Publications by authors named "Benedikt Schoser"

196 Publications

Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort.

Neurology 2019 09 8;93(10):e995-e1009. Epub 2019 Aug 8.

From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Neurology (S.W., B.S.), Friedrich-Baur-Institute, Ludwig-Maximilians-Universität München, Munich, Germany; Neuromuscular Reference Centre (F.D., G.B.), Assistance Publique-Hôpitaux de Paris, France; and Tayside Clinical Trials Unit (F.H., R.L.), The University of Dundee, UK.

Objective: To evaluate the role of genetic variation at the locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial.

Methods: We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats.

Results: We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed test = -3.7, = 0.0019).

Conclusions: Careful characterization of the CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials.
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http://dx.doi.org/10.1212/WNL.0000000000008056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745735PMC
September 2019

Pompe disease: what are we missing?

Authors:
Benedikt Schoser

Ann Transl Med 2019 Jul;7(13):292

Friedrich-Baur-Institute at the Department of Neurology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Pompe disease is a multisystemic metabolic disorder caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) leading to progressive accumulation of lysosomal glycogen, lysosomal swelling and rupture in all tissues of the human body. Furthermore, autophagic buildup, organelle abnormalities, and energy deficit are regularly observed. Enzyme replacement therapy has been available for patients living with Pompe disease for more than 15 years. Although our disease knowledge has grown enormously, we still have multiple challenges to overcome. Here, I will discuss unmet clinical needs, neglected or overlooked aspects of the pathophysiology, and issues related to future therapies.
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http://dx.doi.org/10.21037/atm.2019.05.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642932PMC
July 2019

Assessing metabolic profiles in human myoblasts from patients with late-onset Pompe disease.

Ann Transl Med 2019 Jul;7(13):277

Friedrich-Baur-Institute at the Department of Neurology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Background: Pompe disease is a neuromuscular disease caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) which degrades glycogen, resulting in progressive accumulation of lysosomal glycogen, lysosomal swelling and rupture. In addition, mitochondrial abnormalities have been frequently observed in muscle biopsy specimens of Pompe patients. Enzyme replacement therapy (ERT) using alglucosidase alfa, a recombinant human GAA, is so far the only available therapy. We evaluated glycolysis and basal respiration in primary human myoblasts from patients with Pompe disease and in mouse myoblasts from GAA knockout mice before and after alglucosidase alfa treatment.

Methods: We tested patient-derived primary human myoblasts and immortalized GAA mouse myoblasts for GAA activity, glycolytic activity, and mitochondrial respiration before and after alglucosidase alfa treatment using enzyme activity assays and SeaHorse measurements.

Results: A significant reduction in glycolysis (30%) and in mitochondrial respiration (50%) was observed in both, human and mouse GAA-deficient myoblasts. Treatment with alglucosidase alfa resulted in partial recovery of both metabolic pathways with some variability in human myoblasts.

Conclusions: Future assessments of treatment efficacy should include screening for the metabolic effects on both glycolysis and mitochondrial respiration in order to obtain a better read-out of the cellular energy metabolism.
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http://dx.doi.org/10.21037/atm.2019.04.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642930PMC
July 2019

Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders.

Orphanet J Rare Dis 2019 07 16;14(1):179. Epub 2019 Jul 16.

Department of Pediatric Neurology, University Hospital Essen, Essen, Germany.

Background: The protein O-mannosyltransferase 1, encoded by the POMT1 gene, is a key enzyme in the glycosylation of α-dystroglycan. POMT1-related disorders belong to the group of dystroglycanopathies characterized by a proximally pronounced muscular dystrophy with structural or functional involvement of the brain and/or the eyes. The phenotypic spectrum ranges from the severe Walker-Warburg syndrome (WWS) to milder forms of limb girdle muscular dystrophy (LGMD). The phenotypic severity of POMT1-related dystroglycanopathies depends on the residual enzyme activity. A genotype-phenotype correlation can be assumed.

Results: The clinical, neuroradiological, and genetic findings of 35 patients with biallelic POMT1 mutations (15 WWS, 1 MEB (muscle-eye-brain disease), 19 LGMD) from 27 independent families are reported. The representative clinical course of an infant with WWS and the long-term course of a 32 years old patient with LGMD are described in more detail. Specific features of 15 patients with the homozygous founder mutation p.Ala200Pro are defined as a distinct and mildly affected LGMD subgroup. Ten previously reported and 8 novel POMT1 mutations were identified. Type and location of each of the POMT1 mutations are evaluated in detail and a list of all POMT1 mutations reported by now is provided. Patients with two mutations leading to premature protein termination had a WWS phenotype, while the presence of at least one missense mutation was associated with milder phenotypes. In the patient with MEB-like phenotype two missense mutations were observed within the catalytic active domain of the enzyme.

