Publications by authors named "Joshua L Bonkowsky"

97 Publications

Eif2b3 mutants recapitulate phenotypes of Vanishing White Matter Disease and validate novel disease alleles in zebrafish.

Hum Mol Genet 2021 Jan 30. Epub 2021 Jan 30.

Department of Biology, Chungnam National University, Daejeon, Korea.

Leukodystrophy with Vanishing White Matter (VWM), also called Childhood Ataxia with Central Nervous System Hypomyelination (CACH), is caused by mutations in the subunits of the eukaryotic translation initiation factor, EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. However, little is known regarding the underlying pathogenetic mechanisms, and there is no curative treatment for VWM. In this study, we established the first EIF2B3 animal model for VWM disease in vertebrates by CRISPR mutagenesis of the highly conserved zebrafish ortholog eif2b3. Using CRISPR, we generated two mutant alleles in zebrafish eif2b3, 10- and 16-bp deletions, respectively. The eif2b3 mutants showed defects in myelin development and glial cell differentiation, and increased expression of genes in the induced stress response pathway. Interestingly, we also found ectopic angiogenesis and increased VEGF expression. Ectopic angiogenesis in the eif2b3 mutants was reduced by administration of VEGF receptor inhibitor SU5416. Using the eif2b3 mutant zebrafish model together with in silico protein modeling analysis, we demonstrated the pathogenicity of 18 reported mutations in EIF2B3, as well as of a novel variant identified in a 19-month-old female patient: c.503 T > C (p.Leu168Pro). In summary, our zebrafish mutant model of eif2b3 provides novel insights into VWM pathogenesis and offers rapid functional analysis of human EIF2B3 gene variants.
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http://dx.doi.org/10.1093/hmg/ddab033DOI Listing
January 2021

The Pediatric Neurology 2020 Research Workforce Survey: Optimism in a Time of Challenge.

Pediatr Neurol 2021 03 3;116:62-67. Epub 2020 Dec 3.

Division of Neurology, Hospital for Sick Children, Toronto, Ontario. Electronic address:

Background: The past decades have seen a transformational shift in the understanding and treatment for neurological diseases affecting infants and children. These advances have been driven in part by the pediatric neurology physician-scientist workforce and its efforts. However, pediatric neurology research faces substantial challenges from internal and external forces including work-life balance demands, COVID-19 pandemic effects, and research funding. Understanding the impact of these challenges on the perceptions, planning, and careers of pediatric neurology physician-scientists is needed to guide the research mission.

Methods: Our objective was to survey the research challenges, goals, and priorities of pediatric neurologists. In 2020 we conducted a cross-sectional, 28-question survey emailed to 1,775 members of the Child Neurology Society.

Results: One hundred fifty-one individuals responded to the survey. Most respondents were grant investigators (52%) and conducted clinical research (69%). Research areas included epilepsy (23%), neurodevelopmental and autism (16%), neurocritical care and stroke (11%), neurogenetics and neurometabolics (9%), neonatal neurology (8%), and others. The most common funding source was the National Institutes of Health (37%). Shared major research concerns were funding, utilization of remote technology, overcoming disparities, natural history and multicenter studies, global neurology, and diversification of the research portfolio. Commitment to continuing and increasing research efforts was evident.

Conclusions: Our survey demonstrates obstacles for physician-scientist researchers in pediatric neurology, but it also shows optimism about continued opportunity. Creative approaches to address challenges will benefit the research mission, maximize the current and future pool of researchers, and help improve the lives of children with neurological disorders.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.11.020DOI Listing
March 2021

Novel disease-causing variants in a cohort of Iranian patients with metachromatic leukodystrophy and in silico analysis of their pathogenicity.

Clin Neurol Neurosurg 2021 Feb 22;201:106448. Epub 2020 Dec 22.

Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Objective: Metachromatic leukodystrophy (MLD) is an autosomal recessive leukodystrophy caused by deficiency of aryl sulfatase A (ASA) activity affecting the nervous system. MLD and mutations in ARSA have not been widely studied in non-European cohorts. The genotype-phenotype spectrum of MLD patients was investigated in this study of a cohort of Iranian leukodystrophy patients. In silico analysis was performed to investigate the pathogenicity of the variants.

