Congenital Muscle Research Articles

Clinical Efficacy of Real-Time Sonoelastography for the Follow-Up of Congenital Sternocleidomastoid Muscle Torticollis.

PurposeTo evaluate the clinical efficacy of real-time sonoelastography (RTS) for the follow-up of congenital muscular torticollis, based on measurements of muscle elasticity.Materials and MethodsThirty-four infants (23 male, 11 female) with congenital sternocleidomastoid (SCM) muscle torticollis underwent ultrasonography and elastography between November 2012 and December 2014. We evaluated the thickness, morphology (mass-like, fusiform, or overall thickened shape), and echogenicity of the SCM muscle on grayscale images and color patterns (homogeneous blue, mixed green < 50% and ≥ 50%, and green to red) on elastography. Strain ratios were measured using Q-lab software. A clinician classified the degree of neck rotation and side flexion deficits using a 5-point grade system based on angles of neck rotation and side flexion. Correlations between the ultrasonography and clinical findings were evaluated by statistical analysis.ResultsTwenty-two infants had right and 12 had left SCM torticollis, respectively. Linear regression analysis showed that involved/contralateral SCM thickness differences, morphology, elasticity color scores, and strain ratios of the affected SCM muscles were significantly correlated with neck rotation and side flexion deficit scores (p < 0.05). The elasticity color score of the affected SCM muscle was the most significant factor.ConclusionRTS might provide a reliable means for evaluating and monitoring congenital muscular torticollis.

ASC-1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy.

Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232.

Advanced Coherent System For Predicting Cardiac Risks using Data Mining Techniques

Considering health care and medical industry related data there are millions or tons of data which contains numerous hidden information. This information can be mined through which we can make effective decisions in their related industry. There are numerous far advanced methods and techniques in mining and determining the useful decisions using the retrieved useful information. Such an effective system called Coherent cardiac risk prediction system (CCRPS) is developed using neural networks in early detection or prediction of various risk level in cardiac disease. This work employs a multilayer perception neural network with back propagation as the training algorithm. This system aims in predicting the likelihood of patients getting disease related to cardiac such as CHD, a prior heart attack, uncontrolled hypertension, abnormal heart valves, congenital heart disease (heart defects present at birth) and heart muscle disease. The system uses a total of twenty-one medical related parameters such as age, sex, chest pain type, resting blood pressure (in mm Hg on admission to the hospital), serum cholesterol in mg/dl, Smoking, stress etc for prediction purpose. It enables or activated the important knowledge such as how the medical factors related to cardiac disease and patterns and the relationship to be established. Through this system we obtain effective results that have crafted its own diagnostic method or way to predict the risk level measurement of cardiac disease.

Adult MTM1 -related myopathy carriers

To better characterize adult myotubularin 1 (MTM1)-related myopathy carriers and recommend a phenotypic classification. This cohort study was performed at the NIH Clinical Center. Participants were required to carry a confirmed MTM1 mutation and were recruited via the Congenital Muscle Disease International Registry (n = 8), a traveling local clinic of the Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH and Cure CMD (n = 1), and direct physician referral (n = 1). Neuromuscular examinations, muscle MRI, dynamic breathing MRI, cardiac MRI, pulmonary function tests (PFTs), physical therapy assessments including the Motor Function Measure 32 (MFM-32) scale, and X chromosome inactivation (XCI) studies were performed. Phenotypic categories were proposed based on ambulatory status and muscle weakness. Carriers were categorized as severe (nonambulatory; n = 1), moderate (minimal independent ambulation/assisted ambulation; n = 3), mild (independent ambulation but with evidence of muscle weakness; n = 4), and nonmanifesting (no evidence of muscle weakness; n = 2). Carriers with more severe muscle weakness exhibited greater degrees of respiratory insufficiency and abnormal signal on muscle imaging. Skeletal asymmetries were evident in both manifesting and nonmanifesting carriers. Skewed XCI did not explain phenotypic severity. This work illustrates the phenotypic range of MTM1-related myopathy carriers in adulthood and recommends a phenotypic classification. This classification, defined by ambulatory status and muscle weakness, is supported by muscle MRI, PFT, and MFM-32 scale composite score findings, which may serve as markers of disease progression and outcome measures in future gene therapy or other clinical trials.

MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype–phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

TAZ and myostatin involved in muscle atrophy of congenital neurogenic clubfoot

BACKGROUNDMuscular atrophy is the basic defect of neurogenic clubfoot. Muscle atrophy of clubfoot needs more scientific and reasonable imaging measurement parameters to evaluate. The Hippo pathway and myostatin pathway may be directly correlated in myogenesis. In this study, we will use congenital neurogenic clubfoot muscle atrophy model to verify in vivo. Further, the antagonistic mechanism of TAZ on myostatin was studied in the C2C12 cell differentiation model.AIMTo identify muscle atrophy in fetal neurogenic clubfoot by ultrasound imaging and detect the expression of TAZ and myostatin in gastrocnemius muscle. To elucidate the possible mechanisms by which TAZ antagonizes myostatin-induced atrophy in an in vitro cell model.METHODSMuscle atrophy in eight cases of fetal unilateral clubfoot with nervous system abnormalities was identified by 2D and 3D ultrasound. Western blotting and immunostaining were performed to detect expression of myostatin and TAZ. TAZ overexpression in C2C12 myotubes and the expression of associated proteins were analyzed by western blotting.RESULTSThe maximum cross-sectional area of the fetal clubfoot on the varus side was reduced compared to the contralateral side. Myostatin was elevated in the atrophied gastrocnemius muscle, while TAZ expression was decreased. They were negatively correlated. TAZ overexpression reversed the diameter reduction of the myotube, downregulated phosphorylated Akt, and increased the expression of forkhead box O4 induced by myostatin.CONCLUSIONUltrasound can detect muscle atrophy of fetal clubfoot. TAZ and myostatin are involved in the pathological process of neurogenic clubfoot muscle atrophy. TAZ antagonizes myostatin-induced myotube atrophy, potentially through regulation of the Akt/forkhead box O4 signaling pathway.

In-depth characterization of congenital Zika syndrome in immunocompetent mice: Antibody-dependent enhancement and an antiviral peptide therapy

BackgroundZika virus (ZIKV) infection during pregnancy may cause major congenital defects, including microcephaly, ocular, articular and muscle abnormalities, which are collectively defined as Congenital Zika Syndrome. Here, we performed an in-depth characterization of the effects of congenital ZIKV infection (CZI) in immunocompetent mice. MethodsPregnant dams were inoculated with ZIKV on embryonic day 5.5 in the presence or absence of a sub-neutralizing dose of a pan-flavivirus monoclonal antibody (4G2) to evaluate the potential role of antibody-dependent enhancement phenomenon (ADE) during short and long outcomes of CZI. FindingsZIKV infection induced maternal immune activation (MIA), which was associated with occurrence of foetal abnormalities and death. Therapeutic administration of AH-D antiviral peptide during the early stages of pregnancy prevented ZIKV replication and death of offspring. In the post-natal period, CZI was associated with a decrease in whole brain volume, ophthalmologic abnormalities, changes in testicular morphology, and disruption in bone microarchitecture. Some alterations were enhanced in the presence of 4G2 antibody. InterpretationOur results reveal that early maternal ZIKV infection causes several birth defects in immunocompetent mice, which can be potentiated by ADE phenomenon and are associated with MIA. Additionally, antiviral treatment with AH-D peptide may be beneficial during early maternal ZIKV infection. FundThis work was supported by the Brazilian National Science Council (CNPq, Brazil), Minas Gerais Foundation for Science (FAPEMIG), Funding Authority for Studies and Projects (FINEP), Coordination of Superior Level Staff Improvement (CAPES), National Research Foundation of Singapore and Centre for Precision Biology at Nanyang Technological University.

Biomimetic Scaffolds in Skeletal Muscle Regeneration.

