MYH7-related myopathies: clinical, myopathological and genotypic spectrum in a multicentre French cohort.

BACKGROUND: Myosin heavy chain 7 (MYH7)-related myopathies (MYH7-RMs) are a group of muscle disorders linked to pathogenic variants in the MYH7 gene, encoding the slow/beta-cardiac myosin heavy chain, which is highly expressed in skeletal muscle and heart. The phenotype is heterogeneous including distal, predominantly axial or scapuloperoneal myopathies with variable cardiac involvement. METHODS: We retrospectively analysed the clinical, muscle MRI, genetic and myopathological features of 57 MYH7 patients. Patients received a thorough neurological (n=57, 100%), cardiac (n=51, 89%) and respiratory (n=45, 79%) assessment. Muscle imaging findings and muscle biopsies were reappraised in 19 (33%) and 27 (47%) patients, respectively. RESULTS: We identified three phenotypes with varying degrees of overlap: distal myopathy (70%), scapuloperoneal (23%) and axial with peculiar cervical spine rigidity called the 'sphinx' phenotype (7%). 14% of patients had either dilated cardiomyopathy, hypertrophic cardiomyopathy or left ventricular non-compaction cardiomyopathy. 31% of patients had prominent respiratory involvement, including all patients with the 'sphinx' phenotype. Muscle MRI showed involvement of tibialis anterior, followed by quadriceps, and erector spinae in patients with axial phenotype. Cores represented the most common myopathological lesion. We report 26 pathogenic variants of MYH7 gene, 9 of which are novel. CONCLUSIONS: MYH7-RMs have a large phenotypic spectrum, including distal, scapuloperoneal or axial weakness, and variable cardiac and respiratory involvement. Tibialis anterior is constantly and precociously affected both clinically and on muscle imaging. Cores represent the most common myopathological lesion. Our detailed description of MYH7-RMs should improve their recognition and management.

Use of MFM-20 to monitor SMA types 1 and 2 patients treated with nusinersen.

OBJECTIVE: To evaluate sensitivity to change and discriminant validity of the 20-item Motor Function Measure (MFM-20) in 2-7-year-old patients with spinal muscular atrophy types 1 (SMA1) or 2 (SMA2) treated with nusinersen. METHODS: Children aged 2 to 7 years old with SMA1 or SMA2 treated with nusinersen were assessed at least three times using the MFM-20 over an average follow-up time of 17 months. Evolution of 4-month-standardized MFM-20 scores was calculated for each MFM-20 domain (D1 standing and transfers, D2 axial and proximal, D3 distal) and for the total score (TS). RESULTS: Included in the study were 22 SMA1 subjects and 19 SMA2 subjects. Baseline MFM scores were significantly lower in patients with SMA1 than SMA2 (TS 29.5% vs. 48.3%, D1 4.5% vs. 10.6%, D2 43.6% vs. 72.6%, D3 51.2% vs. 75.0%). When considering the mean change during nusinersen treatment, standardized over a 4-month period, TS was improved for both SMA1 (+ 4.1%, SRM 1.5) and SMA2 (+ 2.8%, SRM 0.89) patients. For SMA1 patients, considerable changes were observed in D2 (+ 6.2%, SRM 0.89) and D3 (+ 6.0%, SRM 0.72), whereas the change in D1 was small (+ 0.5%, SRM 0.44). In SMA2 2 subjects, D3 was improved to a larger extent (+ 4.2%, SRM 0.53) than D1 (+ 1.8% SRM 0.63) or D2 (+ 3.2%, SRM 0.69). CONCLUSION: Our results validate use of MFM-20 to monitor function of young SMA1 and SMA2 subjects treated with nusinersen. Significant motor function improvements following treatment were observed in both SMA1 and SMA2 patients.

Perioperative complications after posterior spinal fusion versus minimally invasive fusionless surgery in neuromuscular scoliosis: a comparative study.