Methods: Genetic analysis for 25 patients was performed with direct sequencing of the ARSA gene. The missense variants underwent in silico analysis to characterize the pathogenicity based on predicted structural and stability changes.

Results: 19 patients had variants in ARSA genes, including 18 homozygotes and one compound heterozygote individual. In 6 individuals no mutations were found in ARSA gene, suggesting an alternative cause of their leukodystrophy. We found 5 novel disease causing variants: p.Phe64Ile, p.Ser292Alafs*34, p.Arg99Profs*35, p.Phe400Leu and p.Leu429Pro. 32 % of the patients had p.Gly311Ser substitution and resulted in juvenile MLD type. Different in silico analysis showed variable pathogenic effect for the variants.

Conclusion: c.931 G > A (p.Gly311Ser) and c.465 + 1 G > A variants are the most frequent alleles among Iranian MLD patients and five mutations appear to be confined to the Iranian patients. Population screening for these variants may be helpful to reduce the burden of the disease in this part of the world.
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http://dx.doi.org/10.1016/j.clineuro.2020.106448DOI Listing
February 2021

Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response.

Elife 2020 12 10;9. Epub 2020 Dec 10.

Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States.

Vanishing white matter disease (VWM) is a severe leukodystrophy of the central nervous system caused by mutations in subunits of the eukaryotic initiation factor 2B complex (eIF2B). Current models only partially recapitulate key disease features, and pathophysiology is poorly understood. Through development and validation of zebrafish () models of VWM, we demonstrate that zebrafish mutants phenocopy VWM, including impaired somatic growth, early lethality, effects on myelination, loss of oligodendrocyte precursor cells, increased apoptosis in the CNS, and impaired motor swimming behavior. Expression of human in the zebrafish mutant rescues lethality and CNS apoptosis, demonstrating conservation of function between zebrafish and human. In the mutants, intron 12 retention leads to expression of a truncated transcript. Expression of the truncated in wild-type larva impairs motor behavior and activates the ISR, suggesting that a feed-forward mechanism in VWM is a significant component of disease pathophysiology.
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http://dx.doi.org/10.7554/eLife.56319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752137PMC
December 2020

Novel and known morbidities of leukodystrophies identified using a phenome-wide association study.

Neurol Clin Pract 2020 Oct;10(5):406-414

Division of Pediatric Neurology (JLB), Department of Pediatrics, University of Utah School of Medicine; Brain and Spine Center (JLB), Primary Children's Hospital, Intermountain Healthcare, Salt Lake City; Intermountain Healthcare (JW), Salt Lake City; Department of Internal Medicine (JY), University of Utah School of Medicine, Salt Lake City; and Department of Biomedical Informatics (W-QW), Vanderbilt University Medical Center, Nashville, TN.

Objective: To determine shared comorbidities and to identify underrecognized or unexpected morbidities in children with leukodystrophies using an unbiased phenome-wide association study (PheWAS) analysis of a nationwide pediatric clinical and financial database.

Methods: Data were extracted from the Pediatric Health Information System database. Patients with leukodystrophy were identified with International Classification of Diseases, 10th revision, clinical modification, diagnostic codes for any of 4 specific leukodystrophies (X-linked adrenoleukodystrophy (E71.52x), Hurler disease (E76.01), Krabbe disease (E75.23), and metachromatic leukodystrophy (E75.25)) over a 3-year time period. Confirmed leukodystrophy cases (n = 553) were matched with 1659 controls. A PheWAS analysis was performed on all available ICD diagnostic codes for cases and controls. Comparisons were performed for all 4 leukodystrophies as a group and individually.

Results: We found 174 phecodes (grouped ICD codes) associated with leukodystrophies, including 28 codes with a rate difference (RD) > 20%. Known comorbidities of leukodystrophies including developmental delay, epilepsy, and adrenal insufficiency were identified. Unexpected associations identified included hypertension (RD 30%, OR 25), hearing loss (RD 28%, OR 15), and cardiac dysrhythmias (RD 27%, OR 9). Hurler disease had a greater number of unique disease conditions.