Conclusions: Our large cohort confirms the importance of type and location of each POMT1 mutation for the individual clinical manifestation and thereby expands the knowledge on the genotype-phenotype correlation in POMT1-related dystroglycanopathies. This genotype-phenotype correlation is further supported by the observation of an intrafamiliar analogous clinical manifestation observed in all affected 13 siblings from 5 independent families. Our data confirm the progressive nature of the disease also in milder LGMD phenotypes, ultimately resulting in loss of ambulation at a variable age. Our data define two major clinical POMT1 phenotypes, which should prompt genetic testing including the POMT1 gene: patients with a severe WWS manifestation predominantly present with profound neonatal muscular hypotonia and a severe and progressive hydrocephalus with involvement of brainstem and/or cerebellum. The presence of an occipital encephalocele in a WWS patient might point to POMT1 as causative gene within the different genes associated with WWS. The milder LGMD phenotypes constantly show markedly elevated creatine kinase values in combination with microcephaly and cognitive impairment.
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http://dx.doi.org/10.1186/s13023-019-1119-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636095PMC
July 2019

Mannose 6-phosphonate labelling: A key for processing the therapeutic enzyme in Pompe disease.

J Cell Mol Med 2019 09 10;23(9):6499-6503. Epub 2019 Jul 10.

NanoMedSyn, Montpellier, France.

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.
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http://dx.doi.org/10.1111/jcmm.14516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714136PMC
September 2019

Decreased water T in fatty infiltrated skeletal muscles of patients with neuromuscular diseases.

NMR Biomed 2019 08 10;32(8):e4111. Epub 2019 Jun 10.

Department of Diagnostic and Interventional Radiology, Technical University of Munich, Munich, Germany.

Quantitative imaging techniques are emerging in the field of magnetic resonance imaging of neuromuscular diseases (NMD). T of water (T ) is considered an important imaging marker to assess acute and chronic alterations of the muscle fibers, being generally interpreted as an indicator for "disease activity" in the muscle tissue. To validate the accuracy and robustness of quantitative imaging methods, H magnetic resonance spectroscopy (MRS) can be used as a gold standard. The purpose of the present work was to investigate T of remaining muscle tissue in regions of higher proton density fat fraction (PDFF) in 40 patients with defined NMD using multi-TE single-voxel H MRS. Patients underwent MR measurements on a 3 T system to perform a multi-TE single-voxel stimulated echo acquisition method (STEAM) MRS (TE = 11/15/20/25(/35) ms) in regions of healthy, edematous and fatty thigh muscle tissue. Muscle regions for MRS were selected based on T -weighted water and fat images of a two-echo 2D Dixon TSE. MRS results were confined to regions with qualitatively defined remaining muscle tissue without edema and high fat content, based on visual grading of the imaging data. The results showed decreased T values with increasing PDFF with R  = 0.45 (p < 10 ) (linear fit) and with R  = 0.51 (exponential fit). The observed dependence of T on PDFF should be considered when using T as a marker in NMD imaging and when performing single-voxel MRS for T in regions enclosing edematous, nonedematous and fatty infiltrated muscle tissue.
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http://dx.doi.org/10.1002/nbm.4111DOI Listing
August 2019

Comparison of recent pivotal recommendations for the diagnosis and treatment of late-onset Pompe disease using diagnostic nodes-the Pompe disease burden scale.

J Neurol 2019 Aug 18;266(8):2010-2017. Epub 2019 May 18.

Department of Radiation Oncology, Cantonal Hospital, 9007, St. Gallen, Switzerland.

Pompe disease is a rare autosomal-recessive disorder characterised by limb-girdle myopathy and respiratory weakness in the late-onset form (LOPD). Various mutations in the acid alpha-glucosidase gene lead to toxic lysosomal and extra-lysosomal glycogen accumulation in all organs due to ineffective glycogen clearance by the encoded enzyme. Only one randomized trial demonstrated beneficial effects of respiratory function and meters walked in the 6-min walking test with enzyme replacement therapy (ERT). These results were confirmed in several retrospective and prospective observations and in meta-analyses. Due to a potential lifelong therapy, moderate efficacy and high treatment costs time of ERT initiation and cessation is an ongoing matter of debate. So far, several national and international recommendations have been published with different criteria concerning diagnosis, initiation and cessation of ERT in LOPD. We therefore formally analysed recent published recommendations and consensus statements of LOPD using diagnostic nodes (DODES) as a special software tool. With DODES, an objective analysis becomes possible if the content of the recommendations is represented as algorithms using cross-compatible elements. This analysis formally disclosed both, areas of great heterogeneity and concordance for the diagnosis and management of LOPD and paved the way for a Pompe disease burden scale focussing on ERT initiation. According to this investigation further clinical research should concentrate on ERT in pre-symptomatic and severely affected LOPD patients and on cessation criteria for ERT as these issues are areas of international uncertainty and discordance.
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http://dx.doi.org/10.1007/s00415-019-09373-2DOI Listing
August 2019

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.

