Combined clinical, structural, and cellular studies discriminate pathogenic and benign TRPV4 variants.

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias, and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear.

Spinal Muscular Atrophy: A (Now) Treatable Neurodegenerative Disease.

Spinal muscular atrophy (SMA) is a progressive disease of the lower motor neurons associated with recessive loss of the SMN1 gene, and which leads to worsening weakness and disability, and is fatal in its most severe forms. Over the past six years, three treatments have emerged, two drugs that modify exon splicing and one gene therapy, which have transformed the management of this disease. When treated pre-symptomatically, many children show normal early motor development, and the benefits extend from the newborn period to adulthood.

Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.

Targeted Treatments for Inherited Neuromuscular Diseases of Childhood.

In the past decade, the number of genes linked to neuromuscular diseases of childhood has expanded dramatically, and this genetic information is forming the basis for gene-specific and even mutation-specific therapies. At the forefront of these advances are the two recently approved treatments for spinal muscular atrophy: one, an antisense oligonucleotide that modifies splicing of the SMN2 gene, and, the other, a gene therapy vector that delivers the gene to motor neurons, both of which are allowing patients to acquire developmental milestones previously unseen in this fatal disease. This review highlights these advances and emerging targeted therapies for Duchenne muscular dystrophy and centronuclear myopathy, while also covering enzyme replacement therapy and small molecule-based targeted therapies for conditions such as Pompe's disease and congenital myasthenic syndromes.

Neuromuscular Diseases of the Newborn.

The peripheral nervous system (PNS) is composed of motor neurons, nerve roots, plexuses, peripheral nerves (motor, sensory and autonomic), neuromuscular junction, and skeletal muscles. Disorders of the PNS in neonates most frequently cause weakness, hypotonia, and contractures, which may be generalized or focal. Since these findings may also occur with brain and spinal cord lesions, key features of the history and neurologic exam, together with diagnostic testing, are helpful in reaching a diagnosis.

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in . The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families.

Treatment of Leukoencephalopathy With Calcifications and Cysts With Bevacizumab.

Background: Leukoencephalopathy with calcifications and cysts is a rare, autosomal recessive cerebral microangiopathy that causes progressive white matter disease, calcifications, and cysts within the brain. It is typically associated with slowly progressive psychomotor regression, seizures, and movement disorders. Although leukoencephalopathy with calcifications and cysts affects only the central nervous system, it demonstrates remarkable neuropathologic and radiologic overlap with Coats plus, a disorder of small vessels of the brain, eyes, gastrointestinal tract, and bone.

Pediatric Hemorrhagic Brainstem Encephalitis Associated With HHV-7 Infection.

Background: Human herpesviruses-6 and -7 have been associated with febrile seizures and with encephalitis, the latter predominantly in immunocompromised individuals. Acute hemorrhagic encephalitis is frequently a fatal disease that can occur in the setting of viral infection or can be a postinfectious phenomenon, often with no cause identified. Although hemorrhagic encephalitis has been reported with human herpesvirus-6 infection, only one individual, an immunocompromised child, has been documented with human herpesvirus-7 infection.

Relapse severity and recovery in early pediatric multiple sclerosis.

Background: Factors determining severity and recovery of early demyelinating events in pediatric multiple sclerosis (MS) patients are unknown.

Objective: The objective of this study was to characterize the severity and recovery of early demyelinating events in pediatric MS.

Methods: Multivariate logistic regression was performed to determine predictors of severe (versus mild/moderate) relapses and poor or fair (versus complete) recovery in patients aged 18 years or less with MS or clinically isolated syndrome (CIS).

Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions.

Gap junctions are intercellular channels that connect the cytoplasms of adjacent cells. For gap junctions to properly control organ formation and electrical synchronization in the heart and the brain, connexin-based hemichannels must be correctly targeted to cell-cell borders. While it is generally accepted that gap junctions form via lateral diffusion of hemichannels following microtubule-mediated delivery to the plasma membrane, we provide evidence for direct targeting of hemichannels to cell-cell junctions through a pathway that is dependent on microtubules; through the adherens-junction proteins N-cadherin and beta-catenin; through the microtubule plus-end-tracking protein (+TIP) EB1; and through its interacting protein p150(Glued).

SK channels mediate NADPH oxidase-independent reactive oxygen species production and apoptosis in granulocytes.

Neutrophils are immune cells that bind to, engulf, and destroy bacterial and fungal pathogens in infected tissue, and their clearance by apoptosis is essential for the resolution of inflammation. Killing involves both oxidative and nonoxidative processes, the oxidative pathway requiring electrogenic production of superoxide by the membrane-bound NADPH oxidase complex. A variety of stimuli, from bacterial chemotactic peptides to complement- or IgG-opsonized microbes, can induce the production of reactive oxygen species (ROS) by neutrophils, presumably by means of NADPH oxidase.