Conclusions: PheWAS analysis from a national database demonstrates shared and unique features of leukodystrophies. Developmental delay, cardiac dysrhythmias, fluid and electrolyte disturbances, and respiratory issues were common to all 4 leukodystrophy diseases. Use of a PheWAS in leukodystrophies and other pediatric neurologic diseases offers a method for targeting improved care for patients by identification of morbidities.
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http://dx.doi.org/10.1212/CPJ.0000000000000783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717630PMC
October 2020

Barriers, access and management of paediatric epilepsy with telehealth.

J Telemed Telecare 2020 Nov 12:1357633X20969531. Epub 2020 Nov 12.

Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine and Primary Children's Hospital, USA.

Access to paediatric neurology care is complex, resulting in significant wait times and negative patient outcomes. The goal of the American Academy of Pediatrics National Coordinating Center for Epilepsy's project, Access Improvement and Management of Epilepsy with Telehealth (AIM-ET), was to identify access and management challenges in the deployment of telehealth technology. AIM-ET organised four paediatric neurology teams to partner with primary-care providers (PCP) and their multidisciplinary teams. Telehealth visits were conducted for paediatric epilepsy patients. A post-visit survey assessed access and satisfaction with the telehealth visit compared to an in-person visit. Pre/post surveys completed by PCPs and neurologists captured telehealth visit feasibility, functionality and provider satisfaction. A provider focus group assessed facilitators and barriers to telehealth. Sixty-one unique patients completed 75 telehealth visits. Paired t-test analysis demonstrated that telehealth enhanced access to epilepsy care. It reduced self-reported out-of-pocket costs (<0.001), missed school hours (<0.001) and missed work hours (<0.001), with 94% equal parent/caregiver satisfaction. Focus groups indicated developing and maintaining partnerships, institutional infrastructure and education as facilitators and barriers to telehealth. Telehealth shortened travelling distance, reduced expenses and time missed from school and work. Further, it provides significant opportunity in an era when coronavirus disease 2019 limits in-person clinics.
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http://dx.doi.org/10.1177/1357633X20969531DOI Listing
November 2020

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Authors:
Félixe Pelletier Stefanie Perrier Ferdy K Cayami Amytice Mirchi Stephan Saikali Luan T Tran Nicole Ulrick Kether Guerrero Emmanouil Rampakakis Rosalina M L van Spaendonk Sakkubai Naidu Daniela Pohl William T Gibson Michelle Demos Cyril Goizet Ingrid Tejera-Martin Ana Potic Brent L Fogel Bernard Brais Michel Sylvain Guillaume Sébire Charles Marques Lourenço Joshua L Bonkowsky Coriene Catsman-Berrevoets Pedro S Pinto Sandya Tirupathi Petter Strømme Ton de Grauw Dorota Gieruszczak-Bialek Ingeborg Krägeloh-Mann Hanna Mierzewska Heike Philippi Julia Rankin Tahir Atik Brenda Banwell William S Benko Astrid Blaschek Annette Bley Eugen Boltshauser Drago Bratkovic Klara Brozova Icíar Cimas Christopher Clough Bernard Corenblum Argirios Dinopoulos Gail Dolan Flavio Faletra Raymond Fernandez Janice Fletcher Maria Eugenia Garcia Garcia Paolo Gasparini Janina Gburek-Augustat Dolores Gonzalez Moron Aline Hamati Inga Harting Christoph Hertzberg Alan Hill Grace M Hobson A Micheil Innes Marcelo Kauffman Susan M Kirwin Gerhard Kluger Petra Kolditz Urania Kotzaeridou Roberta La Piana Eriskay Liston William McClintock Meriel McEntagart Fiona McKenzie Serge Melançon Anjum Misbahuddin Mohnish Suri Fernando I Monton Sebastien Moutton Raymond P J Murphy Miriam Nickel Hüseyin Onay Simona Orcesi Ferda Özkınay Steffi Patzer Helio Pedro Sandra Pekic Mercedes Pineda Marfa Amy Pizzino Barbara Plecko Bwee Tien Poll-The Vera Popovic Dietz Rating Marie-France Rioux Norberto Rodriguez Espinosa Anne Ronan John R Ostergaard Elsa Rossignol Rocio Sanchez-Carpintero Anna Schossig Nesrin Senbil Laura K Sønderberg Roos Cathy A Stevens Matthis Synofzik László Sztriha Daniel Tibussek Dagmar Timmann Davide Tonduti Bart P van de Warrenburg Maria Vázquez-López Sunita Venkateswaran Pontus Wasling Evangeline Wassmer Richard I Webster Gert Wiegand Grace Yoon Joost Rotteveel Raphael Schiffmann Marjo S van der Knaap Adeline Vanderver Gabriel Á Martos-Moreno Constantin Polychronakos Nicole I Wolf Geneviève Bernard