Genet Med 2019 11 16;21(11):2521-2531. Epub 2019 May 16.

CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada.

Purpose: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established.

Methods: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease.

Results: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration.

Conclusion: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
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http://dx.doi.org/10.1038/s41436-019-0532-zDOI Listing
November 2019

A Systematic Review of the Health Economics of Pompe Disease.

Pharmacoecon Open 2019 Dec;3(4):479-493

Audentes Therapeutics, 600 California Street, Floor 17, San Francisco, CA, 94108, USA.

Background: Pompe disease is a rare, severe neuromuscular disease with high mortality and substantial clinical and humanistic burden. However, the economic burden of Pompe disease and the health economic value of its treatments are not well understood. The objectives of this systematic review were to characterize the health economic evidence on Pompe disease, including healthcare resource use and costs (direct and indirect), health utilities, and the cost-effectiveness of current treatments used to manage patients with Pompe disease.

Methods: A systematic search of MEDLINE and Embase was performed to retrieve publications on the health economics of Pompe disease. Publications were screened according to predefined criteria, extracted, and quality assessed using the Newcastle-Ottawa Scale. Data were narratively synthesized.

Results: Eight publications evaluated patients with infantile-onset Pompe disease (IOPD) (two studies), late-onset Pompe disease (LOPD) (four studies), or both (two studies). In IOPD, total cost of supportive therapy (excluding treatment) was €32,871 (equivalent to US$41,667 when adjusted for currency and inflation to 2017 US dollars) over a life expectancy of 0.4 years. In adult LOPD, the average annual cost per patient of supportive therapy was €22,475 (adjusted $28,489). Resource use in LOPD was high, with nursing home admissions accounting for 19% of annual direct medical costs. Health economic evaluations estimating incremental costs per quality-adjusted life year (QALY) gained with enzyme-replacement therapy (ERT) versus supportive therapy ranged from £109,991 (adjusted, $186,851) per QALY gained in Columbia to €1,043,868 (adjusted, $1,323,207) in the Netherlands.

Discussion: Despite a full systematic literature search, only eight relevant publications were identified, most of which were of relatively poor quality. However, a significant economic burden of Pompe disease on patients, families, healthcare systems, and society was found, with the majority of costs driven by the only currently approved treatment, ERT. Health economic evaluations of ERT versus supportive therapy vary significantly, with the majority well above willingness-to-pay thresholds. New therapies and approaches to care are needed to address the persistent and lifelong economic burden of Pompe disease and the large incremental cost-effectiveness ratios observed.
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http://dx.doi.org/10.1007/s41669-019-0142-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861413PMC
December 2019

Charcot-Marie-Tooth disease type 2CC due to a frameshift mutation of the neurofilament heavy polypeptide gene in an Austrian family.

Neuromuscul Disord 2019 05 20;29(5):392-397. Epub 2019 Feb 20.

Friedrich-Baur-Institute, Dep. of Neurology, Ludwig-Maximilians-University of Munich, Ziemssenstraße 1A, 80336 Munich, Germany. Electronic address:

Neurofilaments are structural components of motor axons. Recently different variants resulting in translation of a cryptic amyloidogenic element of the neurofilament-heavy polypeptide (NEFH) gene have been described to cause Charcot-Marie-Tooth disease type 2CC (CMT2CC) by forming amyloidogenic toxic protein aggregation. Until now only few CMT2CC patients have been described. Clinical features include progressive muscle weakness and atrophy mainly affecting the lower limbs, hyporeflexia and distal sensory impairment. In addition to classic CMT features, some patients were reported to have increased serum creatine kinase levels, an electrophysiologic pattern suggestive for myopathies, and pyramidal signs. Ambulation is progressively impaired, most patients are non-ambulant in the 5th decade. Nerve conduction testing shows a symmetrical, distal and proximal sensorimotor axonal neuropathy. Here we describe the first Austrian pedigree suffering from CMT2CC and give an overview on the phenotype of CMT2CC described so far.
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http://dx.doi.org/10.1016/j.nmd.2019.02.007DOI Listing
May 2019

A genetic modifier of symptom onset in Pompe disease.

EBioMedicine 2019 May 25;43:553-561. Epub 2019 Mar 25.

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, Netherlands. Electronic address:

Background: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset.

Methods: We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays.

Findings: In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing.

Interpretation: c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. FUND: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17-32) and Metakids (2016-063).
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http://dx.doi.org/10.1016/j.ebiom.2019.03.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562017PMC
May 2019

Evaluating the diagnostic utility of new line immunoassays for myositis antibodies in clinical practice: a retrospective study.

