Target formation in muscle fibres indicates reinnervation - A proteomic study in muscle samples from peripheral neuropathies.

Aims: Target skeletal muscle fibres - defined by different concentric areas in oxidative enzyme staining - can occur in patients with neurogenic muscular atrophy. Here, we used our established hypothesis-free proteomic approach with the aim of deciphering the protein composition of targets. We also searched for potential novel interactions between target proteins.

FLNC-Associated Myofibrillar Myopathy: New Clinical, Functional, and Proteomic Data.

Objective: To determine whether a new indel mutation in the dimerization domain of filamin C (FLNc) causes a hereditary myopathy with protein aggregation in muscle fibers, we clinically and molecularly studied a German family with autosomal dominant myofibrillar myopathy (MFM).

Methods: We performed mutational analysis in 3 generations, muscle histopathology, and proteomic studies of IM protein aggregates. Functional consequences of the mutation were investigated with interaction and transfection studies and biophysics molecular analysis.

Diffusion tensor imaging reveals changes in non-fat infiltrated muscles in late onset Pompe disease.

MRI is a helpful tool for monitoring disease progression in late-onset Pompe disease (LOPD). Our study aimed to evaluate if muscle diffusion tensor imaging (mDTI) shows alterations in muscles of LOPD patients with <10% fat-fraction. We evaluated 6 thigh and 7 calf muscles (both legs) of 18 LOPD and 29 healthy controls (HC) with muscle diffusion tensor imaging (mDTI), T1w, and mDixonquant sequences in a 3T MRI scanner.

A metastable subproteome underlies inclusion formation in muscle proteinopathies.

Protein aggregation is a pathological feature of neurodegenerative disorders. We previously demonstrated that protein inclusions in the brain are composed of supersaturated proteins, which are abundant and aggregation-prone, and form a metastable subproteome. It is not yet clear, however, whether this phenomenon is also associated with non-neuronal protein conformational disorders.

Chaperones in sporadic inclusion body myositis-Validation of proteomic data.

Introduction: Sporadic inclusion body myositis (sIBM) is characterized by myopathological features including rimmed vacuoles (RVs) and proteins associated with protein aggregation, autophagy, and inflammation. Previous proteomic studies of RV areas revealed an overrepresentation of several chaperones and subunits of the T-complex protein 1 (TCP-1), which is involved in prevention of protein aggregation.

Methods: To validate our proteomic findings, immunofluorescence analyses of selected chaperones and quantitative Western blot analysis of TCP-1 proteins were performed in five sIBM patients and five healthy controls.

Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function.

Myopathies encompass a wide variety of acquired and hereditary disorders. The pathomechanisms include structural and functional changes affecting, e.g.

Diffusion tensor imaging of the human calf: Variation of inter- and intramuscle-specific diffusion parameters.

Purpose: To investigate to what extent inter- and intramuscular variations of diffusion parameters of human calf muscles can be explained by age, gender, muscle location, and body mass index (BMI) in a specific age group (20-35 years).

Materials And Methods: Whole calf muscles of 18 healthy volunteers were evaluated. Magnetic resonance imaging (MRI) was performed using a 3T scanner and a 16-channel Torso XL coil.

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis.

Objective: Sporadic inclusion body myositis (sIBM) pathogenesis is unknown; however, rimmed vacuoles (RVs) are a constant feature. We propose to identify proteins that accumulate within RVs.

Methods: RVs and intact myofibers were laser microdissected from skeletal muscle of 18 sIBM patients and analyzed by a sensitive mass spectrometry approach using label-free spectral count-based relative protein quantification.

Widening the spectrum of filamin-C myopathy: Predominantly proximal myopathy due to the p.A193T mutation in the actin-binding domain of FLNC.

We report three patients with a predominantly proximal myopathy due to p.A193T mutation in the actin-binding domain of FLNC, which has so far only been associated with a distal myopathy. They presented with a late onset myopathy characterized by predominant limb-girdle and proximal weakness.

Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement.

Objective: To expand the spectrum of bicaudal D, Drosophila, homologue 2 (BICD2) gene-related diseases, which so far includes autosomal dominant spinal muscular atrophy with lower extremity predominance 2 and hereditary spastic paraplegia due to mutations in the BICD2 gene.

Methods: We analyzed 2 independent German families with clinical, genetic, and muscle MRI studies. In both index patients, muscle histopathologic studies were performed.

Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue.

Secondary mitochondrial dysfunction is a feature in a wide variety of human protein aggregate diseases caused by mutations in different proteins, both in the central nervous system and in striated muscle. The functional relationship between the expression of a mutated protein and mitochondrial dysfunction is largely unknown. In particular, the mechanism how this dysfunction drives the disease process is still elusive.

New aspects of myofibrillar myopathies.

Purpose Of Review: Myofibrillar myopathies (MFMs) are hereditary muscle disorders characterized by distinct histopathological features. This review provides an overview of recent research with respect to new disease genes, clinical phenotypes, insights into pathomechanisms and therapeutic strategies.