J Clin Endocrinol Metab 2021 Jan;106(2):e660-e674

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

Pediatric Neurology Research in the Twenty-First Century: Status, Challenges, and Future Directions Post-COVID-19.

Pediatr Neurol 2020 12 26;113:2-12. Epub 2020 Aug 26.

Department of Pediatrics, New York-Presbyterian/Weill Cornell Medicine, New York, New York.

Background: The year 2020 marked a fundamental shift in the pediatric neurology field. An impressive positive trajectory of advances in patient care and research faced sudden global disruptions by the coronavirus disease 2019 pandemic and by an international movement protesting racial, socioeconomic, and health disparities. The disruptions revealed obstacles and fragility within the pediatric neurology research mission. However, renewed commitment offers unique opportunities for the pediatric neurology research community to enhance and prioritize research directions for the coming decades.

Methods: The Research Committee of the Child Neurology Society evaluated the challenges and opportunities facing the pediatric neurology research field, including reviewing published literature, synthesizing publically available data, and conducting a survey of pediatric neurologists.

Results: We identified three priority domains for the research mission: funding levels, active guidance, and reducing disparities. Funding levels: to increase funding to match the burden of pediatric neurological disease; to tailor funding mechanisms and strategies to support clinical trial efforts unique to pediatric neurology; and to support investigators across their career trajectory. Active guidance: to optimize infrastructure and strategies, to leverage novel therapeutics, enhance data collection, and improve inclusion of children in clinical trials. Reducing disparities: to reduce health disparities in children with neurological disease, to develop proactive measures to enhance workforce diversity and inclusion, and increase avenues to balance work-life obligations for investigators.

Conclusions: In this uniquely challenging epoch, the pediatric neurology research community has a timely and important mission to re-engage the public and government, advancing the health of children with neurological conditions.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.08.012DOI Listing
December 2020

Elevated Leukodystrophy Incidence Predicted From Genomics Databases.

Pediatr Neurol 2020 10 17;111:66-69. Epub 2020 Jun 17.

Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah; Primary Children's Center for Personalized Medicine, Salt Lake City, Utah. Electronic address:

Background: Leukodystrophies are genetic diseases affecting the white matter and leading to early death. Our objective was to determine leukodystrophy incidence, using genomics sequencing databases allele frequencies of disease-causing variants.

Methods: From 49 genes, representing the standardly defined group of leukodystrophies, we identified potential disease-causing variants from publications in the Human Genetic Mutation Database and from predictions in the Genome Aggregation Database. Allele frequencies were estimated from Genome Aggregation Database. Allele frequencies for each gene were summed to generate a super allele frequency and we used the Hardy-Weinberg equation to calculate overall expected live birth incidence associated with the gene in question.

Results: We identified 4564 pathogenic variants for 25 discrete leukodystrophies. The largest effect was from GALC variants (Krabbe disease), which had a predicted incidence of one in 12,080 live births, 8.3 times higher than published estimates. The second most frequently predicted leukodystrophy was the RNA polymerase III-related disorders, which had an incidence of 1:26,160. Overall, we found a leukodystrophy incidence of 1 in 4733 live births, significantly higher than previous estimates.