INTRODUCTION: Early-onset scoliosis is a common deformity in neuromuscular disease. When conservative treatment becomes ineffective, several surgical options can be proposed. The most common technique is posterior spinal fusion (PSF) consisting of performing a multiple segmental instrumentation with pedicular screws on the full spine associated with decortication and bone graft. Minimally invasive fusionless surgery (MIFS) is an alternative to correct and fix definitively the spine without graft. The objective of this study was to compare early surgical inpatient period between PSF and MIFS in neuromuscular scoliosis. MATERIAL AND METHODS: 140 NMS operated by PSF or MIFS between 2012 and 2017 was retrospectively reviewed. The following data were compared between groups: general characteristics (age, sex, etiology), preoperative preparation (halo traction, noninvasive ventilation or tracheostomy), Cobb angle and pelvic obliquity correction, use of drugs (vasopressor and/or inotropes, expansion fluids, transfusion and volumes), postoperative complications, and need of noninvasive ventilation. RESULTS: 75 patients were managed by PSF with a mean age of 14.3 ± 2.3y and 65 by MIFS with a mean age of 11.8 ± 3y. Average pelvic obliquity and major curve correction were similar postoperatively. Intraoperative blood transfusion was significantly more common in PSF group (OR, 14; 95% CI [6.3-33.0]). Vasopressors were used non-significantly more often in the PSF group and expansion fluids similar in the two groups. PSF group had more overall complications (OR, 4.6; 95% CI [2.3-9.8]), more infections (OR, 3.6; 95% CI [1.5-9.3]) and more hemodynamic complications (OR, 4.1; 95% CI [1.4-15.1]). Average intubation duration was 5 days in the PSF and 4 days in MIFS (p = 0.05). CONCLUSION: In this series of neuromuscular patients, the complication rate was reduced in MIFS comparatively to PSF, with lower blood transfusion and less infections.

NTRK1 gene-related congenital insensitivity to pain with anhidrosis: a nationwide multicenter retrospective study.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease resulting from mutations in the NTRK1 gene encoding the neurotrophic tyrosine kinase-1 receptor. In this multicenter observational retrospective study, we investigated CIPA patients identified from French laboratories sequencing the NTRK1 gene, and seven patients were identified. Patients originated from France (2), Suriname (2), Mali (1), Kazakhstan (1), and Algeria (1). Mean age of patients was 9.8 years (4-20), four patients were female (57%), infant developmental milestones were delayed in four cases (57%), and four patients had a family history of consanguinity (57%). Mean age at diagnosis was 4.8 months (3-6), and all patients presented with pain insensitivity, anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, and autonomous nervous system impairment. Patients also showed an assortment of associated findings, including hyperactivity (86%), emotional lability (86%), joint deformities (71%), bone fractures (57%), abnormal sense of touch, vibration and position (50%), skin, hair and nails abnormalities (28%), and hypothermia episodes (28%). Two patients died at age 9 and 12 years from infection. In three cases, nerve conduction studies showed absent lower limbs sensory nerve action potentials. In one case, sensory nerve biopsy showed complete absence of unmyelinated fibers. Nine NTRK1 pathogenic variants were found, including three newly described mutations. This nationwide study confirms that NTRK1 gene-related CIPA is an extremely rare disorder and expands the genotypic spectrum of NTRK1 mutations.

Minimally Invasive Fusionless Surgery for Scoliosis in Spinal Muscular Atrophy: Long-term Follow-up Results in a Series of 59 Patients.

BACKGROUND: Treatment of spinal muscular atrophy (SMA) scoliosis has evolved in the last decade, with the emergence of fusionless surgical techniques that allow correction of the deformity before the end of growth spurt. These techniques are expected to delay definitive spine fusion and preserve trunk growth. PURPOSE: The aim was to evaluate long-term clinical, radiologic, and respiratory outcomes of a minimally invasive fusionless surgery (MIFLS) in SMA scoliosis. METHODS: All children affected with SMA scoliosis who underwent MIFLS in our department from 2011 to 2019 were included. The instrumentation consisted in a bilateral sliding rod construct from T1 to the sacrum, anchored proximally by double-hook claws and distally by iliosacral screws. Clinical, genetic, respiratory and radiographic data were retrospectively reviewed. A patient's satisfaction survey was performed. RESULTS: A total of 59 children with genetic confirmation of SMA (9SMA1c, 47SMA2, and 3SMA3) underwent MIFLS at a mean age of 11±1.9 years. All of them were nonwalker at the time of surgery. Twenty-six were treated with intrathecal Nusinersen. Mean follow-up was 5.2 years (2 to 9.6 y). Mean major coronal curve improved from 79±15 to 41±16 degrees and pelvic obliquity decreased from 24±11 to 5.9±4 degrees. Mean space available for lung improved from 77% to 93%. Mechanical or infectious complications occurred in 9 patients, with removal of the implant in 1. 6 children required unplanned surgeries. Postoperative bracing was needed in 13 children. Mean gain weight 3 years after the first surgery was 6 kg. 91.5% of patients had a positive satisfaction of the surgery. There was no significant impact in respiratory function postoperatively. Only 30 children required rod lengthening procedures, with a mean interval between procedures of 1.9 years (0.5 to 3.7 y). No arthrodesis was required at last follow-up in any patient. CONCLUSION: Bipolar MIFLS in SMA preserves spinal and thoracic growth without interference with respiratory function. It provides a significant correction of spinal deformity and pelvic obliquity, having a reduced rate of complications. The correction of spinal deformity was maintained at long term, not requiring definitive fusion at the end of growth. LEVEL OF EVIDENCE: Level IV.

Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.

BACKGROUND: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. METHODS: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. RESULTS: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. CONCLUSIONS: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM).

Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.

Utility and practice of electrodiagnostic testing in the pediatric population: An AANEM consensus statement.

Nerve conduction studies and needle electromyography, collectively known as electrodiagnostic (EDX) studies, have been available for pediatric patients for decades, but the accessibility of this diagnostic modality and the approach to testing vary significantly depending on the physician and institution. The maturation of molecular diagnostic approaches and other diagnostic technologies such as neuromuscular ultrasound indicate that an analysis of current needs and practices for EDX studies in the pediatric population is warranted. The American Association of Neuromuscular & Electrodiagnostic Medicine convened a consensus panel to perform literature searches, share collective experiences, and develop a consensus statement. The panel found that electrodiagnostic studies continue to have high utility for the diagnosis of numerous childhood neuromuscular disorders, and that standardized approaches along with the use of high-quality reference values are important to maximize the diagnostic yield of these tests in infants, children, and adolescents.

CHRNG-related nonlethal multiple pterygium syndrome: Muscle imaging pattern and clinical, histopathological, and molecular genetic findings.

Mutations in the CHRNG gene cause autosomal recessive multiple pterygium syndrome (MPS). Herein we present a long-term follow-up of seven patients with CHRNG-related nonlethal MPS and we compare them with the 57 previously published patients. The objective is defining not only the clinical, histopathological, and molecular genetic characteristics, but also the type and degree of muscle involvement on whole-body magnetic resonance imaging (WBMRI). CHRNG mutations lead to a distinctive phenotype characterized by multiple congenital contractures, pterygium, and facial dysmorphism, with a stable clinical course over the years. Postnatal abnormalities at the neuromuscular junction were observed in the muscle biopsy of these patients. WBMRI showed distinctive features different from other arthrogryposis multiple congenita. A marked muscle bulk reduction is the predominant finding, mostly affecting the spinal erector muscles and gluteus maximus. Fatty infiltration was only observed in deep paravertebral muscles and distal lower limbs. Mutations in CHRNG are mainly located at the extracellular domain of the protein. Our study contributes to further define the phenotypic spectrum of CHRNG-related nonlethal MPS, including muscle imaging features, which may be useful in distinguishing it from other diffuse arthrogryposis entities.

Disease duration and disability in dysfeRlinopathy can be described by muscle imaging using heatmaps and random forests.

INTRODUCTION: The manner in which imaging patterns change over the disease course and with increasing disability in dysferlinopathy is not fully understood. METHODS: Fibroadipose infiltration of 61 muscles was scored based on whole-body MRI of 33 patients with dysferlinopathy and represented in a heatmap. We trained random forests to predict disease duration, Motor Function Measure dimension 1 (MFM-D1), and modified Rankin scale (MRS) score based on muscle scoring and selected the most important muscle for predictions. RESULTS: The heatmap delineated positive and negative fingerprints in dysferlinopathy. Disease duration was related to infiltration of infraspinatus, teres major-minor, and supraspinatus muscles. MFM-D1 decreased with higher infiltration of teres major-minor, triceps, and sartorius. MRS related to infiltration of vastus medialis, gracilis, infraspinatus, and sartorius. DISCUSSION: Dysferlinopathy shows a recognizable muscle MRI pattern. Fibroadipose infiltration in specific muscles of the thigh and the upper limb appears to be an important marker for disease progression. Muscle Nerve 59:436-444, 2019.

STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.

SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.

MRI in sarcoglycanopathies: a large international cohort study.

OBJECTIVES: To characterise the pattern and spectrum of involvement on muscle MRI in a large cohort of patients with sarcoglycanopathies, which are limb-girdle muscular dystrophies (LGMD2C-2F) caused by mutations in one of the four genes coding for muscle sarcoglycans. METHODS: Lower limb MRI scans of patients with LGMD2C-2F, ranging from severe childhood variants to milder adult-onset forms, were collected in 17 neuromuscular referral centres in Europe and USA. Muscle involvement was evaluated semiquantitatively on T1-weighted images according to a visual score, and the global pattern was assessed as well. RESULTS: Scans from 69 patients were examined (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F). A common pattern of involvement was found in all the analysed scans irrespective of the mutated gene. The most and earliest affected muscles were the thigh adductors, glutei and posterior thigh groups, while lower leg muscles were relatively spared even in advanced disease. A proximodistal gradient of involvement of vasti muscles was a consistent finding in these patients, including the most severe ones. CONCLUSIONS: Muscle involvement on MRI is consistent in patients with LGMD2C-F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time.

Muscle imaging in laminopathies: Synthesis study identifies meaningful muscles for follow-up.

INTRODUCTION: Particular fibroadipose infiltration patterns have been recently described by muscle imaging in congenital and later onset forms of LMNA-related muscular dystrophies (LMNA-RD). METHODS: Scores for fibroadipose infiltration of 23 lower limb muscles in 34 patients with LMNA-RD were collected from heat maps of 2 previous studies. Scoring systems were homogenized. Relationships between muscle infiltration and disease duration and age of onset were modeled with random forests. RESULTS: The pattern of infiltration differs according to disease duration but not to age of disease onset. The muscles whose progression best predicts disease duration were semitendinosus, biceps femoris long head, gluteus medius, and semimembranosus. DISCUSSION: In LMNA-RD, our synthetic analysis of lower limb muscle infiltration did not find major differences between forms with different ages of onset but allowed the identification of muscles with characteristic infiltration during disease progression. Monitoring of these specific muscles by quantitative MRI may provide useful imaging biomarkers in LMNA-RD. Muscle Nerve 58:812-817, 2018.

Clinical and imaging hallmarks of the MYH7-related myopathy with severe axial involvement.

INTRODUCTION: MYH7 gene mutations are related to a heterogeneous group of skeletal and cardiac myopathies. METHODS: We evaluated clinical and muscle MRI changes in patients with mutations in the rod domain of MYH7, including 1 with mosaicism and 3 with novel missense mutations. RESULTS: Patients presented in childhood with a distal and axial phenotype. Biopsy findings were variable. Half of the cases displaying some type of core pathology, including minicores and eccentric cores. Most patients demonstrated internal bands of infiltration ("inverted-collagen-VI sign") in multiple muscles, particularly the soleus, and prominent atrophy and fatty infiltration of the tongue and the paraspinal, gluteus minimus, sartorius, gracilis, tibialis anterior, and extensor digitorum longus muscles. DISCUSSION: Muscle imaging findings in patients with axial involvement provide significant clues permitting the distinction between MYH7-related myopathies and other axial myopathies such as those related to SEPN1 and LMNA genes. Muscle Nerve 58: 224-234, 2018.

Muscular MRI-based algorithm to differentiate inherited myopathies presenting with spinal rigidity.