Skeletal muscle tissue has inherent capacity for regeneration in response to minor injuries. However, in the case of severe trauma, tumor ablations, or in congenital muscle defects, these myopathies can cause irreversible loss of muscle mass and function, a condition referred to as volumetric muscle loss (VML). The natural muscle repair mechanisms are overwhelmed, prompting the search for new muscle regenerative strategies, such as using biomaterials that can provide regenerative signals to either transplanted or host muscle cells. Recent studies involve the use of suitable biomaterials which may be utilized as a template to guide tissue reorganization and ultimately provide optimum micro-environmental conditions to cells. These strategies range from approaches that utilize biomaterials alone to those that combine materials with exogenous growth factors, and ex vivo cultured cells. A number of scaffold materials have been used in the development of grafts to treat VML. In this brief review, we outline the natural skeletal regeneration process, available treatments used in the clinic for muscle injury and promising tissue bioengineering and regenerative approaches for muscle loss treatment.

The Effects of Chronic Electrical Stimulation Evaluation Functional and Electrical Properties of Muscle in a Small Group of Patients with Congenital Muscle Disorders

BackgroundIn the case of Congenital Muscle Disorders like Myotonic Dystrophy type 1 (DM1) the rehabilitative interventions have always been aimed at muscle strengthening, increasing of fatigue resistance and improving of aerobic metabolism efficiency whereas the electrical membrane fault has always been addressed pharmacologically. Neuromuscular electrical stimulation (NMES) is a useful therapeutic tool in sport medicine and in the rehabilitation of many clinical conditions characterized by motor impairment such as stroke, cerebral palsy and spinal cord injury.The aim of our pilot study was to evaluate the effects of chronic electrical stimulation both on functional and electrical properties of muscle in a small group of patients with condenital muscle disorders.Materials and methodsfive DM1 patients and one patient with Congenital Myotonia (CM) performed a home electrical stimulation of the tibialis anterior muscle lasting 15 days with a frequency of two daily sessions of 60 minutes each. Muscle strength was assessed according to the MRC scale (Medical Research Council) and functional tests (10 Meter Walking Test, 6 Minutes Walking Test – MWT and Timed Up and Go Test – TUG test) were performed. We analyzed the average rectified value of sEMG signal amplitude (ARV) to characterize the sarcolemmal excitability.ResultsAfter the treatment an increase of muscle strength in those DM1 patients with a mild strength deficit was observed. In all subjects an improvement of 10 MWT was recorded. Five patients improved their performance in the 6 MWT. In TUG test 4 out of 6 patients showed a slight reduction in execution time. All patients reported a subjective improvement when walking. A complete recovery of the normal increasing ARV curve was observed in 4 out of 5 DM1 patients; the CM patient didn't show modification of the ARV pattern.ConclusionsNMES determined a clear‐cut improvement of both the muscular weakness and the sarcolemmal excitability alteration in our small group of DM1 patients. Therefore this rehabilitative approach, if confirmed by further extensive studies, could be considered early in the management of muscular impairment in these patients. An attractive hypothesis to explain our encouraging result could be represented by a functional inhibition of small conductance calcium‐activated potassium channels expressed 3 (SK3) in muscle of DM1 subjects.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The impact of Megf10/Drpr gain‐of‐function on muscle development in Drosophila

Recessive mutations in multiple epidermal growth factor-like domains 10 (MEGF10) underlie a rare congenital muscle disease known as MEGF10 myopathy. MEGF10 and its Drosophila homolog Draper (Drpr) are transmembrane receptors expressed in muscle and glia. Drpr deficiency is known to result in muscle abnormalities in flies. In the current study, flies that ubiquitously overexpress Drpr, or mouse Megf10, display developmental arrest. The phenotype is reproduced with overexpression in muscle, but not in other tissues, and with overexpression during intermediate stages of myogenesis, but not in myoblasts. We find that tubular muscle subtypes are particularly sensitive to Megf10/Drpr overexpression. Complementary genetic analyses show that Megf10/Drpr and Notch may interact to regulate myogenesis. Our findings provide a basis for investigating MEGF10 in muscle development using Drosophila.