Conclusions: Our data are consistent with a significant underdiagnosis of leukodystrophy patients. An intriguing additional consideration is that there may be genetic modifiers that lead to weaker, absent, or adult-onset disease phenotypes.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506144PMC
October 2020

Expanded Phenotypic Definition Identifies Hundreds of Potential Causative Genes for Leukodystrophies and Leukoencephalopathies.

Child Neurol Open 2020 Jan-Dec;7:2329048X20939003. Epub 2020 Jul 8.

Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.

Background: The genes responsible for genetic white matter disorders (GWMD; leukodystrophies and leukoencephalopathies) are incompletely known. Our goal was to revise the list of genes considered to cause GWMD. We considered a GWMD to consist of any genetic disease causing T2 signal white matter changes in magnetic resonance images.

Methods And Results: Using a systematic review of PubMed, Google, published literature reviews, and commercial gene panels, we identified 399 unique genes meeting the GWMD definition. Of this, 87 (22%) genes were hypomyelinating. Only 3 genes had contrast enhancement on magnetic resonance imaging (MRI): , , and .

Conclusions: A significantly greater number of genes than previously recognized, 399, are associated with white matter signal changes on T2 MRI. This expansion of GWMD genes can be useful in analysis and interpretation of next-generation sequencing results for GWMD diagnosis, and for understanding shared pathophysiological mechanisms of GWMDs.
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http://dx.doi.org/10.1177/2329048X20939003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359642PMC
July 2020

Geographic and Specialty Access Disparities in US Pediatric Leukodystrophy Diagnosis.

J Pediatr 2020 05 3;220:193-199. Epub 2020 Mar 3.

Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT; Brain and Spine Center, Primary Children's Hospital, Salt Lake City, UT; Primary Children's Center for Personalized Medicine, Salt Lake City, UT. Electronic address:

Objective: To examine disparities in the diagnosis of leukodystrophies including geographic factors and access to specialty centers.

Study Design: Retrospective cohort study of pediatric patients admitted to Pediatric Health Information System hospitals. Patients with leukodystrophy were identified with International Classification of Diseases, Tenth Revision, Clinical Modification diagnostic codes for any of 4 leukodystrophies (X-linked adrenoleukodystrophy, Hurler disease, Krabbe disease, and metachromatic leukodystrophy). We used 3-level hierarchical generalized logistic modeling to predict diagnosis of a leukodystrophy based on distance traveled for hospital, neighborhood composition, urban/rural context, and access to specialty center.

Results: We identified 501 patients with leukodystrophy. Patients seen at a leukodystrophy center of excellence hospital were 1.73 times more likely to be diagnosed than patients at non-center of excellence hospitals. Patients who traveled farther were more likely to be diagnosed than those who traveled shorter. Patients living in a Health Professionals Shortage Area zip code were 0.86 times less likely to be diagnosed than those living in a non-Health Professionals Shortage Area zip code.

Conclusions: Geographic factors affect the diagnosis of leukodystrophies in pediatric patients, particularly in regard to access to a center with expertise in leukodystrophies. Our findings suggest a need for improving access to pediatric specialists and possibly deploying specialists or diagnostic testing more broadly.
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http://dx.doi.org/10.1016/j.jpeds.2020.01.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186149PMC
May 2020

Racial/Ethnic and Insurance Status Disparities in Distance Traveled to Access Children's Hospital Care for Severe Illness: the Case of Children with Leukodystrophies.

J Racial Ethn Health Disparities 2020 10 24;7(5):975-986. Epub 2020 Feb 24.

Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way/Williams Building, Salt Lake City, UT, 84108, USA.

