Expanding the spectrum of variants in neonatal hypotonia - a family report of a homozygous loss of function.

The gene is crucial for skeletal muscle function, and pathogenic variants have been linked to congenital myopathies characterized by hypotonia, muscle weakness, and respiratory insufficiency. To date, -related myopathies have been associated only with autosomal dominant missense variants. We report here the first family case of a recessive form of myopathy related to .

Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel.

Background: Congenital myopathies are a group of neuromuscular disorders that typically present at birth or early childhood with hypotonia and non-progressive or slowly progressive muscle weakness. They are classically subclassified by characteristic structural changes and histopathological findings in skeletal muscle. Variants in over 40 genes have been described to date in patients with various forms of congenital myopathy with overlapping phenotypic and histological features, which poses a challenge for laboratories and clinicians in interpreting genetic findings.

Disease Trajectories of a Large French Cohort of 142 Congenital Myopathy Patients in Adult Age.

Background: Congenital myopathies (CMyo) are a group of rare inherited muscle disorders classified to date according to myopathological features on muscle biopsy. They usually present with an early onset, with a slow or non-progressive muscle weakness. The phenotypic spectrum is wide, ranging from severe early onset forms to milder and later onset conditions.

[From gene to cell: Functional validation of RYR1 variants].

Genetic screening of rare diseases allows identification of the responsible gene(s) in about 50% of patients. The remaining cases are in a diagnostic deadlock as current knowledge fails to identify the correct gene or determine if the detected variant on the gene is pathogenic. These are named "variants of unknown significance" (VUS).

Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review.

Malignant hyperthermia susceptibility (MHS) designates individuals at risk of developing a hypermetabolic reaction triggered by halogenated anaesthetics or the depolarising neuromuscular blocking agent suxamethonium. Over the past few decades, beyond the operating theatre, myopathic manifestations impacting daily life are increasingly recognised as a prevalent phenomenon in MHS patients. At the request of the European Malignant Hyperthermia Group, we reviewed the literature and gathered the opinion of experts to define MHS-related myopathy as a distinct phenotype expressed across the adult lifespan of MHS patients unrelated to anaesthetic exposure; this serves to raise awareness about non-anaesthetic manifestations, potential therapies, and management of MHS-related myopathy.

Muscular phenotype description of abnormal THOC2 splicing.

Until recently, the disease known to be associated with THOC2 mutations was Intellectual developmental disorder, X-linked 12 (MIM300957). However, recently, fetal arthrogryposis multiplex congenita has been associated with a specific splice site mutation in the THOC2 gene. We report a family with the same splice site mutation in the THOC2 gene involved in fetal arthrogryposis as well.

Prenatal diagnosis of Lowe syndrome in a male fetus with isolated bilateral cataract.

Background: Lowe syndrome is a rare disease characterized by the association of congenital cataract, hypotonia, followed by global psychomotor delay and intellectual disability, as well as progressive renal dysfunction, and renal failure occurring at around 20 years of age.

Case Presentation: We discuss the case of a male fetus diagnosed with isolated bilateral cataract on the sonography performed at 21 + 5 weeks of gestation, confirmed by a fetal MRI at 23 weeks of gestation.After ruling out infectious etiologies, a genetic consult was conducted at 26 weeks of gestation, and an amniocentesis was realized to search for a chromosomal cause, Norrie's disease and Lowe syndrome by Sanger analysis.

Gene therapies for RyR1-related myopathies.

Myopathies related to variations in the RYR1 gene are genetic diseases for which the therapeutic options are sparse, in part because of the very large size of the gene and protein, and of the distribution of variations all along the sequence. Taking advantage of the progress made in the gene therapy field, different approaches can be applied to the different genetic variations, either at the mRNA level or directly at the DNA level, specifically with the new gene editing tools. Some of those have already been tested in cellulo and/or in vivo, and for the development of the most innovative gene editing technology, inspiration can be sought in other genetic diseases.

Objective Evaluation of Clinical Actionability for Genes Involved in Myopathies: 63 Genes with a Medical Value for Patient Care.

The implementation of high-throughput diagnostic sequencing has led to the generation of large amounts of mutational data, making their interpretation more complex and responsible for long delays. It has been important to prioritize certain analyses, particularly those of "actionable" genes in diagnostic situations, involving specific treatment and/or management. In our project, we carried out an objective assessment of the clinical actionability of genes involved in myopathies, for which only few data obtained methodologically exist to date.

Development of Knock-Out Muscle Cell Lines using Lentivirus-Mediated CRISPR/Cas9 Gene Editing.

One important application of clustered regulatory interspaced short palindromic repeats (CRISPR)/Cas 9 is the development of knock-out cell lines, specifically to study the function of new genes/proteins associated with a disease, identified during the genetic diagnosis. For the development of such cell lines, two major issues have to be untangled: insertion of the CRISPR tools (the Cas9 and the guide RNA) with high efficiency into the chosen cells, and restriction of the Cas9 activity to the specific deletion of the chosen gene. The protocol described here is dedicated to the insertion of the CRISPR tools in difficult to transfect cells, such as muscle cells.

Regulation of citrulline synthesis in human enterocytes: Role of hypoxia and inflammation.

Intensive care unit patients and chronic airway inflammatory disease are characterized by chronic systemic hypoxia and inflammation inducing a decrease in nitric oxide release due to impaired l-arginine (ARG) homeostasis. As ARG is synthesized from circulating l-citrulline (CIT), an alteration of CIT production in small intestine by ornithine carbamoyltransferase could be involved. Here, we posit that hypoxia and/or inflammation has effects on ornithine carbamoyltransferase regulation in enterocytes.

Challenging indication of cardioverter defibrillator implantation after sudden cardiac arrest in the very young: a case series of catecholaminergic polymorphic ventricular tachycardia secondary to calmodulin p.Asn98Ser.

Background: Calmodulinopathy is an emerging group of primary electrical disease with various, severe, and early onset phenotype. Sudden cardiac arrest (SCA)/death can be the first symptom and current medical management seems insufficient to prevent recurrences. Implantable cardioverter-defibrillator (ICD) in the young is challenging and can be harmful.

Ornithine Transcarbamylase - From Structure to Metabolism: An Update.

Ornithine transcarbamylase (OTC; EC 2.1.3.

A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course.

The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families.

Second Report of Chronic Granulomatous Disease in Jordan: Clinical and Genetic Description of 31 Patients From 21 Different Families, Including Families From Lybia and Iraq.

Chronic granulomatous Disease (CGD) is a rare innate immunodeficiency disorder caused by mutations in one of the six genes (, and /EROS) encoding the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase complex in phagocytes. In the Western population, the most prevalent form of CGD (about two-thirds of all cases) is the X-linked form (X-CGD) caused by mutations in . The autosomal recessive forms (AR-CGD), due to mutations in the other genes, collectively account for the remaining one-third of CGD cases.