J Neurol 2019 Jun 6;266(6):1358-1366. Epub 2019 Mar 6.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Ziemssenstr. 1a, 80336, Munich, Germany.

Background: Myositis-associated antibodies (MAA) and myositis-specific antibodies (MSA) are detected in patients with idiopathic inflammatory myopathies (IIM); their role as diagnostic biomarkers is however still debated. The aim of our study was to assess the utility of MAA/MSA assessed by new line immunoassays in detecting myositis among neuromuscular patients.

Methods: We retrospectively analysed sera samples obtained from patients tested for myositis antibodies with the "Euroline: Autoimmune Inflammatory Myopathies 16Ag" and "myositis profile 3" kits (Mi-2, TIF1γ, MDA5, NXP2, SAE1, Jo-1, SRP, PL-7/12, EJ, OJ, Ro-52, Ku, PM-Scl75/100). First symptom, CK, EMG, muscle biopsy and diagnosis were also analysed. Using logistic regression analysis, two diagnostic models were built to evaluate the diagnostic power of MAA/MSA in distinguishing myositis patients from controls and other myopathies.

Results: 1229 patients were identified. 141 patients had a bioptic confirmed IIM; other diagnoses included: myopathy (n = 357), other neuromuscular diseases (n = 144) and no neuromuscular diseases (n = 587). The specificity was 95% for MSA and 89% for MAA, the sensitivity 20% and 22%, respectively. MAA showed no use in differentiating myositis patients from controls, whereas MSA had limited effect (OR = 5.165), compared to other variables as EMG (OR = 47.755) or CK > 2000 U/L (OR = 45.307). MSA were, however, the most useful parameter differentiating IIM from non-IIM patients (OR = 7.259), better than CK > 2000 U/L (OR = 4.033) and MAA (OR = 2.737).

Conclusions: Line immunoassays for myositis antibodies show high specificity but low sensitivity. Their usefulness as diagnostic biomarkers widely depends on the clinical settings. Our study suggests that MSA/MAA should be used for confirmatory and differential diagnosis rather than for screening purposes in inflammatory myopathies.
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http://dx.doi.org/10.1007/s00415-019-09266-4DOI Listing
June 2019

CRISPR-cas gene-editing as plausible treatment of neuromuscular and nucleotide-repeat-expansion diseases: A systematic review.

PLoS One 2019 22;14(2):e0212198. Epub 2019 Feb 22.

Friedrich Baur Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.

Introduction: The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (cas) is a new technology that allows easier manipulation of the genome. Its potential to edit genes opened a new door in treatment development for incurable neurological monogenic diseases (NMGDs). The aim of this systematic review was to summarise the findings on the current development of CRISPR-cas for therapeutic purposes in the most frequent NMGDs and provide critical assessment.

Methods And Data Acquisition: We searched the MEDLINE and EMBASE databases, looking for original studies on the use of CRISPR-cas to edit pathogenic variants in models of the most frequent NMGDs, until end of 2017. We included all the studies that met the following criteria: 1. Peer-reviewed study report with explicitly described experimental designs; 2. In vitro, ex vivo, or in vivo study using human or other animal biological systems (including cells, tissues, organs, organisms); 3. focusing on CRISPR as the gene-editing method of choice; and 5. featured at least one NMGD.

Results: We obtained 404 papers from MEDLINE and 513 from EMBASE. After removing the duplicates, we screened 490 papers by title and abstract and assessed them for eligibility. After reading 50 full-text papers, we finally selected 42 for the review.

Discussion: Here we give a systematic summary on the preclinical development of CRISPR-cas for therapeutic purposes in NMGDs. Furthermore, we address the clinical interpretability of the findings, giving a comprehensive overview of the current state of the art. Duchenne's muscular dystrophy (DMD) paves the way forward, with 26 out of 42 studies reporting different strategies on DMD gene editing in different models of the disease. Most of the strategies aimed for permanent exon skipping by deletion with CRISPR-cas. Successful silencing of the mHTT gene with CRISPR-cas led to successful reversal of the neurotoxic effects in the striatum of mouse models of Huntington's disease. Many other strategies have been explored, including epigenetic regulation of gene expression, in cellular and animal models of: myotonic dystrophy, Fraxile X syndrome, ataxias, and other less frequent dystrophies. Still, before even considering the clinical application of CRISPR-cas, three major bottlenecks need to be addressed: efficacy, safety, and delivery of the systems. This requires a collaborative approach in the research community, while having ethical considerations in mind.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212198PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386526PMC
November 2019

Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study.

Neuromuscul Disord 2019 03 17;29(3):167-186. Epub 2018 Dec 17.

Erasmus Medical Center, Pompe Center, Rotterdam, The Netherlands.

This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.
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http://dx.doi.org/10.1016/j.nmd.2018.12.004DOI Listing
March 2019

A systematic review on the definition of rhabdomyolysis.

