Progressive central cardiorespiratory rate downregulation and intensifying epilepsy lead to sudden unexpected death in epilepsy in mouse model of the most common human ATP1A3 mutation.

Objective: This study was undertaken to test the following hypotheses in the Atp1a3 mouse (which carries the most common human ATP1A3 (the major subunit of the neuronal Na/K-adenosine triphosphatase [ATPase]) mutation, D801N): sudden unexpected death in epilepsy (SUDEP) occurs during seizures and is due to terminal apneas in some and due to lethal cardiac arrhythmias in others; and Atp1a3 mice have central cardiorespiratory dysregulation and abnormal respiratory drive.

Methods: Comparison was made of littermate wild-type and Atp1a3 groups using (1) simultaneous in vivo video-telemetry recordings of electroencephalogram, electrocardiogram, and breathing; (2) whole-body plethysmography; and (3) hypoglossal nerve recordings.

Results: In Atp1a3 mice, (1) SUDEP consistently occurred during seizures that were more severe than preterminal seizures; (2) seizure clustering occurred in periods preceding SUDEP; (3) slowing of breathing rate (BR) and heart rate was observed preictally before preterminal and terminal seizures; and (4) the sequence during terminal seizures was as follows: bradypnea with bradycardia/cardiac arrhythmias, then terminal apnea, followed by terminal cardiac arrhythmias.

Respiratory neuropathology in spinocerebellar ataxia type 7.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurological disorder caused by deleterious CAG repeat expansion in the coding region of the ataxin 7 gene (polyQ-ataxin-7). Infantile-onset SCA7 leads to severe clinical manifestation of respiratory distress, but the exact cause of respiratory impairment remains unclear. Using the infantile-SCA7 mouse model, the SCA7266Q/5Q mouse, we examined the impact of pathological polyQ-ataxin-7 on hypoglossal (XII) and phrenic motor units.

Respiratory characterization of a humanized Duchenne muscular dystrophy mouse model.

Duchenne muscular dystrophy (DMD) is the most common X-linked disease. DMD is caused by a lack of dystrophin, a critical structural protein in striated muscle. Dystrophin deficiency leads to inflammation, fibrosis, and muscle atrophy.

The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt.

Biallelic loss-of-function variants in the MUSK gene result in two allelic disorders: (1) congenital myasthenic syndrome (CMS; OMIM: 616325), a neuromuscular disorder that has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness, and (2) fetal akinesia deformation sequence (OMIM: 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle-specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here, we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene, including (1) a deletion of exons 2-3 leading to an in-frame MuSK protein lacking the immunoglobulin 1 (Ig1) domain and (2) a deletion of exons 7-11 leading to an out-of-frame, truncated MuSK protein.

Transitional cell states sculpt tissue topology during lung regeneration.

Organ regeneration requires dynamic cell interactions to reestablish cell numbers and tissue architecture. While we know the identity of progenitor cells that replace lost tissue, the transient states they give rise to and their role in repair remain elusive. Here, using multiple injury models, we find that alveolar fibroblasts acquire distinct states marked by Sfrp1 and Runx1 that influence tissue remodeling and reorganization.

Monitoring and Management of Respiratory Function in Pompe Disease: Current Perspectives.

Pompe disease (PD) is a neuromuscular disorder caused by a deficiency of acid alpha-glucosidase (GAA) - a lysosomal enzyme responsible for hydrolyzing glycogen. GAA deficiency leads to accumulation of glycogen in lysosomes, causing cellular disruption. The severity of PD is directly related to the extent of GAA deficiency - if no or minimal GAA is produced, symptoms are severe and manifest in infancy, known as infantile onset PD (IOPD).

GAA deficiency disrupts distal airway cells in Pompe disease.

Pompe disease is an autosomal recessive glycogen storage disease caused by mutations in the gene that encodes acid alpha-glucosidase (GAA)-an enzyme responsible for hydrolyzing lysosomal glycogen. GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption. Glycogen accumulation in skeletal muscles, motor neurons, and airway smooth muscle cells is known to contribute to respiratory insufficiency in Pompe disease.

X-linked SBMA model mice display relevant non-neurological phenotypes and their expression of mutant androgen receptor protein in motor neurons is not required for neuromuscular disease.

X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness and lower motor neuron degeneration. SBMA was the first human disease found to be caused by a repeat expansion mutation, as affected patients possess an expanded tract of CAG repeats, encoding polyglutamine, in the androgen receptor (AR) gene. We previously developed a conditional BAC fxAR121 transgenic mouse model of SBMA and used it to define a primary role for skeletal muscle expression of polyglutamine-expanded AR in causing the motor neuron degeneration.

ATS Core Curriculum 2022. Pediatric Pulmonary Medicine: Updates in pediatric neuromuscular disease.

The American Thoracic Society Core Curriculum updates clinicians annually in pediatric pulmonary disease. This is a concise review of the Pediatric Pulmonary Medicine Core Curriculum presented at the 2022 American Thoracic Society International Conference. Neuromuscular diseases (NMD) comprise a variety of conditions that commonly affect the respiratory system and cause significant morbidity including dysphagia, chronic respiratory failure, and sleep disordered breathing.

Congenital lobar emphysema in monozygotic twins.

