Inherited leukodystrophies are a group of diseases affecting central nervous system myelin that lead to death or significant health problems. Although for most leukodystrophies there are no curative ...treatments, for a handful of diseases hematopoietic stem cell transplantation (HSCT; bone marrow transplant) can stop disease progression, and if initiated in a timely fashion, prevent many or all neurologic and other systems involvement. However, HSCT is a complex procedure with significant morbidity and mortality risks. The study goal was to determine whether HSCT was being more widely used outside of those leukodystrophies for which HSCT is typically employed. The authors conducted a 2-year retrospective review of HSCT performed across the United States in 51 children’s hospitals that are part of the Pediatric Health Information System. The authors screened for 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes for leukodystrophies in which HSCT is “nonstandard,” including sphingolipidoses, Fabry disease, Gaucher disease, and Niemann-Pick disease, and excluded patients who had ICD-10 codes for leukodystrophies that are HSCT candidates, specifically X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease, and Hurler disease. The authors identified 91 patients (from a total cohort of 937) with one of the nonstandard leukodystrophies who had HSCT. HSCT was performed at 20 of the hospitals, with the majority performed at only 6 hospitals. Average costs ($786 846) per patient were more than 6 times higher than patients who did not have HSCT. The data show that an unexpectedly large number of leukodystrophy patients are receiving transplants for conditions in which HSCT is not typically used, and which are associated with high medical costs.
To identify novel disease associated loci for amyotrophic lateral sclerosis (ALS), we used sequencing data and performed in vitro and in vivo experiments to demonstrate pathogenicity of mutations ...identified in
.
We analyzed exome sequences of 87 patients with sporadic ALS and 324 controls, with confirmatory sequencing in independent ALS cohorts of >2,800 patients. For the top hit,
, a regulator of apoptosis and differentiation and a binding partner and homolog of the tumor suppressor gene
, we assayed mutation effects using in vitro and in vivo experiments. C2C12 myoblast differentiation assays, characterization of myotube appearance, and immunoprecipitation of p53-p73 complexes were performed in vitro. In vivo, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 targeting of zebrafish
to assay motor neuron number and axon morphology.
Four heterozygous rare, nonsynonymous mutations in
were identified in our sporadic ALS cohort. In independent ALS cohorts, we identified an additional 19 rare, deleterious variants in
. Patient
mutations caused abnormal differentiation and increased apoptosis in the myoblast differentiation assay, with abnormal myotube appearance. Immunoprecipitation of mutant ΔN-p73 demonstrated that patient mutations hinder the ability of ΔN-p73 to bind p53. CRISPR/Cas9 knockout of
in zebrafish led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology.
Together, these results strongly suggest that variants in
correlate with risk for ALS and indicate a role for apoptosis in ALS disease pathology.
Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia, spasticity, neurological ...degeneration, seizures, and premature death. A distinctive feature is episodes of rapid neurological deterioration provoked by stressors such as infection, seizures, or trauma. VWM is caused by autosomal recessive mutations in one of five genes that encode the eukaryotic initiation factor 2B complex, which is necessary for protein translation and regulation of the integrated stress response. The majority of mutations are in EIF2B5. Astrocytic dysfunction is central to pathophysiology, thereby constituting a potential therapeutic target. Herein we characterize two VWM murine models and investigate astrocyte-targeted adeno-associated virus serotype 9 (AAV9)-mediated EIF2B5 gene supplementation therapy as a therapeutic option for VWM. Our results demonstrate significant rescue in body weight, motor function, gait normalization, life extension, and finally, evidence that gene supplementation attenuates demyelination. Last, the greatest rescue results from a vector using a modified glial fibrillary acidic protein (GFAP) promoter—AAV9-gfaABC(1)D-EIF2B5—thereby supporting that astrocytic targeting is critical for disease correction. In conclusion, we demonstrate safety and early efficacy through treatment with a translatable astrocyte-targeted gene supplementation therapy for a disease that has no cure.
Display omitted
Herstine and colleagues detail the first-ever adeno-associated virus gene supplementation therapy for the rare leukodystrophy, vanishing white matter disease. Through the characterization of two mouse models utilizing translatable readouts such as MRI, they were able to show promising signs of efficacy and safety in treating this stress-sensitive disease.
The leukodystrophy "Vanishing White Matter" (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding ...pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase. Clinical trials in VWM pose serious challenges, as VWM has an episodic disease course; disease phenotype is highly heterogeneous and predictable only for early onset; and study power is limited by the small patient numbers. To address these challenges and accelerate therapy delivery, the VWM Consortium, a group of academic clinicians with expertise in VWM, decided to develop a core protocol to function as a template for trials, to improve trial design and facilitate sharing of control data, while permitting flexibility regarding other trial details. Overall aims of the core protocol are to collect safety, tolerability, and efficacy data for treatment assessment and marketing authorization.
To develop the core protocol, the VWM Consortium designated a committee, including clinician members of the VWM Consortium, family and patient group advocates, and experts in statistics, clinical trial design and alliancing with industries. We drafted three age-specific protocols, to stratify into more homogeneous patient groups, of ages ≥ 18 years, ≥ 6 to < 18 years and < 6 years. We chose double-blind, randomized, placebo-controlled design for patients aged ≥ 6 years; and open-label non-randomized natural-history-controlled design for patients < 6 years. The protocol describes study populations, age-specific endpoints, inclusion and exclusion criteria, study schedules, sample size determinations, and statistical considerations.