OBJECTIVES: Inherited myopathies are major causes of muscle atrophy and are often characterized by rigid spine syndrome, a clinical feature designating patients with early spinal contractures. We aim to present a decision algorithm based on muscular whole body magnetic resonance imaging (mWB-MRI) as a unique tool to orientate the diagnosis of each inherited myopathy long before the genetically confirmed diagnosis. METHODS: This multicentre retrospective study enrolled 79 patients from referral centres in France, Brazil and Chile. The patients underwent 1.5-T or 3-T mWB-MRI. The protocol comprised STIR and T1 sequences in axial and coronal planes, from head to toe. All images were analyzed manually by multiple raters. Fatty muscle replacement was evaluated on mWB-MRI using both the Mercuri scale and statistical comparison based on the percentage of affected muscle. RESULTS: Between February 2005 and December 2015, 76 patients with genetically confirmed inherited myopathy were included. They were affected by Pompe disease or harbored mutations in RYR1, Collagen VI, LMNA, SEPN1, LAMA2 and MYH7 genes. Each myopathy had a specific pattern of affected muscles recognizable on mWB-MRI. This allowed us to create a novel decision algorithm for patients with rigid spine syndrome by segregating these signs. This algorithm was validated by five external evaluators on a cohort of seven patients with a diagnostic accuracy of 94.3% compared with the genetic diagnosis. CONCLUSION: We provide a novel decision algorithm based on muscle fat replacement graded on mWB-MRI that allows diagnosis and differentiation of inherited myopathies presenting with spinal rigidity. KEY POINTS: • Inherited myopathies are rare, diagnosis is challenging and genetic tests require specialized centres and often take years. • Inherited myopathies are often characterized by spinal rigidity. • Whole body magnetic resonance imaging is a unique tool to orientate the diagnosis of each inherited myopathy presenting with spinal rigidity. • Each inherited myopathy in this study has a specific pattern of affected muscles that orientate diagnosis. • A novel MRI-based algorithm, usable by every radiologist, can help the early diagnosis of these myopathies.

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.

Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.

Cardiac manifestations of congenital LMNA-related muscular dystrophy in children: three case reports and recommendations for care.

Skeletal and cardiac muscle laminopathies, caused by mutations in the lamin A/C gene, have a clinical spectrum from congenital LMNA-related muscular dystrophy to later-onset Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, and dilated cardiomyopathy. Although cardiac involvement is observed at all ages, it has only been well described in adults. We present the evolution of cardiac disease in three children with congenital muscular dystrophy presentation of LMNA-related muscular dystrophy. In this series, atrial arrhythmia was the presenting cardiac finding in all three patients. Heart failure developed up to 5 years later. Symptoms of right heart failure, including diarrhoea and peripheral oedema, preceded a rapid decline in left ventricular ejection fraction. Recommendations for cardiac surveillance and management in these patients are made.

Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects.

Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures resulting from reduced fetal mobility. Genetic mapping and whole exome sequencing (WES) were performed in 31 multiplex and/or consanguineous undiagnosed AMC families. Although this approach identified known AMC genes, we here report pathogenic mutations in two new genes. Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families. Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s) and transmission electron microscopy (TEM) of sciatic nerve in the index cases revealed severe abnormalities of both nodes of Ranvier width and myelinated axons. CNTNAP1 encodes CASPR, an essential component of node of Ranvier domains which underlies saltatory conduction of action potentials along the myelinated axons, an important process for neuronal function. A homozygous missense mutation in adenylate cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the peripheral nervous system (PNS) as determined by TEM. Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells. ADCY6 encodes a protein that belongs to the adenylate cyclase family responsible for the synthesis of cAMP. Elevation of cAMP can mimic axonal contact in vitro and upregulates myelinating signals. Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through the cAMP pathway. Mutations of genes encoding proteins of Ranvier domains or involved in myelination of Schwann cells are responsible for novel and severe human axoglial diseases.

Cellular microenvironments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors.

The mechanisms underlying the cell response to mechanical forces are crucial for muscle development and functionality. We aim to determine whether mutations of the LMNA gene (which encodes lamin A/C) causing congenital muscular dystrophy impair the ability of muscle precursors to sense tissue stiffness and to respond to mechanical challenge. We found that LMNA-mutated myoblasts embedded in soft matrix did not align along the gel axis, whereas control myoblasts did. LMNA-mutated myoblasts were unable to tune their cytoskeletal tension to the tissue stiffness as attested by inappropriate cell-matrix adhesion sites and cytoskeletal tension in soft versus rigid substrates or after mechanical challenge. Importantly, in soft two-dimensional (2D) and/or static three-dimensional (3D) conditions, LMNA-mutated myoblasts showed enhanced activation of the yes-associated protein (YAP) signaling pathway that was paradoxically reduced after cyclic stretch. siRNA-mediated downregulation of YAP reduced adhesion and actin stress fibers in LMNA myoblasts. This is the first demonstration that human myoblasts with LMNA mutations have mechanosensing defects through a YAP-dependent pathway. In addition, our data emphasize the crucial role of biophysical attributes of cellular microenvironment to the response of mechanosensing pathways in LMNA-mutated myoblasts.