J Neurol 2020 Apr 7;267(4):877-882. Epub 2019 Jan 7.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Ziemssenstr. 1a, 80336, Munich, Germany.

Background: Rhabdomyolysis (RML) is an interdisciplinary condition due to muscle cell injury followed by the release of cell components into circulation. Etiology of RML has a broad range; a serious complication is acute kidney injury (AKI). Despite its high relevance, there is no established formal definition for RML.

Objectives: A systematic review, focusing on RML definition, providing a recommendation for clinicians.

Method: Systematic literature research in PubMed and Embase (1968-07/2018).

Results: The database research presented 8136 articles in PubMed and 2151 in Embase. After screening, 614 papers were retained for statistical analysis. A retrospective study was the most used design (44%). A definition of RML was stated in 231 studies (37.6%), including a precise creatine kinase level (CK) cut-off most frequently (67.1%). In 53/231 (22.9%) studies the CK cut-off was > 5 × upper limit of normal (ULN), and in 64/231 (27.7%) studies > 1000 IU/L. Further components of definitions were elevated CK without specific thresholds, and clinical symptoms. Exclusion criteria referring to the definition of RML were established in 113 studies, including myocardial, renal, cerebral and neuromuscular characteristics.

Conclusion: At present, we recommend a clinical syndrome of acute muscle weakness, myalgia, and muscle swelling combined with a CK cut-off value of > 1000 IU/L/ or CK > 5 × ULN for the standard definition of a mild RML. Additionally measured myoglobinuria and AKI indicate a severe type of RML. Exclusion criteria as well as the chronological sequence need to be considered for a conclusive RML definition.
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http://dx.doi.org/10.1007/s00415-019-09185-4DOI Listing
April 2020

Consensus-based care recommendations for adults with myotonic dystrophy type 1.

Neurol Clin Pract 2018 Dec;8(6):507-520

Purpose Of Review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit.

Recent Findings: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations.

Summary: The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.
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http://dx.doi.org/10.1212/CPJ.0000000000000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294540PMC
December 2018

Cannabis use in myotonic dystrophy patients in Germany and USA: a pilot survey.

J Neurol 2019 Feb 15;266(2):530-532. Epub 2018 Dec 15.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Ziemssenstr. 1, 80336, Munich, Germany.

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http://dx.doi.org/10.1007/s00415-018-9159-2DOI Listing
February 2019

Safety and efficacy of short- and long-term inspiratory muscle training in late-onset Pompe disease (LOPD): a pilot study.

J Neurol 2019 Jan 14;266(1):133-147. Epub 2018 Nov 14.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians University Munich, Ziemssenstr. 1a, 80336, Munich, Germany.

Background: In patients with late-onset Pompe disease, progressive respiratory muscle weakness with predominantly diaphragmatic involvement is a frequent finding at later stages of the disease. Respiratory muscle training (RMT) is an established therapy option for patients with several neuromuscular disorders including Duchenne muscular dystrophy. Forced voluntary muscle contractions of inspiration and/or expiration muscles enhance ventilation by increasing respiratory coordination, endurance, and strength. Efficacy of RMT in LOPD is rarely examined, and the clinical studies performed are difficult to compare because of different training programs and protocols. This impedes a useful statement and recommendation about the safety and efficacy of respiratory muscle training.

Methods: We conducted a monocentric unblinded single-arm pilot study in patients with LOPD to evaluate the safety and efficacy of inspiratory muscle training (IMT). The primary objective was to determine the efficacy of a 6-week repetitive IMT with a gradual increase of inspiratory resistance, measured by MIP (maximum inspiratory pressure) in the upright position. For statistical analysis, we used an A-B-C single subject design. The 6-week training-period A was followed by a 6-week non-training period B and an optional training period of 40 weeks in period C. The total study duration for the periods A, B and C was 52 weeks. Throughout the study, spirometry assessments (FCV, FEV1) and measurements of respiratory strength (MIP, MEP) were performed at defined time points, as well as capillary oximetry and capnometry, motor function test and patient's questionnaires for quality of life and dyspnea, measured by St. George's Respiratory Questionnaire (SGRQ) and MMRC-Dyspnea scale. For the cross-sectional comparison, a paired two-sided t test, and for the longitudinal comparison, a two-sample, two-sided t test were used. When data were not normally distributed, a Wilcoxon-Mann-Whitney test was added. Finally, the annual decline in FVC and FEV1 before and after IMT was compared.