The core protocol provides a shared uniformity across trials, enables a pool of shared controls, and reduces the total number of patients necessary per trial, limiting the number of patients on placebo. All VWM clinical trials are suggested to adhere to the core protocol. Other trial components such as choice of primary outcome, pharmacokinetics, pharmacodynamics, and biomarkers are flexible and unconstrained by the core protocol. Each sponsor is responsible for their trial execution, while the control data are handled by a shared research organization. This core protocol benefits the efficiency of parallel and consecutive trials in VWM, and we hope accelerates time to availability of treatments for VWM.
NA. From a scientific and ethical perspective, it is strongly recommended that all interventional trials using this core protocol are registered in a clinical trial register.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In 2016, the American Academy of Pediatrics published a clinical practice guideline that more specifically defined apparent life-threatening events as brief resolved unexplained events (BRUEs) and ...provided evidence-based recommendations for the evaluation of infants who meet lower-risk criteria for a subsequent event or serious underlying disorder. The clinical practice guideline did not provide recommendations for infants meeting higher-risk criteria, an important and common population of patients. Therefore, we propose a tiered approach for clinical evaluation and management of higher-risk infants who have experienced a BRUE. Because of a vast array of potential causes, the initial evaluation prioritizes the diagnosis of time-sensitive conditions for which delayed diagnosis or treatment could impact outcomes, such as child maltreatment, feeding problems, cardiac arrhythmias, infections, and congenital abnormalities. The secondary evaluation addresses problems that are less sensitive to delayed diagnosis or treatment, such as dysphagia, intermittent partial airway obstruction, and epilepsy. The authors recommend a tailored, family-centered, multidisciplinary approach to evaluation and management of all higher-risk infants with a BRUE, whether accomplished during hospital admission or through coordinated outpatient care. The proposed framework was developed by using available evidence and expert consensus.
The 2009 pandemic influenza A (H1N1) has been recognized to cause neurological complications including seizures and encephalopathy. We identified 18 children with 2009 H1N1 influenza and neurological ...complications from first and second wave activity, and compared characteristics to seasonal influenza. Seizures, encephalopathy, and status epilepticus were common presentations. Focal neurological symptoms persisted in 22% of patients at discharge. Compared to seasonal influenza, patients with pandemic 2009 influenza were more likely to have encephalopathy, focal neurological findings, aphasia, and abnormal electroencephalographic findings. In addition, we noted a trend toward heightened neurological complications following second wave influenza activity. ANN NEUROL 2010
Apparent life-threatening events in infants constitute a significant challenge for health care providers. Apparent life-threatening event evaluation and management are poorly defined, and outcomes ...have not been clearly determined. Our objectives were to characterize short- and long-term risks for death, child abuse, and abnormal neurological outcomes of infants after an apparent life-threatening event and to identify clinical features that are predictive of these outcomes.
We collected data from infants ages birth to 12 months of age who were hospitalized after an apparent life-threatening event during a 5-year time period. Patients were evaluated for subsequent death, child abuse, or adverse neurological outcome (chronic epilepsy or developmental delay).
A total of 471 patients met inclusion criteria and were followed an average of 5.1 years. Two patients died after developing chronic epilepsy and severe developmental delay. Fifty-four (11%) patients were diagnosed as being a victim of child abuse, but only 2 were identified at initial presentation. There were 23 (4.9%) patients with adverse neurological outcomes, including 17 (3.6%) with chronic epilepsy and 14 (3.0%) with developmental delay. Of those who developed chronic epilepsy, 71% returned within 1 month of the initial apparent life-threatening event with a second event. Neurological evaluation at the time of the apparent life-threatening event had low yield for predicting those who would develop chronic epilepsy.
Infants who suffer an apparent life-threatening event are at risk for subsequent child abuse and adverse neurological outcomes. Deaths were uncommon and only occurred in the setting of severe developmental delay and seizure disorders. Neurological evaluation during hospitalization for a first apparent life-threatening event is of low yield, but close follow-up is essential.
Abstract
Objective
Querying large data sets in the United States is challenging due to limitations of International Classification of Diseases 10th edition Clinical Modification (ICD‐10‐CM) codes. ...ICD codes were developed for tracking mortality and for billing purposes but are also the most widely used data structure to represent clinically significant and distinct disorders. We report an approach for developing new ICD codes based on our work creating new codes for leukodystrophies.
Methods
Important steps in ICD‐10‐CM code development include working with the ICD‐10‐CM Coordination and Maintenance Committee, a subset of the National Center of Health Statistics (NCHS); working to ensure the code has the best placement and is appropriate for submission; presenting the code and accompanying proposal (rationale) at a Coordination and Maintenance Committee Meeting; and requesting letters of support and addressing concerns raised by various groups.
Results
We describe the historical development of ICD codes as well as their current hierarchical structure. Important features for successful code development included consulting future ICD‐11‐CM code structure; determining which codes are most important to the community; having a multidisciplinary approach; and obtaining organizational and institutional support.
Conclusion
Focusing on the clinical importance of leukodystrophy codes was important for their approval. Although challenging, there is a route for new code development, and we were ultimately successful in obtaining approval for 10 new leukodystrophy ICD‐10‐CM codes. Understanding ICD codes and their structure, considering their usage for clinical and research work, and appreciating how new codes can be developed is important for the pediatric neurology community.
Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this ...group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records.
Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into “original” and “imputed” encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics.
The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.
The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate ...Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
