Objective
This study was undertaken to determine whether a low residual quantity of dystrophin protein is associated with delayed clinical milestones in patients with DMD mutations.
Methods
We ...performed a retrospective multicentric cohort study by using molecular and clinical data from patients with DMD mutations registered in the Universal Mutation Database–DMD France database. Patients with intronic, splice site, or nonsense DMD mutations, with available muscle biopsy Western blot data, were included irrespective of whether they presented with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD). Patients were separated into 3 groups based on dystrophin protein levels. Clinical outcomes were ages at appearance of first symptoms; loss of ambulation; fall in vital capacity and left ventricular ejection fraction; interventions such as spinal fusion, tracheostomy, and noninvasive ventilation; and death.
Results
Of 3,880 patients with DMD mutations, 90 with mutations of interest were included. Forty‐two patients expressed no dystrophin (group A), and 31 of 42 (74%) developed DMD. Thirty‐four patients had dystrophin quantities < 5% (group B), and 21 of 34 (61%) developed BMD. Fourteen patients had dystrophin quantities ≥ 5% (group C), and all but 4 who lost ambulation beyond 24 years of age were ambulant. Dystrophin quantities of <5%, as low as <0.5%, were associated with milder phenotype for most of the evaluated clinical outcomes, including age at loss of ambulation (p < 0.001).
Interpretation
Very low residual dystrophin protein quantity can cause a shift in disease phenotype from DMD toward BMD. ANN NEUROL 2021;89:280–292
Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 ...family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.
Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by severe intellectual disability, early-onset epileptic seizures, and amelogenesis imperfecta. Here, we present ...a novel Rogdi mutant mouse deleting exons 6-11- a mutation found in KTS patients disabling ROGDI function. This Rogdi
mutant model recapitulates most KTS symptoms. Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility. Spontaneous locomotion and circadian activity tests demonstrate Rogdi mutant hyperactivity mirroring patient spasticity. Object recognition impairment indicates memory deficits. Rogdi
mutant enamel was markedly less mature. Scanning electron microscopy confirmed its hypomineralized/hypomature crystallization, as well as its low mineral content. Transcriptomic RNA sequencing of postnatal day 5 lower incisors showed downregulated enamel matrix proteins Enam, Amelx, and Ambn. Enamel crystallization appears highly pH-dependent, cycling between an acidic and neutral pH during enamel maturation. Rogdi
teeth exhibit no signs of cyclic dental acidification. Additionally, expression changes in Wdr72, Slc9a3r2, and Atp6v0c were identified as potential contributors to these tooth acidification abnormalities. These proteins interact through the acidifying V-ATPase complex. Here, we present the Rogdi
mutant as a novel model to partially decipher KTS pathophysiology. Rogdi
mutant defects in acidification might explain the unusual combination of enamel and rare neurological disease symptoms.
Background Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding ...genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end. Methods To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes. Results Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical-histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets. Conclusions Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments. Keywords: Congenital myopathy, Myopathy, Exome sequencing, Genetic diagnosis, Genetic heterogeneity, Phenotypic heterogeneity, Core myopathy, Nemaline myopathy, Centronuclear myopathy, Tubular aggregate myopathy
Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder ...childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes alpha-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle alpha-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac alpha-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation. Keywords: ACTA1, Congenital myopathy, Nemaline rods, Intranuclear rods, Cytoplasmic bodies, Nuclear envelope, Neuromuscular junction
L’électroneuromyogramme (ENMG) est utilisée pour le diagnostic des pathologies neuromusculaires de l’enfant. Il peut cependant être mal toléré et ne retrouve pas toujours d’anomalie.
Nous avons voulu ...évaluer la fréquence des anomalies en ENMG chez les enfants, leurs facteurs prédictifs et la concordance entre les conclusions de l’ENMG et les diagnostics finaux retenus.
Les données cliniques et ENMG de tous les patients de moins de 16 ans ayant eu un ENMG au CHU de Strasbourg de 2017 à 2021 ont été analysées rétrospectivement. Nous avons notamment étudié les symptômes ayant motivé la demande d’EMG, les anomalies retrouvées à la neurographie, aux stimulations répétées et celles évocatrices d’un syndrome myogène. Ces données ont été comparées aux diagnostics à l’issue de tout le bilan et le suivi.
Sur 137 patients inclus, 41 ENMG (30 %) étaient anormaux. Une anomalie évocatrice d’une maladie neuromusculaire était plus souvent retrouvée en cas d’abolition/diminution des réflexes ostéo tendineux, de faiblesse musculaire, de paresthésies et/ou d’hypoesthésie (p<0,05). La concordance entre anomalie ENMG et diagnostic final était plus forte pour les neuropathies (95 %) que pour les syndromes myogènes (44 %) et chez les patients>5 ans (aucune discordance chez eux).
L’ENMG sera plus contributif en cas d’anomalies objectives à l’examen clinique et de paresthésies hors douleur. Avant 1 an, l’ENMG retrouvera plus d’anomalies évocatrices de myopathies mais cela ne sera pas toujours confirmé par la suite du bilan. Après 5 ans, il orientera plus vers des neuropathies avec une meilleure concordance.
L’ENMG est particulièrement utile pour suspecter une myopathie chez l’enfant<1 an et diagnostiquer une neuropathie chez l’enfant>5 ans.
Genetic epilepsy diagnosis is increasing due to technological advancements. Although the use of molecular diagnosis is increasing, chromosomal microarray analysis (CMA) remains an important ...diagnostic tool for many patients. We aim to explore the role and indications of CMA in epilepsy, given the current genomic advances.
We obtained data from 378 epileptic described patients, who underwent CMA between 2015 and 2021. Different types of syndromic or nonsyndromic epilepsy were represented.
After excluding patients who were undertreated or had missing data, we included 250 patients with treated epilepsy and relevant clinical information. These patients mostly had focal epilepsy or developmental and epileptic encephalopathy, with a median start age of 2 years. Ninety percent of the patients had intellectual disability, more than two thirds had normal head size, and 60% had an abnormal magnetic resonance imaging. We also included 10 patients with epilepsy without comorbidities. In our cohort, we identified 35 pathogenic copy number variations (CNVs) explaining epilepsy with nine recurrent CNVs enriched in patients with epilepsy, 12 CNVs related to neurodevelopmental disorder phenotype with possible epilepsy, five CNVs including a gene already known in epilepsy, and nine CNVs based on size combined with de novo occurrence. The diagnosis rate in our study reached 14% (35 of 250) with first-line CMA, as previously reported. Although targeted gene panel sequencing could potentially diagnose some of the reported epilepsy CNVs (34% 12 of 35).
CMA remains a viable option as the first-line genetic test in cases where other genetic tests are not available and as a second-line diagnostic technique if gene panel or exome sequencing yields negative results.
Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors ...(antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines.
In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or “stroke mimic” (SM: normal brain imaging or evoking a migraine).
Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found.
Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy.
Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.
Abstract Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to ...milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1 -related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation.