Primary Muscle Disorders Research Articles

Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant.

Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy. This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records. All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene. This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.

Hospital admissions from the emergency department of adult patients affected by myopathies.

Myopathies are associated with classic signs and symptoms, but also with possible life-threatening complications that may require assistance in an emergency setting. This phenomenon is understudied in the literature. We aimed to assess the presentation, management, and outcomes of clinical manifestations potentially related to a muscle disorder requiring referral to the adult emergency department (ED) and hospitalization. Anonymized patient data retrieved using the International Classification of Diseases, Ninth Revision codes related to muscle disorders over 4 years were retrospectively analyzed. Medical reports were evaluated to extract demographic and clinical variables, along with outcomes. Two groups were defined based on the presence (known diagnosis [KD] group) or absence (unknown diagnosis [UD] group) of a diagnosed muscle disorder at arrival. A total of 244 patients were included, 51% of whom were affected by a known myopathy, predominantly limb-girdle muscular dystrophies and myotonic dystrophies. The main reasons for ED visits in the KD group were respiratory issues, worsening of muscle weakness, and gastrointestinal problems. Heart complications were less prevalent. In the UD group, 27 patients received a new diagnosis of a specific primary muscle disorder after the ED access, mostly an inflammatory myopathy. Death during hospitalization was recorded in 26 patients, with a higher rate in the KD group and in patients affected by mitochondrial and inflammatory myopathies. Sepsis and dyspnea were associated with increased death risk. Respiratory complications are the most common reason for myopathic patients accessing the ED, followed by gastrointestinal issues. Infections are severe threats and, once hospitalized, these patients have relatively high mortality.

Protocolo diagnóstico de las mialgias

Myalgia, or muscle pain, is a common complaint among the adult population. Diffuse myalgias are more frequent than localized myalgias. Excessive physical effort, trauma, medications, and viral infections are among the most common causes. Myalgias are most often benign, but in a certain percentage of cases, they are the symptom of muscle disease (myopathy) or muscle inflammation (myositis). Myaglias caused by a primary muscle disorder are generally triggered with exercise and are accompanied by other signs/symptoms. In patients with carbohydrate metabolism disorders, muscle symptoms are triggered by brief isometric exercise or less intense, sustained dynamic exercise and can cause cramps and recurrent myoglobinuria. In lipid metabolism disorders, the symptoms tend to be induced by infections, fever, prolonged or intense exercise, and prolonged fasting. These patients do not develop true muscle cramps or contractures and do not experience the phenomenon known as “second wind.”

EP394: Investigation and functional characterization of genomic signatures in congenital muscular dystrophy and congenital myopathy patients from India

Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods. Furthermore, functional characterization of the novel pathogenic stop-gain variant NM_001927.4:c.448C>T in the DES gene identified in one patient of our cohort was done in order to understand their pathological role in disease phenotypes.

Single-cell transcriptome analysis yields new insights into the pathogenic mechanisms and possible genetic etiology of cardiomyopathies

Abstract Background Inherited cardiomyopathies (CM) represent a clinically heterogeneous group of primary cardiac muscle disorders with a strong genetic underpinning. Recent rapid genomic advances have led to the identification of numerous disease-causing genes for both non-syndromic (nsCM) and syndromic (sCM) cardiomyopathies. This has greatly facilitated molecular genetic testing, thus enabling accurate disease diagnosis needed for the practice of precision medicine and the optimization of patient outcome. However, many cardiomyopathies remain unexplained with the known genes and dominant genetic model of disease. Purpose To reassess the genetic features of known CM genes as a strategy to recover novel candidate CM genes. Methods Known hypertrophic CM (HCM), dilated CM (DCM) and pediatric CM genes were curated from the literature and from 23 commercial CM diagnostic panels. They were classified as non-syndromic and syndromic, and further annotated using two constraint metrics, the missense Z score and pLI score obtained from the GnomAD database. Publicly available mouse (n=6) and human (n=3) single-cell RNA (scRNA) datasets were downloaded and cardiomyocyte specific differentially expressed genes (DEGs) (fold change >0.1; adjusted P<0.0001) were recovered. Genes identified as DEGs in at least 4 mouse or 3 human scRNA datasets were recovered as nsCM candidate genes. Results Analyses of 9 scRNA datasets showed the majority of known nsCM genes are cardiomyocyte specific (Fig. 1a-b). nsCM and sCM genes have distinct expression and genetic profile. nsCM genes are associated with higher heart expression and lower loss intolerance (Fig. 1c). In contrast, syndromic CM genes mostly showed lower expression with high loss intolerance, consistent with their higher clinical impact. However, interestingly some of the nsCM genes (MYLK2, TMPO and KLF10) show low or even no detectable expression in mouse and human cardiac cells. Using the scRNA data, we assessed cellular expression of genes in the 23 commercial CM diagnostic panels. This analysis showed some of the CM genes with high cardiomyocytes expression have low coverage on the current commercial CM panels (Fig. 1d). Using human and mouse scRNA data, we recovered 224 mouse and 157 human nsCM candidate genes. MTUS2 (microtubule-associated tumor suppressor candidate 2) was identified as a strong nsCM candidate gene supported by evidence from both mouse and human studies (Fig. 1e-f). Conclusions Our analysis showed many of the nsCM genes have differential cardiomyocyte expression with low loss intolerance, while the reverse was observed for many sCM genes. We propose increasing commercial panel coverage of cardiomyocytes-specific expressed genes may help increase disease diagnostic yield. Additionally, novel candidate genes uncovered trained on cardiomyocyte expression profile may help accelerate elucidation of unsolved cardiomyopathy cases. Funding Acknowledgement Type of funding sources: None.

Panorama of the distal myopathies.

Distal myopathies are genetic primary muscle disorders with a prominent weakness at onset in hands and/or feet. The age of onset (from early childhood to adulthood), the distribution of muscle weakness (upper versus lower limbs) and the histological findings (ranging from nonspecific myopathic changes to myofibrillar disarrays and rimmed vacuoles) are extremely variable. However, despite being characterized by a wide clinical and genetic heterogeneity, the distal myopathies are a category of muscular dystrophies: genetic diseases with progressive loss of muscle fibers. Myopathic congenital arthrogryposis is also a form of distal myopathy usually caused by focal amyoplasia.Massive parallel sequencing has further expanded the long list of genes associated with a distal myopathy, and contributed identifying as distal myopathy-causative rare variants in genes more often related with other skeletal or cardiac muscle diseases.Currently, almost 20 genes (ACTN2, CAV3, CRYAB, DNAJB6, DNM2, FLNC, HNRNPA1, HSPB8, KHLH9, LDB3, MATR3, MB, MYOT, PLIN4, TIA1, VCP, NOTCH2NLC, LRP12, GIPS1) have been associated with an autosomal dominant form of distal myopathy. Pathogenic changes in four genes (ADSSL, ANO5, DYSF, GNE) cause an autosomal recessive form; and disease-causing variants in five genes (DES, MYH7, NEB, RYR1 and TTN) result either in a dominant or in a recessive distal myopathy. Finally, a digenic mechanism, underlying a Welander-like form of distal myopathy, has been recently elucidated. Rare pathogenic mutations in SQSTM1, previously identified with a bone disease (Paget disease), unexpectedly cause a distal myopathy when combined with a common polymorphism in TIA1.The present review aims at describing the genetic basis of distal myopathy and at summarizing the clinical features of the different forms described so far.

Whole-exome analyses of congenital muscular dystrophy and congenital myopathy patients from India reveal a wide spectrum of known and novel mutations.

Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. Due to vast heterogeneity, clinical examination and protein-based analyses often fail to identify the genetic causes of these diseases. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods. Whole-exome sequencing (WES) was performed to identify pathogenic mutations in previously reported CMD and CM-related genes using variant calling and stringent variant filtration process. Subsequently, in silico homology modelling and molecular dynamics simulations (MDS) studies were undertaken for a number of novel and missense variants. A total of 33 and 21 rare and deleterious mutations were identified in 28 genes previously reported in CMD and CM based on OMIM, ClinVar and Orphanet, respectively. We could accurately diagnose 54% patients (n=12/22) in the CMD group and 35% patients (n=5/14) in the CM group. Furthermore, MDS studies for mutations located in LMNA, LAMA2 and RYR1 suggest that the wild-type proteins are more stable than their mutant counterparts, implying a potential mechanism of pathogenesis. The WES findings led us to identify reported as well as novel variants for the first time in Indian patients with CMD and CM. This allowed us to achieve an accurate genetic diagnosis, which was difficult using conventional diagnostic tools. Transferring these WES findings to clinical practice will help guide clinical care of the affected patients and inform genetic counselling.

Speech treatment in nemaline myopathy: A single-subject experimental study

PurposeThe objective of this work was to verify the efficacy of a treatment based on myofunctional therapy techniques which aimed to improve the tongue strength, precision, and speed of a ten-year-old girl with nemaline myopathy (NM) and the repercussions of this therapy on her speech intelligibility. NM is a rare congenital muscle disorder that causes extreme muscle weakness, especially in the face and neck, as well as severe dysarthria and dysphagia, although this does not affect the nervous system or cognitive development. MethodThis was a single-subject experimental study which used an interrupted pre- and post-treatment time-series design, and which applied autoregressive integrated moving-average predictive models and Holt exponential smoothing. During the treatment phases, the participant’s tongue strength and the rate of speech diadochokinesia and voluntary lingual movements were estimated and the repercussions of the intervention in terms of speech intelligibility were ascertained via an experiment with ‘naïve’ judges. ResultsThe treatment produced a sustained and significant increase in the maximum strength of the patient’s tongue, which increased from an initial 4 kPa to 11 kPa at the end of the treatment phase. However, this was far from the average 58 kPa for age- and sex-matched normative data. There were no significant changes either in the rates of voluntary lingual mobility or speech diadochokinesia. Speech intelligibility, as assessed by naïve judges, improved from 40 % in the pre-treatment phase to 67 % in the post-treatment phase. ConclusionsNM and other rare primary muscle disorders allow us to estimate the effects of severe muscle weakness in people with dysarthria without cognitive impairment or alterations in central nervous system, peripheral nervous system or in gap junction. In this case, the treatment did not increase the patient’s lingual and articulatory movement speed but did increase her tongue strength from 5 % to 10 % of the levels otherwise expected for her age and significantly improved the intelligibility of her speech and communication.

CONGENITAL MYOPATHIES 1 – NEMALINE: P.25 Autosomal recessive congenital myopathy with splicing mutation (c.21522+3A>G) of NEB gene

Congenital myopathies are a heterogeneous group of hereditary primary muscle disorders that are present from birth, although their onset may be delayed until later in infancy or early childhood. The most common of these rare disorders are nemaline myopathy, central core disease, centronuclear (myotubular) myopathies, and congenital fiber type disproportion. Among them, nemaline myopathy, a rare congenital myopathy, is characterized by generalized muscle weakness, respiratory insufficiency, and the presence of rod structures on muscle biopsy, which is caused by mutations in at least 13 known genes.

Neuromuscular Disease Affecting the Larynx.

Neuromuscular diseases (NMDs) are diseases involving the motor nuclei of the cranial nerves and anterior horn cells of the spinal cord, the peripheral nerves, the neuromuscular junction, and/or muscle itself. The following groups of disorders from the WHO International Classification of Diseases are usually included in the classification of NMDs: (1) Motor neuron diseases or related disorders; (2) Disorders of nerve root, plexus or peripheral nerves; (3) Diseases of neuromuscular junction or muscle. These diseases include myasthenia gravis or certain specified neuromuscular junction disorders, primary disorders of muscle, and secondary myopathies. The following discussion selects NMDs from each group, which may have unique laryngeal features and more commonly involve the laryngologist and highlights different diagnostic and treatment considerations related to the larynx.

Protocolo diagnóstico de las mialgias

Diffuse musculoskeletal pain is a very frequent and non-specific symptom. Etiologically can be related or not with systemic diseases (endocrine disorders, connective-tissue diseases, infections), they can be secondaries to drugs (statins) or appear within primary muscle disorders like metabolic and inflammatory myopathies. Chronic diffuse myalgias, without muscle weakness or without elevation of creatine kinase (CK) levels, will be very rarely be related to myopathy. Key differential diagnostic tools are: clinical history (onset form, progression, triggering factors, related symptoms, drug and medical history) and changes in CK profile, in case they exit. General blood test, including ions, vitamin D and thyroid function is mandatory. According to diagnosis suspicion, antibodies test and erythrocyte sedimentation rate/C-reactive protein will be requested. Muscle biopsy is necessary in those cases in which muscle weakness is observed.

CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.239Congenital titinopathy: severe and atypical presentations

Congenital titinopathy is a prenatal/infant-onset genetic muscle disorder caused by recessive TTN mutations. The true prevalence of of this disorder remains unknown, however the number of confirmed cases is climbing exponentially. We have identified four informative congenital titinopathy cases with convincingly pathogenic TTN mutations in trans. These cases extend our understanding of the spectrum of weakness and additional clinical features that can be associated with this emerging titinopathy. The first three cases are severely affected infants. All had a history of reduced fetal movements and were born at term with profound hypotonia and no respiratory effort. All required immediate resuscitation and intubation. One had congenital fractures, two had congenital quadrimelic joint contractures, two had atrial or ventricular septal cardiac defects, and two had intracerebral abnormalities likely secondary to birth trauma. Two died shortly after withdrawal of care on day one of life & three months of age respectively. The third remains reliant on full time ventilatory support (age 9 months). The fourth case is a 21-year-old female who was born with several congenital-titinopathy-like features including congenital contractures (camptodactyly, unilateral talipes), a cardiac abnormality (peripheral pulmonary stenosis), ptosis (congenital), and a high arched palate. However, this patient was not clinically weak at birth and has remained strong over time. She also has a range of striking additional features including Noonan-like facies, a low posterior hairline, neck webbing, short stature and bilateral axillary pterygia. She has no pathogenic-looking variants within established Noonan syndrome/syndrome-like genes. In view of the features present in these patients, we recommend that congenital titinopathy be considered in all weak infants with features suggestive of a primary muscle disorder and in patients with Noonan-like or multiple-pterygia-contracture phenotypes.

A Novel FLNC Frameshift and an OBSCN Variant in a Family with Distal Muscular Distrophy

Distal muscular dystrophies are a group of inherited primary muscle disorders showing progressive muscle atrophy and weakness preferentially in the hands and/or feet. We identified a novel frameshift mutation in the filamin C (FLNC c.5161delG) gene in two members of a French family affected by distal myopathy and in one healthy relative. Interestingly, the two affected members, but not the healthy relative, also carry a p.Arg4444Trpvariant in the gene coding for the giant protein obscurin(OBSCN). Both OBSCN and FLNC are Z-disk associated proteins. FLNC is an actin cross-linking protein, involved with Z-disk organization and muscle integrity. The FLNC c.5161delG mutation here described is one nucleotide away from a previously reported FLNC mutation (c.5160delC), identified in patients and in asymptomatic carriers of three families with distal muscular dystrophy, indicating a low penetrance of these FLNC frameshift mutations. Obscurin is a giant protein, which interacts with titin at both the M-band and the Z-disk and with muscle-specific ankyrins at the sarcoplasmic reticulum and the sarcolemma. The p.Arg4444Trpvariant we identified is localized within the OBSCN Ig59 that, together with Ig58, binds to the ZIg9/ZIg10 domains of titin at Z-disks. Structural and functional studies indicated that the OBSCN p.Arg4444Trp variant results in a 10-fold decrease in binding to titin. Interestingly, in vitro and in vivo models show that loss of FLNC results in myofibril destabilization and that the decrease in the interaction between titin and obscurin is associated with cardiac and skeletal muscle diseases. On this line, we suggest that the combination of the OBSCN p.Arg4444Trp variant and of the FLNC c.5161delG mutation can cooperatively affect myofibril stability and increase the penetrance of muscular dystrophy.