The Use of Muscle Ultrasound in the Diagnosis and Differential Diagnosis of Congenital Disorders of Muscle in the Age of Next Generation Genetics

Congenital disorders of muscle most importantly encompass the congenital muscular dystrophies as well as the congenital myopathies. With the broader availability of next generation genetic testing there has been an expansion of phenotypes and genotypes, while the very large genes such as titin, nebulin, and RYR1 have also become accessible to complete sequencing. This development has had considerable diagnostic power while at the same time also creating challenges in the interpretation of the many variants of uncertain significance that will need a solid clinical plausibility test, based on "deep" phenotyping, taking into account clinical, extended clinical, histological, and physiological data. One tool in this context is imaging of skeletal muscle, including by ultrasound. Muscle ultrasound is a useful, noninvasive, child-friendly technique for visualizing normal and pathological skeletal muscle. By virtue of its different mode of image acquisition compared to muscle MRI, it allows for the assessment of different and often earlier changes, also circumventing the need for sedation. Herein we highlight the important role of muscle ultrasound as a diagnostic tool and an extension of the physical exam in the work-up of congenital onset muscle disease, presenting various relevant clinical scenarios. We show how muscle ultrasound can confirm or refute skeletal muscle involvement and yield information about the nature of the involvement (myopathic vs neurogenic). Muscle ultrasound can also guide the appropriate next diagnostic steps and recognize diagnostically important qualitative patterns to help confirm or refute genetic considerations raised by next generation sequencing. We illustrate specific muscle ultrasound involvement patterns, which constitute accessible diagnostic hints and show that muscle ultrasound, in conjunction with the clinical phenotype, the histological appearance of the muscle biopsy (when available), and the ascertained genotype, can be a very powerful tool in integrating all available information into a final accurate and precise diagnosis in the age of next generation sequencing.

Myostatin Inhibition Using ActRIIB-mFc Does Not Produce Weight Gain or Strength in the Nebulin Conditional KO Mouse.

Mutations in at least 12 genes are responsible for a group of congenital skeletal muscle diseases known as nemaline myopathies (NMs). NMs are associated with a range of clinical symptoms and pathological changes often including the presence of cytoplasmic rod-like structures (nemaline bodies) and myofiber hypotrophy. Our recent work has identified a variable degree of behavioral benefit when treating 2 NM mouse models due to mutations in Acta1 with myostatin inhibition. This study is focused on the effects of delivering ActRIIB-mFc (Acceleron; a myostatin inhibitor) to the nebulin conditional knockout KO (Neb cKO) mouse model of NM. Treatment of Neb cKO mice with ActRIIB-mFc did not produce increases in weight gain, strength, myofiber size, or hypertrophic pathway signaling. Overall, our studies demonstrate a lack of response in Neb cKO mice to myostatin inhibition, which differs from the response observed when treating other NM models.

Reductions in ATPase activity, actin sliding velocity, and myofibril stability yield muscle dysfunction in Drosophila models of myosin-based Freeman-Sheldon syndrome.

Using Drosophila melanogaster, we created the first animal models for myosin-based Freeman–Sheldon syndrome (FSS), a dominant form of distal arthrogryposis defined by congenital facial and distal skeletal muscle contractures. Electron microscopy of homozygous mutant indirect flight muscles showed normal (Y583S) or altered (T178I, R672C) myofibril assembly followed by progressive disruption of the myofilament lattice. In contrast, all alleles permitted normal myofibril assembly in the heterozygous state but caused myofibrillar disruption during aging. The severity of myofibril defects in heterozygotes correlated with the level of flight impairment. Thus our Drosophila models mimic the human condition in that FSS mutations are dominant and display varied degrees of phenotypic severity. Molecular modeling indicates that the mutations disrupt communication between the nucleotide-binding site of myosin and its lever arm that drives force production. Each mutant myosin showed reduced in vitro actin sliding velocity, with the two more severe alleles significantly decreasing the catalytic efficiency of actin-activated ATP hydrolysis. The observed reductions in actin motility and catalytic efficiency may serve as the mechanistic basis of the progressive myofibrillar disarray observed in the Drosophila models as well as the prolonged contractile activity responsible for skeletal muscle contractures in FSS patients.

DYRK1A Protein, A Promising Therapeutic Target to Improve Cognitive Deficits in Down Syndrome.