Findings: 11 subjects were included in this pilot study. Overall, IMT was well tolerated. In four subjects, a total of six adverse events related to the study procedures were noticed. Training compliance was excellent in the first weeks of training, but declined continuously in the extension period. There was a significant increase in our primary outcome measure MIP within the 6-week period of frequent IMT with a mean of 15.7% (p =0.024; d =0.402). A significant increase was also seen after week 52 by a mean of + 26.4% (mean + 13.4 cmHO, p =0.001, d =0.636). In the 6-week non-training interim-period (period B), the values remained stable, and there was no clinically meaningful decline in secondary outcome measures. The increase in MIP did not have any effect on secondary outcome measures like spirometry tests (FVC, FEV1), capillary blood gas analysis, motor function tests, patient's perceived quality of life or any significant change in dyspnea score.

Conclusions: Frequent IMT improves MIP and thereby stabilizes and decelerates the decline of the diaphragm strength. The gradual increase of inspiratory resistance is well tolerated without any increase of side effects, as long as IMT is supervised and resistance is individually adjusted to the patient's perceived grade of exhaustion. Although we could not detect a significant impact on secondary outcome measures, IMT should be offered to all LOPD patients, especially to those who demonstrate a progressive decline in respiratory muscle function or are unable to receive ERT.
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http://dx.doi.org/10.1007/s00415-018-9112-4DOI Listing
January 2019

Nuclear Envelope Transmembrane Proteins in Myotonic Dystrophy Type 1.

Front Physiol 2018 30;9:1532. Epub 2018 Oct 30.

Friedrich-Baur-Institute at the Department of Neurology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder with predominant myotonia and muscular dystrophy which is caused by CTG-repeat expansions in the gene. These repeat expansions are transcribed and the resulting mRNA accumulates RNA-binding proteins involved in splicing, resulting in a general splicing defect. We observed nuclear envelope (NE) alterations in DM1 primary myoblasts. These included invaginations of the NE as well as an altered composition of the nuclear lamina. Specifically, we investigated NE transmembrane proteins (NETs) in DM1 primary myoblasts, staining to determine if their distribution was altered compared to controls and if this could contribute to these structural defects. We also tested the expression of these NETs in muscle and how localization changes in the DM1 primary myoblasts undergoing differentiation in vitro to myotubes. We found no changes in the localization of the tested NETs, but most tended to exhibit reduced expression with increasing -repeat length. Nonetheless, the DM1 patient expression range was within the expression range of the controls. Additionally, we found a down-regulation of the possible nesprin 1 giant isoform in DM1 primary myoblasts which could contribute to the increased NE invaginations. Thus, nesprin 1 may be an interesting target for further investigation in DM1 disease pathology.
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http://dx.doi.org/10.3389/fphys.2018.01532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218431PMC
October 2018

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

EMBO J 2018 12 12;37(23). Epub 2018 Nov 12.

Friedrich Baur Institute at the Department of Neurology, Friedrich Baur Institute, University Hospital, LMU Munich, Munich, Germany

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the () mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.
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http://dx.doi.org/10.15252/embj.2018100540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276871PMC
December 2018

Pattern of myogenesis and vascular repair in early and advanced lesions of juvenile dermatomyositis.

Neuromuscul Disord 2018 12 19;28(12):973-985. Epub 2018 Sep 19.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Regenerative processes that counteract perifascicular muscle atrophy and capillary loss in juvenile dermatomyositis (JDM) are not well characterized. We aimed to analyze the pattern of myo-regeneration in relation to vascular damage and repair in muscle specimens from JDM patients. Myogenic regulatory factors that are sequentially expressed during myogenesis were studied by immunohistochemistry. Capillary density, numbers of CD34 endothelial progenitor cells within the endomysium and molecules implicated in angiogenesis were evaluated by double-immunofluorescence techniques. Myogenic regulatory factors were significantly up-regulated in JDM muscle exhibiting a different pattern in early and advanced lesions. In early lesions Pax7 satellite cells and both MyoD and Myogenin myogenic cells were moderately increased. In lesions with advanced perifascicular atrophy Pax7 satellite cells were numerous, but absence of MyoD in the context of increased Myogenin expression suggested a dysregulation of the myogenic regenerative pathway. The overall capillary density in JDM was decreased, but regions of capillary loss in advanced lesions alternated with focal increase of hyperplastic endothelial cells in early lesions. Up-regulation of endoglin in hyperplastic endothelial cells in conjunction with overexpression of TGF-β1 and VEGF suggested activation of neovascularization. Conversely, CD34 endothelial progenitor cells were not increased arguing against relevant contribution to vascular repair. Our results demonstrate substantial induction of myogenesis in JDM. While the early phase of myogenesis appears to be associated with endothelial cell activation, an altered expression of MRFs in perifascicular regions with capillary depletion suggests an impairment of myogenic differentiation that may contribute to perifascicular muscle fiber atrophy in JDM.
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http://dx.doi.org/10.1016/j.nmd.2018.09.002DOI Listing
December 2018

Editorial: Beyond Borders: Myotonic Dystrophies-A European Perception.

Front Neurol 2018 20;9:787. Epub 2018 Sep 20.