Differential Diagnosis of HyperCKemia

AbstractElevated serum creatine kinase (CK) activity is usually an indicator of muscle damage. HyperCKemia is often an incidental finding and should be controlled after refraining from physical activity for some days, especially in asymptomatic patients. Furthermore, data from recent studies indicate that the upper limits of normal (ULN) need to be revised upward. This review includes an algorithm for the differential diagnosis of CK elevation in patients without muscular symptoms. In the field of neurology, in particular myopathies and neuropathies with affection of the lower motor neuron can cause symptomatic hyperCKemia, with CK values >1000 U/l (16,7 µkat/l) being indicative of a primary muscle disorder. Diseases with very high CK values include subtypes of muscular dystrophies, idiopathic inflammatory myopathies and metabolic myopathies. However, a normal or only slightly elevated CK value does not exclude the presence of a myopathy. The individual diagnostic procedure (e. g., muscle imaging, special laboratory studies, muscle biopsy and genetic testing) depends on the clinical phenotype and the results of electrophysiological studies. HyperCKemia can also be an adverse effect of several drugs including statins. In asymptomatic patients, statin-associated CK elevations <5 times the ULN can be tolerated. In patients with higher CK values and/or muscle symptoms, LDL-cholesterol lowering therapy should be changed. Rhabdomyolysis is a potentially life-threatening condition and is accompanied by highly elevated CK values. Acute phase treatment includes preserving renal function and restoring metabolic derangements.

Epidural Anesthesia for Pelvic fracture in a Patient with dilated cardiomyopathy - Case Report -

Dilated cardiomyopathy (DCM) is defined as a primary heart muscle disorder characterizedby decreased myocardialcontractility, impairment of the ventricular function of the myocardium. The management of a patient with dilatedcardiomyopathy is always a challenge for an anesthesiologist, as this situation is associated with severe cardiac failureand a high mortality rate during or after anesthesia. We report the successful anesthetic management of a patient withdilated cardiomyopathy undergoing surgery for pelvic fracture.

Tumor Necrosis Factor Alpha and Insulin-Like Growth Factor 1 Induced Modifications of the Gene Expression Kinetics of Differentiating Skeletal Muscle Cells.

IntroductionTNF-α levels are increased during muscle wasting and chronic muscle degeneration and regeneration processes, which are characteristic for primary muscle disorders. Pathologically increased TNF-α levels have a negative effect on muscle cell differentiation efficiency, while IGF1 can have a positive effect; therefore, we intended to elucidate the impact of TNF-α and IGF1 on gene expression during the early stages of skeletal muscle cell differentiation.Methodology/Principal FindingsThis study presents gene expression data of the murine skeletal muscle cells PMI28 during myogenic differentiation or differentiation with TNF-α or IGF1 exposure at 0 h, 4 h, 12 h, 24 h, and 72 h after induction. Our study detected significant coregulation of gene sets involved in myoblast differentiation or in the response to TNF-α. Gene expression data revealed a time- and treatment-dependent regulation of signaling pathways, which are prominent in myogenic differentiation. We identified enrichment of pathways, which have not been specifically linked to myoblast differentiation such as doublecortin-like kinase pathway associations as well as enrichment of specific semaphorin isoforms. Moreover to the best of our knowledge, this is the first description of a specific inverse regulation of the following genes in myoblast differentiation and response to TNF-α: Aknad1, Cmbl, Sepp1, Ndst4, Tecrl, Unc13c, Spats2l, Lix1, Csdc2, Cpa1, Parm1, Serpinb2, Aspn, Fibin, Slc40a1, Nrk, and Mybpc1. We identified a gene subset (Nfkbia, Nfkb2, Mmp9, Mef2c, Gpx, and Pgam2), which is robustly regulated by TNF-α across independent myogenic differentiation studies.ConclusionsThis is the largest dataset revealing the impact of TNF-α or IGF1 treatment on gene expression kinetics of early in vitro skeletal myoblast differentiation. We identified novel mRNAs, which have not yet been associated with skeletal muscle differentiation or response to TNF-α. Results of this study may facilitate the understanding of transcriptomic networks underlying inhibited muscle differentiation in inflammatory diseases.