Down syndrome (DS) caused by a trisomy of chromosome 21 (HSA21), is the most common genetic developmental disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment, early onset of Alzheimer’s disease, congenital heart disease, hypotonia, muscle weakness and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. Among the numerous protein coding genes of HSA21, dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) encodes a proline-directed serine/threonine and tyrosine kinase that plays pleiotropic roles in neurodevelopment in both physiological and pathological conditions. Numerous studies point to a crucial role of DYRK1A protein for brain defects in patients with DS. Thus, DYRK1A inhibition has shown benefits in several mouse models of DS, including improvement of cognitive behaviour. Lastly, a recent clinical trial has shown that epigallocatechine gallate (EGCG), a DYRK1A inhibitor, given to young patients with DS improved visual recognition memory, working memory performance and adaptive behaviour.

Bi-allelic mutations in MYL1 cause a severe congenital myopathy.

Congenital myopathies are typically characterised by early onset hypotonia, weakness and hallmark features on biopsy. Despite the rapid pace of gene discovery, ∼50% of patients with a congenital myopathy remain without a genetic diagnosis following screening of known disease genes. We performed exome sequencing on two consanguineous probands diagnosed with a congenital myopathy and muscle biopsy showing selective atrophy/hypotrophy or absence of type II myofibres. We identified variants in the gene (MYL1) encoding the skeletal muscle fast-twitch specific myosin essential light chain (ELC) in both probands. A homozygous essential splice acceptor variant (c.479-2A>G, predicted to result in skipping of exon 5 was identified in Proband 1, and a homozygous missense substitution (c.488T>G, p.(Met163Arg)) was identified in Proband 2. Protein modelling of the p.(Met163Arg) substitution predicted it might impede intermolecular interactions that facilitate binding to the IQ domain of myosin heavy chain, thus likely impacting on the structure and functioning of the myosin motor. MYL1 was markedly reduced in skeletal muscle from both probands, suggesting that the missense substitution likely results in an unstable protein. Knock down of myl1 in zebrafish resulted in abnormal morphology, disrupted muscle structure and impaired touch-evoked escape responses, thus confirming that skeletal muscle fast-twitch specific myosin ELC is critical for myofibre development and function. Our data implicate MYL1 as a crucial protein for adequate skeletal muscle function and that MYL1 deficiency is associated with severe congenital myopathy.

CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.235Recessive congenital fiber type disproportion caused by TPM3 mutation

Mutations in TPM3 gene represent a common cause of congenital fiber type disproportion (CFTD), but can also lead to other phenotypes like nemaline myopathy, cap myopathy, and congenital muscle stiffness. The clinical severity is also highly variable and genotype/phenotype correlations have been inconsistent. The majority of previously reported TPM3-associated diseases are dominantly acting, either inherited or de novo. Recessive cases are very rare and previously related to severe forms of recessive nemaline myopathy and one severely affected patient with CFTD. Here we present an autosomal recessive CFTD case harboring a novel homozygous mutation in TPM3 presenting with a mild proximal phenotype. Case Report: a 14-year-old female, only child of consanguineous parents. She was born hypotonic followed by delayed acquisition of motor milestones. Head support was achieved at the age of 6 months and gait at 30 months. At the time of the evaluation, she could walk for more than 1000 meters, climb stairs without support, but could never jump. The physical exam showed facial weakness, mild ptosis but no ophtalmoparesis and mild thoracic deformity. She presented a mild proximal cervical weakness combined with a moderate involvement of cervical flexors and no distal weakness. Muscle biopsy of the biceps brachii performed at the age of 4 years showed fiber type disproportion with type 1 predominance and smallness without other structural features like rods, nuclear centralization or cores. Whole exome sequencing revealed a novel homozygous missense variant (p.R179G) in exon 5 of TPM3 gene. The variant is not present in the population databases (EXAC, GNoMED, EVS), it is located in a very conserved residue and is predicted to be damaging according MetaSVM and MetaLR. Herein we presented a novel homozygous variant in TPM3 gene causing a mild CFTD expanding the phenotype-genotype correlations related to this gene and also adding a new variant associated with muscle disease.

Can McArdle disease be induced by infection associated with rhabdomyolysis case report?