Congenital lobar emphysema (CLE) is caused by airway defects resulting in air trapping and hyperinflation of the affected lobe. Case reports of families affected with CLE imply a genetic etiology. However, the genetic contributions have not been well-described.

Neuro-respiratory pathology in spinocerebellar ataxia.

The spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders with an autosomal dominant inheritance. Symptoms include poor coordination and balance, peripheral neuropathy, impaired vision, incontinence, respiratory insufficiency, dysphagia, and dysarthria. Although many patients with SCA have respiratory-related complications, the exact mechanism and extent of this pathology remain unclear.

Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing.

Recombinant adeno-associated viral (AAV) vectors are a promising gene delivery platform, but ongoing clinical trials continue to highlight a relatively narrow therapeutic window. Effective clinical translation is confounded, at least in part, by differences in AAV biology across animal species. Here, we tackle this challenge by sequentially evolving AAV capsid libraries in mice, pigs and macaques.

Breathing in Duchenne muscular dystrophy: translation to therapy.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a deficiency in dystrophin - a structural protein which stabilises muscle during contraction. Dystrophin deficiency adversely affects the respiratory system leading to sleep-disordered breathing, hypoventilation, and weakness of the expiratory and inspiratory musculature, which culminate in severe respiratory dysfunction. Muscle degeneration-associated respiratory impairment in neuromuscular disease is a result of disruptions at multiple sites of the respiratory control network, including sensory and motor pathways.

What's new and what's next for gene therapy in Pompe disease?

Introduction: Pompe disease is an autosomal recessive disorder caused by a deficiency of acid-α-glucosidase (GAA), an enzyme responsible for hydrolyzing lysosomal glycogen. A lack of GAA leads to accumulation of glycogen in the lysosomes of cardiac, skeletal, and smooth muscle cells, as well as in the central and peripheral nervous system. Enzyme replacement therapy has been the standard of care for 15 years and slows disease progression, particularly in the heart, and improves survival.

Respiratory dysfunction in a mouse model of spinocerebellar ataxia type 7.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the ataxin-7 gene. Infantile-onset SCA7 patients display extremely large repeat expansions (>200 CAGs) and exhibit progressive ataxia, dysarthria, dysphagia and retinal degeneration. Severe hypotonia, aspiration pneumonia and respiratory failure often contribute to death in affected infants.

Glycogen accumulation in smooth muscle of a Pompe disease mouse model.

Pompe disease is a lysosomal storage disease caused by mutations within the GAA gene, which encodes acid α-glucosidase (GAA)-an enzyme necessary for lysosomal glycogen degradation. A lack of GAA results in an accumulation of glycogen in cardiac and skeletal muscle, as well as in motor neurons. The only FDA approved treatment for Pompe disease-an enzyme replacement therapy (ERT)-increases survival of patients, but has unmasked previously unrecognized clinical manifestations of Pompe disease.

Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, , Mouse Model of Alternating Hemiplegia of Childhood.

Alternating Hemiplegia of Childhood (AHC) is a devastating autosomal dominant disorder caused by mutations, resulting in severe hemiplegia and dystonia spells, ataxia, debilitating disabilities, and premature death. Here, we determine the effects of delivering an extra copy of the normal gene in a mouse model carrying the most common mutation causing AHC in humans, the D801N mutation. We used an adeno-associated virus serotype 9 (AAV9) vector expressing the human gene under the control of a human Synapsin promoter.

Genetic deletion of the Tas2r143/Tas2r135/Tas2r126 cluster reveals that TAS2Rs may not mediate bitter tastant-induced bronchodilation.

Bitter taste receptors (TAS2Rs) and their signaling elements are detected throughout the body, and bitter tastants induce a wide variety of biological responses in tissues and organs outside the mouth. However, the roles of TAS2Rs in these responses remain to be tested and established genetically. Here, we employed the CRISPR/Cas9 gene-editing technique to delete three bitter taste receptors-Tas2r143/Tas2r135/Tas2r126 (i.

Respiratory pathology in the Optn mouse model of Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder that results in death due to respiratory failure. Many genetic defects are associated with ALS; one such defect is a mutation in the gene encoding optineurin (OPTN). Using an optineurin null mouse (Optn), we sought to characterize the impact of optineurin deficiency on respiratory neurodegeneration.

Intralingual Administration of AAVrh10-miR Improves Respiratory But Not Swallowing Function in a Superoxide Dismutase-1 Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by degeneration of motor neurons and muscles, and death is usually a result of impaired respiratory function due to loss of motor neurons that control upper airway muscles and/or the diaphragm. Currently, no cure for ALS exists and treatments to date do not significantly improve respiratory or swallowing function. One cause of ALS is a mutation in the superoxide dismutase-1 () gene; thus, reducing expression of the mutated gene may slow the progression of the disease.

Motor axonopathies in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by deleterious mutations in the DMD gene which encodes the dystrophin protein. Skeletal muscle weakness and eventual muscle degradation due to loss of dystrophin are well-documented pathological hallmarks of DMD. In contrast, the neuropathology of this disease remains understudied despite the emerging evidence of neurological abnormalities induced by dystrophin loss.

The Respiratory Phenotype of Pompe Disease Mouse Models.

Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA), a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease mouse models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life.