Families of children with special health care needs may travel substantial distances to access specialized health care. However, it is not known how race/ethnicity, insurance status, and access to disease-specific specialty care affect travel distances. This analysis examines patients aged 18 years or younger who were discharged from a Pediatric Health Information System (PHIS) children's hospital (n = 52) with a diagnosis of an inherited leukodystrophy between October 1, 2015, and September 30, 2018 (n = 950 patients). Leukodystrophies are rare but very serious neurological illnesses, with elevated mortality and morbidity rates. Bivariate and hierarchical generalized linear models reveal that white children, privately insured children, and children visiting leukodystrophy specialist centers travel farther for children's hospital care. These findings indicate that socially privileged families travel greater distances to obtain specialized health care, which could affect clinical outcomes.
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http://dx.doi.org/10.1007/s40615-020-00722-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483148PMC
October 2020

Dopaminergic Co-Regulation of Locomotor Development and Motor Neuron Synaptogenesis is Uncoupled by Hypoxia in Zebrafish.

eNeuro 2020 Jan/Feb;7(1). Epub 2020 Feb 27.

Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132

Hypoxic injury to the developing human brain is a complication of premature birth and is associated with long-term impairments of motor function. Disruptions of axon and synaptic connectivity have been linked to developmental hypoxia, but the fundamental mechanisms impacting motor function from altered connectivity are poorly understood. We investigated the effects of hypoxia on locomotor development in zebrafish. We found that developmental hypoxia resulted in decreased spontaneous swimming behavior in larva, and that this motor impairment persisted into adulthood. In evaluation of the diencephalic dopaminergic neurons, which regulate early development of locomotion and constitute an evolutionarily conserved component of the vertebrate dopaminergic system, hypoxia caused a decrease in the number of synapses from the descending dopaminergic diencephalospinal tract (DDT) to spinal cord motor neurons. Moreover, dopamine signaling from the DDT was coupled jointly to motor neuron synaptogenesis and to locomotor development. Together, these results demonstrate the developmental processes regulating early locomotor development and a requirement for dopaminergic projections and motor neuron synaptogenesis. Our findings suggest new insights for understanding the mechanisms leading to motor disability from hypoxic injury of prematurity.
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http://dx.doi.org/10.1523/ENEURO.0355-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046933PMC
February 2020

Disparities in Pediatric Epilepsy Remission Are Associated With Race and Ethnicity.

J Child Neurol 2019 12 10;34(14):928-936. Epub 2019 Sep 10.

Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.

Objective: The purpose of our study was to assess whether race/ethnicity was associated with seizure remission in pediatric epilepsy.

Methods: This was a retrospective population-based cohort study of children who were evaluated for new-onset epilepsy in the clinic, emergency department, and/or hospital by a pediatric neurologist in an integrated health care delivery system. Children were between ages 6 months and 15 years at their initial presentation of epilepsy. The cohort, identified through an electronic database, was assembled over 6 years, with no less than 5 years of follow-up. All children were evaluated for race, ethnicity, insurance type, and socioeconomic background. Patient outcome was determined at the conclusion of the study period and categorized according to their epilepsy control as either drug resistant (pharmacoresistant and intractable) or drug responsive (controlled, probable remission, and terminal remission).

Results: In the final cohort of 776 patients, 63% were drug responsive (control or seizure remission). After controlling for confounding socioeconomic and demographic factors, children of Hispanic ethnicity experienced reduced likelihood (hazard) of drug-responsive epilepsy (hazard ratio 0.6, < .001), and had longer median time to remission (8 years; 95% CI 5.9-9.6 years) compared to white non-Hispanic patients (5.6 years; 95% CI 4.9-6.1 years). Among Hispanic patients, higher health care costs were associated with reduced likelihood of drug responsiveness.

Significance: We found that Hispanic ethnicity is associated with a reduced likelihood of achieving seizure control and remission. This study suggests that factors associated with the race/ethnicity of patients contributes to their likelihood of achieving seizure freedom.
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http://dx.doi.org/10.1177/0883073819866623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842107PMC
December 2019

A Framework for Evaluation of the Higher-Risk Infant After a Brief Resolved Unexplained Event.

Pediatrics 2019 08;144(2)

Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, Washington.