Introduction: Rhabdomyolysis is the clinicopathologic presentation that is caused by striated muscle damage with leaking of toxic pigments into the blood. Clinical findings of rhabdomyolysis ranges from asymptomatic increase of muscle enzymes to the fatal forms of acute renal failure (ARF) and electrolyte disturbance. The causes of rhabdomyolysis can be classified under several groups: (a) direct injury from trauma, (b) overuse of muscle, (c) congenital muscle enzyme errors, and (d) uncommon pathogens like drugs and toxins, ischemia of muscle, metabolic and endocrine disorders, and finally infections. The diagnosis of rhabdomyolysis is based on myalgia and weakness, tea-colored urine (myoglobinuria), an increase in muscle enzymes that is not caused by myocardial infarction (MI) or polymyositis (PM). The most important goal of treatment is to diagnose and cure complications like electrolyte disturbances and acute tubular necrosis (ATN). Case Report: The case in the present study was a young man who was admitted with fever and chill and generalized myalgia with tea-colored urine. Finally, he died because of acute adult respiratory distress syndrome (RDS), acute renal tubular necrosis, and hyperkalemia. Among congenital muscle enzyme disorders, the most common type is the carnitine-palmitotransferase defect (CPT), and after that, the second most common is myophosphorylase deficiency. Among muscle carbohydrate metabolism defects, McArdle disease (MD), or glycogenosis type V (GSD-V), is the most prevalent, which is caused by a deficiency in glycogen-phosphorylase enzyme. In this disorder, only striated muscles are affected, which leads to rhabdomyolysis in the primary steps, and exercise intolerance, muscle cramps, and myoglobinuria, when reaches more developed levels. This predisposition to rhabdomyolysis in patients with MD prevents us from administrating certain drugs in these cases. Conclusion: Rhabdomyolysis may develop among individuals with abnormal muscles as in congenital diseases of glycogenolysis, glycolysis, purine, and lipid metabolism. Considering the rare causes of rhabdomyolysis like MD permits physicians to diagnose and treat this potentially fatal occult causes.

Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy

Nemaline myopathies are heterogeneous congenital muscle disorders causing skeletal muscle weakness and, in some cases, death soon after birth. Mutations in nebulin, encoding a large sarcomeric protein required for thin filament function, are responsible for approximately 50% of nemaline myopathy cases. Despite the severity of the disease there is no effective treatment for nemaline myopathy with limited research to develop potential therapies. Several supplements, including L-tyrosine, have been suggested to be beneficial and consequently self-administered by nemaline myopathy patients without any knowledge of their efficacy. We have characterized a zebrafish model for nemaline myopathy caused by a mutation in nebulin. These fish form electron-dense nemaline bodies and display reduced muscle function akin to the phenotypes observed in nemaline myopathy patients. We have utilized our zebrafish model to test and evaluate four treatments currently self-administered by nemaline myopathy patients to determine their ability to increase skeletal muscle function. Analysis of muscle pathology and locomotion following treatment with L-tyrosine, L-carnitine, taurine, or creatine revealed no significant improvement in skeletal muscle function emphasizing the urgency to develop effective therapies for nemaline myopathy.

Upper limb congenital muscular hypertrophy and aberrant muscle syndrome in children.

IV.

Hitherto unknown detailed muscle anatomy in an 8-week-old embryo.

Congenital muscle diseases, such as myopathies or dystrophies, occur relatively frequently, with estimated incidences of up to 4.7 per 100 000 newborns. To diagnose congenital diseases in the early stages of pregnancy, and to interpret the results of increasingly advanced in utero imaging techniques, a profound knowledge of normal human morphological development of the locomotor system and the nervous system is necessary. Muscular development, however, is an often neglected topic or is only described in a general way in embryology textbooks and papers. To provide the required detailed and updated comprehensive picture of embryologic muscular anatomy, three‐dimensional (3D) reconstructions were created based on serial histological sections of a human embryo at Carnegie stage 23 (8 weeks of development, crown–rump length of 23.8 mm), using amira reconstruction software. Reconstructed muscles, tendons, bones and nerves were exported in a 3D‐PDF file to permit interactive viewing. Almost all adult skeletal muscles of the trunk and limbs could be individually identified in their relative adult position. The pectoralis major muscle was divided in three separate muscle heads. The reconstructions showed remarkable highly developed extraocular, infrahyoid and suprahyoid muscles at this age but surprisingly also absence of the facial muscles that have been described to be present at this stage of development. The overall stage of muscle development suggests heterochrony of skeletal muscle development. Several individual muscle groups were found to be developed earlier and in more detail than described in current literature.