The investigation and management of metabolic myopathies

Metabolic myopathies (MM) are rare inherited primary muscle disorders that are mainly due to abnormalities of muscle energy metabolism resulting in skeletal muscle dysfunction. These diseases include disorders of fatty...

Thyrotoxic neuropathy; an under recognized condition: A clinical vignette

Neurological sequelae such as neuromuscular or primary muscle disorders are well recognized complications of hyperthyroidism. However, the association of neuropathy with thyrotoxicosis is uncommon. Thyrotoxic neuropathy or Basedow's paraplegia is a rarely reported entity, which was first described by Charcot in 1889. We are reporting the case of a middle-aged man with subacute distal neuropathy as the presenting manifestation of thyrotoxicosis which improved on antithyroid treatment. Peripheral neuropathy in hyperthyroidism is underdiagnosed and may be found even in patients with mild thyrotoxicosis. Thyroid function tests can be helpful in the diagnosis of this treatable neuropathy in such cases and hence should be included in the routine workup in patients with peripheral neuropathy.

Modeling of Arrhythmogenic Right Ventricular Cardiomyopathy With Human Induced Pluripotent Stem Cells

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disorder resulting from desmosomal protein mutations. ARVC is characterized pathologically by fibrofatty infiltration and clinically by arrhythmias and sudden cardiac death. We aimed to establish a patient-/disease-specific human induced pluripotent stem cell (hiPSC) model of ARVC. Dermal fibroblasts were obtained from 2 patients with ARVC with plakophilin-2 (PKP2) mutations, reprogrammed to generate hiPSCs, coaxed to differentiate into cardiomyocytes (CMs), and then compared with healthy control hiPSC-derived CMs (hiPSC-CMs). Real-time polymerase chain reaction showed a significant decrease in the expression of PKP2 in the ARVC-hiPSC-CMs. Immunostainings revealed reduced densities of PKP2, the associated desmosomal protein plakoglobin, and the gap-junction protein connexin-43. Electrophysiological assessment demonstrated prolonged field potential rise time in the ARVC-hiPSC-CMs. Transmission electron microscopy identified widened and distorted desmosomes in the ARVC-hiPSC-CMs. Clusters of lipid droplets were identified in the ARVC-CMs that displayed the more severe desmosomal pathology. This finding was associated with upregulation of the proadipogenic transcription factor peroxisome proliferator-activated receptor-γ. Exposure of the cells to apidogenic stimuli augmented desmosomal distortion and lipid accumulation. The latter phenomenon was prevented by application of a specific inhibitor of glycogen synthase kinase 3β (6-bromoindirubin-3'-oxime). This study highlights the unique potential of the hiPSC technology for modeling inherited cardiac disorders in general and ARVC specifically. The hiPSC-CMs were demonstrated to recapitulate the ARVC phenotype in the dish, provide mechanistic insights into early disease pathogenesis, and provide a unique platform for drug discovery and testing in this disorder.

Compound heterozygous mutations of the TNXB gene cause primary myopathy

Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30kb deletion and a non-synonymous novel missense mutation in the TNXB gene. This study identifies a TNX-deficient patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that TNX deficiency leads to muscle softness and to mislocalization of myotendinous junctions.