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.
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http://dx.doi.org/10.1542/peds.2018-4101DOI Listing
August 2019

Targeted gene panel sequencing for the rapid diagnosis of acutely ill infants.

Mol Genet Genomic Med 2019 07 13;7(7):e00796. Epub 2019 Jun 13.

University of Utah School of Medicine, Salt Lake City, Utah.

Background: Exome/genome sequencing (ES/GS) have been recently used in neonatal and pediatric/cardiac intensive care units (NICU and PICU/CICU) to diagnose and care for acutely ill infants, but the effectiveness of targeted gene panels for these purposes remains unknown.

Methods: RapSeq, a newly developed panel targeting 4,503 disease-causing genes, was employed on selected patients in our NICU/PICU/CICU. Twenty trios were sequenced from October 2015 to March 2017. We assessed diagnostic yield, turnaround times, and clinical consequences.

Results: A diagnosis was made in 10/20 neonates (50%); eight had de novo variants (ASXL1, CHD, FBN1, KMT2D, FANCB, FLNA, PAX3), one was a compound heterozygote for CHAT, and one had a maternally inherited GNAS variant. Preliminary reports were generated by 9.6 days (mean); final reports after Sanger sequencing at 16.3 days (mean). In all positive infants, the diagnosis changed management. In a case with congenital myasthenia, diagnosis and treatment occurred at 17 days versus 7 months in a historical control.

Conclusions: This study shows that a gene panel that includes the majority of known disease-causing genes can rapidly identify a diagnosis in a large number of tested infants. Due to simpler deployment and interpretation and lower costs, this approach might represent an alternative to ES/GS in the NICU/PICU/CICU.
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http://dx.doi.org/10.1002/mgg3.796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625092PMC
July 2019

Development, Implementation, and Use of a Neurology Therapeutics Committee.

Child Neurol Open 2019 14;6:2329048X19830473. Epub 2019 Feb 14.

Division of Pediatric Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.

Innovative therapeutics are transforming care of children with previously untreatable neurological disorders. However, there are challenges in the use of new therapies: the medicine may not be effective in all patients, administration may not be tolerated, and matching therapy choice to patient is complex. Finally, costs are high, which imposes financial burdens on insurance companies, families, and the health-care system. Our objective was to address challenges for clinical implementation of the new therapeutics. We sought to develop a process that would be personalized for patient and disease, encourage appropriate use of a therapeutic agent while mitigating pressure on a clinician to prescribe the therapy in all instances, and assist third-party payers in approving therapeutic use based on safety and efficacy. We report our creation of a Neurology Therapeutics Committee for pediatric patients. We review the committee's mechanisms, describe its use and report outcomes, and suggest the Neurology Therapeutics Committee's broader applicability.
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http://dx.doi.org/10.1177/2329048X19830473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378459PMC
February 2019

Association of Diagnosis of Leukodystrophy With Race and Ethnicity Among Pediatric and Adolescent Patients.

JAMA Netw Open 2018 11 2;1(7):e185031. Epub 2018 Nov 2.

Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.

Importance: Inherited leukodystrophies are a group of neurological diseases affecting myelin that cause significant morbidities and death. Timely and correct diagnosis is important for initiating treatment, designing disease screening, and offering care and guidance to patients and families.

Objective: To determine whether there are disparities in leukodystrophy diagnosis in different racial backgrounds.

Design, Setting, And Participants: This case-control study involved a retrospective review of patients aged 18 years or younger who were diagnosed with 1 of 4 leukodystrophies (metachromatic leukodystrophy, X-linked adrenoleukodystrophy, Krabbe disease, and Hurler disease) in the US Children's Hospital Association's Pediatric Health Information System database from October 1, 2015, through September 30, 2017.

Main Outcomes And Measures: Leukodystrophy diagnosis and racial background of the patients were analyzed. Adjusted prevalence estimates of leukodystrophies were obtained by controlling for sex, insurance type, urban or rural status, 2010 median household income for patient zip code, number of inpatient days, and age at first visit. Pathogenic leukodystrophy gene allele frequencies in different racial backgrounds for ABCD1, ARSA, GALC, and IDUA were determined using the gnomAD database.

