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.
Glycogen storage disease type 2/Pompe disease is a progressive muscle disorder with a wide range of phenotypic presentations, caused by an inherited deficiency of acid alpha-glucosidase. Since 2004 ...only a limited number of patients have been treated with recombinant human alpha-glucosidase from rabbit milk whereas since 2006 enzyme replacement therapy (ERT) with alglucosidase alfa has been licensed for the treatment of Pompe disease. This systematic review evaluates the clinical efficacy and safety of alglucosidase alfa treatment of juvenile and adult patients with late-onset Pompe disease (LOPD). Studies of alglucosidase alfa treatment of LOPD patients—published up to January 2012—were identified by electronic searching of the EMBASE and MEDLINE databases, and manual searching of the reference lists. Data on ERT outcomes were extracted from selected papers and analyzed descriptively. No statistical analysis was performed owing to data heterogeneity. Twenty-one studies containing clinical data from 368 LOPD patients were analyzed. Overall, at least two-thirds of patients were stabilized or had improved creatine kinase levels and muscular and/or respiratory function following treatment with alglucosidase alfa. ERT was well tolerated; most adverse events were mild or moderate infusion-related reactions. In conclusion, alglucosidase alfa treatment is effective and well tolerated and attenuates progression of LOPD in most patients. Further research is required to investigate factors such as age at diagnosis, phenotypic presentation, and genotypic characteristics, identification of which may enable better clinical and therapeutic management of LOPD patients.
Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive disorder with heterogenous phenotypic manifestations and genetic background. We describe seven patients from five independent families with ...an isolated myopathic phenotype of CoQ10 deficiency. The clinical, histological and biochemical presentation of our patients was very homogenous. All patients presented with exercise intolerance, fatigue, proximal myopathy and high serum CK. Muscle histology showed lipid accumulation and subtle signs of mitochondrial myopathy. Biochemical measurement of muscle homogenates showed severely decreased activities of respiratory chain complexes I and II + III, while complex IV (COX) was moderately decreased. CoQ10 was significantly decreased in the skeletal muscle of all patients. Tandem mass spectrometry detected multiple acyl-CoA deficiency, leading to the analysis of the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, previously shown to result in another metabolic disorder, glutaric aciduria type II (GAII). All of our patients carried autosomal recessive mutations in ETFDH, suggesting that ETFDH deficiency leads to a secondary CoQ10 deficiency. Our results indicate that the late-onset form of GAII and the myopathic form of CoQ10 deficiency are allelic diseases. Since this condition is treatable, correct diagnosis is of the utmost importance and should be considered both in children and in adults. We suggest to give patients both CoQ10 and riboflavin supplementation, especially for long-term treatment.
Introduction
Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in
CLCN1
and
SCN4A
. The study aimed to describe the clinical and genetic spectrum of NDM in a large German ...cohort.
Methods
We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy.
Results
70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient’s perceived efficacy were mexiletine and lamotrigine.
Conclusion
This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) represent the most frequent multisystemic muscular dystrophies in adulthood. They are progressive, autosomal dominant diseases caused by an abnormal ...expansion of an unstable nucleotide repeat located in the non-coding region of their respective genes DMPK for DM1 and CNBP in DM2. Clinically, these multisystemic disorders are characterized by a high variability of muscular and extramuscular symptoms, often causing a delay in diagnosis. For both subtypes, many symptoms overlap, but some differences allow their clinical distinction. This article highlights the clinical core features of myotonic dystrophies, thus facilitating their early recognition and diagnosis. Particular attention will be given to signs and symptoms of muscular involvement, to issues related to respiratory impairment, and to the multiorgan involvement. This article is part of a Special Issue entitled "Beyond Borders: Myotonic Dystrophies-A European Perception."
Myofibrillar myopathies (MFMs) are histopathologically characterized by desmin‐positive protein aggregates and myofibrillar degeneration. Because of the marked phenotypic and pathomorphological ...variability, establishing the diagnosis of MFM can be a challenging task. While MFMs are partly caused by mutations in genes encoding for extramyofibrillar proteins (desmin, αB‐crystallin, plectin) or myofibrillar proteins (myotilin, Z‐band alternatively spliced PDZ‐containing protein, filamin C, Bcl‐2‐associated athanogene‐3, four‐and‐a‐half LIM domain 1), a large number of these diseases are caused by still unresolved gene defects. Although recent years have brought new insight into the pathogenesis of MFMs, the precise molecular pathways and sequential steps that lead from an individual gene defect to progressive muscle damage are still unclear. This review focuses on the clinical and myopathological aspects of genetically defined MFMs, and shall provide a diagnostic guide for this numerically significant group of protein aggregate myopathies.
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.
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.
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.
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.
Background
The symptomatic treatment of myotonia and myalgia in patients with dystrophic and non-dystrophic myotonias is often not satisfactory. Some patients anecdotally report symptoms’ relief ...through consumption of cannabis.
Methods
A combination of cannabidiol and tetrahydrocannabinol (CBD/THC) was prescribed as compassionate use to six patients (four patients with myotonic dystrophy types 1 and 2, and 2 patients with CLCN1-myotonia) with therapy-resistant myotonia and myalgia. CBD/THC oil was administered on a low dose in the first 2 weeks and adjusted to a higher dose in the following 2 weeks. Myotonia behaviour scale (MBS), hand-opening time, visual analogue scales (VAS) for myalgia and myotonia, and fatigue and daytime sleepiness severity scale (FSS, ESS) were performed weekly to monitor treatment response.
Results
All patients reported an improvement of myotonia especially in weeks 3 and 4 of treatment: MBS improved of at least 2 points in all patients, the hand-opening time variously improved in 5 out of 6 patients. Chronic myalgia was reported by both DM2 patients at baseline, one of them experienced a significant improvement of myalgia under treatment. Some gastrointestinal complaints, as abdominal pain and diarrhoea, improved in 3 patients; however, 4 out of 6 patients reported new-onset constipation. No other relevant side effect was noticed.
Conclusions
These first empirical results suggest a potentially beneficial role of CBD/THC in alleviating myotonia and should encourage further research in this field including a randomized-controlled trial on larger cohorts.
Mutations in the valosin-containing protein (VCP, p97) gene on chromosome 9p13–p12 cause a late-onset form of autosomal dominant inclusion body myopathy associated with Paget disease of the bone and ...frontotemporal dementia (IBMPFD). We report on the pathological consequences of three heterozygous VCP (R93C, R155H, R155C) mutations on human striated muscle. IBMPFD skeletal muscle pathology is characterized by degenerative changes and filamentous VCP- and ubiquitin-positive cytoplasmic and nuclear protein aggregates. Furthermore, this is the first report demonstrating that mutant VCP leads to a novel form of dilatative cardiomyopathy with inclusion bodies. In contrast to post-mitotic striated muscle cells and neurons of IBMPFD patients, evidence of protein aggregate pathology was not detected in primary IBMPFD myoblasts or in transient and stable transfected cells using wild-type-VCP and R93C-, R155H-, R155C-VCP mutants. Glutathione S-transferase pull-down experiments showed that all three VCP mutations do not affect the binding to Ufd1, Npl4 and ataxin-3. Structural analysis demonstrated that R93 and R155 are both surface-accessible residues located in the centre of cavities that may enable ligand-binding. Mutations at R93 and R155 are predicted to induce changes in the tertiary structure of the VCP protein. The search for putative ligands to the R93 and R155 cavities resulted in the identification of cyclic sugar compounds with high binding scores. The latter findings provide a novel link to VCP carbohydrate interactions in the complex pathology of IBMPFD.
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