to stroke care in rural regions. Standardization of network structures, financial assurance and uniform quality measurements may further strengthen the importance of telestroke networks in the future