Department of Biomedical Sciences for Health University of Milan, Milan, Italy.

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http://dx.doi.org/10.3389/fneur.2018.00787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158325PMC
September 2018

Evidence of mild founder mutations causing nemaline myopathy 10 in Germany and Austria.

Neurology 2018 10 5;91(18):e1690-e1694. Epub 2018 Oct 5.

From the Department of Human Genetics (UA.S., AS.S., S.R.), Department of Pediatrics (M.B.), Medical University Innsbruck, Austria; Department of Pediatrics, Kaiser Franz Josef Hospital, Vienna, Austria (S.W.); Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University Munich, Germany (St.W., B.S.); Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität Munich, Germany (UA.S., AS.S.); Institute of Pathology, SALK-LKH and PMU (Paracelsus Medical University) Salzburg, Austria (WH.M, retired); Neuromuscular Research Department, Center for Anatomy and Cell Biology, Medical University of Vienna, Austria (RE.B., WM.S.).

Objective: To expand the clinical and genetic spectrum of nemaline myopathy 10 by a series of Austrian and German patients with a milder disease course and missense mutations in .

Methods: We characterized the clinical features and the genetic status of 4 unrelated adolescent or adult patients with nemaline myopathy.

Results: The 4 patients showed a relatively mild disease course. They all have survived into adulthood, 3 of 4 have remained ambulatory, and all showed marked facial weakness. Muscle biopsy specimens gave evidence of nemaline bodies. All patients were unrelated but originated from Austria (Tyrol and Upper Austria) and Southern Germany (Bavaria). All patients carried the missense variant c.1648C>T, p.(Leu550Phe) in the gene, either on both alleles or with another missense variant (c.1004A>G, p.Gln335Arg). Both variants were not reported previously.

Conclusions: In 2014, a severe form of congenital nemaline myopathy caused by disrupting mutations in was identified and denoted as NEM10. Unlike the previously reported patients, who had a severe clinical picture with a substantial risk of early death, our patients showed a relatively mild disease course. As the missense variant c.1648C>T is located further downstream compared to all previously published mutations, it might be associated with higher protein expression compared to the reported loss-of-function mutations. The apparent clusters of 2 mild mutations in Germany and Austria in 4 unrelated families may be explained by a founder effect.
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http://dx.doi.org/10.1212/WNL.0000000000006428DOI Listing
October 2018

How to Interpret Abnormal Findings of Spirometry and Manometry in Myotonic Dystrophies?

J Neuromuscul Dis 2018 ;5(4):451-459

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University of Munich, Germany.

Background/aim: Pulmonary function tests are used for screening respiratory insufficiency in patients with myotonic dystrophy (DM). We analysed the agreement between two different approaches in assessment of abnormal findings of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP), in DM patients.

Methods: We used Cohen's κ- and Bangdiwala's B- statistic to compare the agreement between different cut-off values recommended by experts (ENMC) and the cut-off values based on the reference range (RR). We further analysed their sensitivity (Sn) and specificity (Sp) in detecting symptoms associated with respiratory insufficiency.

Results: The observed agreement was: 1) for FVC: κ= -0.002, B = 0.406; 2) for FEV1: κ= 0.944, B = 0.946; 3) for MIP: κ= 0.625, B = 0.674; and 4) for MEP: κ= 0.241, B = 0.373. Overall, RR cut-off values showed higher sensitivity, whereas the ENMC values showed higher specificity in detecting symptoms of respiratory involvement.

Conclusions: The two approaches showed perfect agreement in assessment of FEV1, substantial agreement for MIP, and weak agreement for FVC and MEP. RR is an established method of assessment for spirometry and should be favoured because it takes variability within the population into account. Further development and validation of regression equations for RR calculations of predicted maximal respiratory pressures, with corresponding lower limits of normal, is required.The B statistic is more robust in assessing agreement between two diagnostic methods, resolving the issue of the κ paradox.
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http://dx.doi.org/10.3233/JND-180331DOI Listing
January 2019

[Anti-IgLON5 syndrome - what is our current understanding?]

Fortschr Neurol Psychiatr 2018 09 26;86(9):559-565. Epub 2018 Sep 26.

Friedrich-Baur-Institut, Klinikum der Universität München.