Recent Findings: Beyond the known disease genes DES, FLNC, MYOT, CRYAB, ZASP, BAG3, FHL1 and TTN, mutations in PLEC, ACTA1, HSPB8 and DNAJB6 have also been associated with a MFM phenotype.

Muscle imaging data in late-onset Pompe disease reveal a correlation between the pre-existing degree of lipomatous muscle alterations and the efficacy of long-term enzyme replacement therapy.

Background: Late-onset Pompe disease (LOPD) is a metabolic myopathy caused by mutations in GAA and characterized by proximal muscle weakness and respiratory insufficiency. There is evidence from clinical studies that enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase improves motor performance and respiratory function in LOPD.

Objective: We analyzed quantitative muscle MRI data of lower limbs to evaluate the effects of long-term ERT on muscle parameters.

Myofibrillar instability exacerbated by acute exercise in filaminopathy.

Filamin C (FLNC) mutations in humans cause myofibrillar myopathy (MFM) and cardiomyopathy, characterized by protein aggregation and myofibrillar degeneration. We generated the first patient-mimicking knock-in mouse harbouring the most common disease-causing filamin C mutation (p.W2710X).

Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum.

Homozygosity for the common Caucasian splice site mutation c.-32-13T>G in intron 1 of the GAA gene is rather rare in Pompe patients. We report on the clinical, biochemical, morphological, muscle imaging, and genetic findings of six adult Pompe patients from five unrelated families with the c.

Magnetic resonance imaging pattern recognition in sporadic inclusion-body myositis.

Introduction: In sporadic inclusion-body myositis (IBM), additional tools are needed to confirm the diagnosis, particularly in clinically atypical or pathologically unproven patients. The aims of this study were to define the pattern of muscle MRI in IBM and to assess its accuracy in differentiating IBM from other myopathies that overlap with it clinically or pathologically.

Methods: Blind assessment was done on the scans of 17 definite IBM, 2 possible IBM, and 118 patients with other myopathies.

Two novel nebulin variants in an adult patient with congenital nemaline myopathy.

Congenital myopathies are clinically and genetically heterogeneous disorders, which often remain genetically undiagnosed for many years. Here we present a 40-year old patient with an almost lifelong history of a congenital myopathy of unknown cause. Muscle biopsy in childhood revealed mild myopathic features and rods.

Th2-M2 immunity in lesions of muscular sarcoidosis and macrophagic myofasciitis.

Objective: To analyse the paradox of a lack of giant cell formation and fibrosis in chronic lesions of macrophagic myofasciitis (MMF) in comparison with muscular sarcoidosis (MuS).

Methods: Inflammatory lesions and contiguous muscle regions from biopsy samples of 10 patients with MuS and 10 patients with MMF were cut out by laser microdissection. Mediators of the T helper cell (Th)1 inducing classical macrophage activation (e.

ATOH8: a novel marker in human muscle fiber regeneration.

Regenerating muscle fibers emerge from quiescent satellite cells, which differentiate into mature multinuclear myofibers upon activation. It has recently been found that ATOH8, a bHLH transcription factor, is regulated during myogenic differentiation. In this study, expression and localization of ATOH8, the other well-described regeneration markers, vimentin, nestin and neonatal myosin, and the satellite cell marker Pax7 were analyzed on protein level in human myopathy samples by immunofluorescence studies.

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.

Urge incontinence and gastrointestinal symptoms in adult patients with pompe disease: a cross-sectional survey.

Objective: To determine the frequency and impact of gastrointestinal symptoms, and bowel and urinary incontinence, as this is currently unknown in adults with Pompe disease.

Methods: Adult German Pompe patients and age- and gender-matched controls were asked about symptoms in the upper and lower intestinal tract as well as urinary incontinence using the Gastrointestinal Symptoms Questionnaire and the International Consultation on Incontinence Questionnaires for Bowel Symptoms and Urinary Incontinence.

Results: The overall response rate was 78%; 57 patients and 57 controls participated.

Pregnancy and delivery in women with Pompe disease.

Background: The obstetric risk in patients with Pompe disease (glycogen storage disease type II), a mainly skeletal muscle disorder, is unknown.

Methods: The clinical course and the outcome of pregnancy, and the effect of pregnancy on disease manifestations or clinical signs and symptoms in Pompe disease were analyzed retrospectively using a questionnaire. Participating women with Pompe disease were recruited by the German and the UK sections of the International Pompe Association, and by centers associated within the German Pompe Group.

Mitochondrial abnormalities in myofibrillar myopathies.

Histological mitochondrial changes are generally found to be associated with late onset myofibrillar myopathies (MFMs). How these changes contribute to the pathogenesis of MFMs is unknown. Mitochondrial changes, including COX-deficient fibers (n = 8), biochemical activities of respiratory chain complexes (n = 7), and multiple mtDNA deletions by long-range PCR (n = 9) were examined in patients with genetically confirmed MFMs [MYOT (n = 2), DES (n = 1), ZASP (n = 2), FLNC (n = 4)] and compared with age and sex matched normal controls (n = 27) and patients with a mitochondrial disorder with multiple mtDNA deletions due to nuclear genetic defects (n = 8).