In 2014, antibodies against the cell surface protein IgLON5 were first described in patients with a complex neurological syndrome of sleep disturbances and movement disorders. Since then, the clinical spectrum has steadily expanded and now includes brainstem syndromes, autonomic and neuropsychiatric disorders and, more rarely, peripheral symptoms such as fasciculations and neuromyotonia. Anti-IgLON5 antibodies are thought to cause neurodegeneration in specific CNS regions with tau deposits ("tauopathy"). There is a clear association with the HLA alleles DQB1*05:01 and DRB1*10:01. Anti-IgLON5 antibodies have been identified with a prevalence of 12 in 150,000 patients per year, but the estimated number of unreported patients might be much higher. Current therapeutic options include immunomodulation and immunosuppression; however, the clinical response remains poor and the mortality continues to be high. The unsatisfactory response seems to be related to a pathogenic mechanism that is still enigmatic, and as well to the delayed start of treatment in most cases. This review summarizes the current opinion on the pathogenic mechanism, clinical presentation and recommendations for diagnostics and therapy.
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http://dx.doi.org/10.1055/a-0665-4593DOI Listing
September 2018

[Dystrophic and non-dystrophic myotonias].

Fortschr Neurol Psychiatr 2018 09 24;86(9):575-583. Epub 2018 Sep 24.

Friedrich-Baur-Institut, Neurologische Klinik, Ludwig Maximilian Universität München.

Myotonic syndromes are rare neuromuscular diseases characterized by the clinical or neurophysiological detection of myotonia. The genetic defects involve primarily or secondarily the muscular isoforms of the ion channels. The channel dysfunction consecutively leads to a hyper-excitability of the muscle membrane and the clinical symptom myotonia. Two forms of dystrophic myotonic diseases are currently known: the myotonic dystrophy type 1 (DM1) and the myotonic dystrophy type 2 (DM2). They are multisystemic diseases clinically characterized by a combination of myotonia and other muscular symptoms (muscle weakness, wasting and myalgia) together with the involvement of other organs and systems (cataract, diabetes, heart diseases, hormone dysfunctions). The non-dystrophic myotonic diseases are caused by mutations affecting either the chloride ion channels or the sodium ion channels. The clinical picture is dominated by the presence of myotonia and other minor muscular complaints as mild episodic weakness and muscle hypertrophy. The differential diagnosis among the myotonic syndromes is extremely challenging leading to a significant diagnostic delay. This review will update on the main clinical, diagnostic and therapeutic aspects of myotonic syndromes to guide general neurologists through an earlier diagnosis and better management.
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http://dx.doi.org/10.1055/a-0635-8285DOI Listing
September 2018

[Myasthenia gravis: current status of antibody diagnostics and aspects on refractory myasthenia gravis].

Fortschr Neurol Psychiatr 2018 09 24;86(9):551-558. Epub 2018 Sep 24.

Friedrich-Baur-Institut, Klinikum der Universität München.

Acquired myasthenia gravis (MG) is an autoimmune disease that leads to fluctuating muscle weakness and fatigue, caused by circulating antibodies against different structures of the neuromuscular junction. In most patients, antibodies against acetylcholine receptor (AChR) can be detected. In a smaller proportion of patients with and without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin, cortactin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. With current therapy, most patients achieve a stable condition with good quality of life and normal life expectancy. Nevertheless, 10 to 15 % of patients fail to respond ad equately to current therapies and are defined as refractory myasthenia gravis. Their clinical course is characterized by recurrent episodes of severe, acute deterioration, which sometimes appear life threatening. This article gives an overview of the current state of myasthenic antibody diagnostics and recommended treatment of refractory myasthenia gravis.
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http://dx.doi.org/10.1055/a-0624-9397DOI Listing
September 2018

Sarcopenia - Endocrinological and Neurological Aspects.

Exp Clin Endocrinol Diabetes 2019 Jan 10;127(1):8-22. Epub 2018 Sep 10.

Department of Medicine IV, University Hospital, LMU Munich, Germany.

Sarcopenia in geriatric patients is often associated with or even caused by changes of the endocrine and nervous system. The multifactorial pathogenesis of sarcopenia and additional multimorbidity in geriatric patients makes it difficult to study distinct pathogenic pathways leading to sarcopenia. Patients suffering from diabetes, Cushing's syndrome, chronic kidney disease, Klinefelter's syndrome or motor neuron diseases, such as amyotrophic lateral sclerosis for example are known to have impaired muscle property and reduced physical performance. These patients are typically younger and suffer from conditions caused by a known molecular disease mechanism and a peculiar sarcopenic phenotype. Therefore, these sequelae can serve as prototypic disease models to study isolated endocrinological and neurodegenerative causes for sarcopenia. This review focuses on diseases whose etiopathogenesis of muscle impairment is known. The idea is to use these diseases as proof of principles to develop a classification algorithm of sarcopenia in the elderly to make a more mechanism-oriented therapy be possible.
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http://dx.doi.org/10.1055/a-0672-1007DOI Listing
January 2019

Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease.

Orphanet J Rare Dis 2018 09 5;13(1):155. Epub 2018 Sep 5.

Department of Neuropediatrics and Muscle Disorders, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania).

Results: The registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact.

Conclusions: The community should consider how to maximise this collective resource in future therapeutic programmes.
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http://dx.doi.org/10.1186/s13023-018-0889-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126043PMC
September 2018