Results: Of the 557 patients identified with a leukodystrophy (221 [40%] female; 321 [58%] white non-Hispanic, 54 [10%] black non-Hispanic, and 51 [9%] white Hispanic; median [range] age, 7 [0-18] years), nonwhite race, including black non-Hispanic, black Hispanic, and white Hispanic, was associated with not having a leukodystrophy diagnosis. The adjusted prevalence for a leukodystrophy diagnosis in white non-Hispanic patients was 13.8 (95% CI, 10.6-17.9) per 100 000 patients, compared with 5.8 (95% CI, 3.8-8.9), 2.4 (95% CI, 1.1-5.2), and 7.4 (95% CI, 5.2-10.4) per 100 000 in black non-Hispanic, black Hispanic, and white Hispanic patients, respectively. This reduced rate of diagnosis was out of proportion to the frequency of the different races in the Pediatric Health Information System database. Similar or higher frequencies of missense or loss-of-function alleles were measured in populations of Latino and African descent for the pathogenic leukodystrophy gene alleles. For example, for ABCD1, allele frequencies in those of Latino or African descent were 2.1 × 10-5 and 2.2 × 10-5, as compared with 1.4 × 10-5 for those of European non-Finnish descent.

Conclusions And Relevance: Patients of racial/ethnic minorities, including those from black, black Hispanic, and white Hispanic backgrounds, were significantly less likely to be diagnosed with a leukodystrophy. Leukodystrophy disease-associated allele frequencies were the same or higher in populations of Latino or African descent, arguing against a genetic founder effect being responsible for the lower diagnosis rates. This underdiagnosis has implications for newborn screening programs and treatment access and may reflect a more widespread problem in pediatric neurological and orphan diseases.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.5031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324379PMC
November 2018

Hypoxia and connectivity in the developing vertebrate nervous system.

Dis Model Mech 2018 12 12;11(12). Epub 2018 Dec 12.

Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA.

The developing nervous system depends upon precise regulation of oxygen levels. Hypoxia, the condition of low oxygen concentration, can interrupt developmental sequences and cause a range of molecular, cellular and neuronal changes and injuries. The roles and effects of hypoxia on the central nervous system (CNS) are poorly characterized, even though hypoxia is simultaneously a normal component of development, a potentially abnormal environmental stressor in some settings, and a clinically important complication, for example of prematurity. Work over the past decade has revealed that hypoxia causes specific disruptions in the development of CNS connectivity, altering axon pathfinding and synapse development. The goals of this article are to review hypoxia's effects on the development of CNS connectivity, including its genetic and molecular mediators, and the changes it causes in CNS circuitry and function due to regulated as well as unintended mechanisms. The transcription factor HIF1α is the central mediator of the CNS response to hypoxia (as it is elsewhere in the body), but hypoxia also causes a dysregulation of gene expression. Animals appear to have evolved genetic and molecular responses to hypoxia that result in functional behavioral alterations to adapt to the changes in oxygen concentration during CNS development. Understanding the molecular pathways underlying both the normal and abnormal effects of hypoxia on CNS connectivity may reveal novel insights into common neurodevelopmental disorders. In addition, this Review explores the current gaps in knowledge, and suggests important areas for future studies.
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http://dx.doi.org/10.1242/dmm.037127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307895PMC
December 2018

Scope and Burden of Non-Standard of Care Hematopoietic Stem Cell Transplantation in Pediatric Leukodystrophy Patients.

J Child Neurol 2018 12 28;33(14):882-887. Epub 2018 Sep 28.

2 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.

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.
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http://dx.doi.org/10.1177/0883073818798090DOI Listing
December 2018

Autism Spectrum Disorder and Neonatal Serum Magnesium Levels in Preterm Infants.

Child Neurol Open 2018 18;5:2329048X18800566. Epub 2018 Sep 18.

Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.

Premature birth is associated with increased risk of autism spectrum disorder. Antenatal maternal magnesium administration is known to reduce subsequent risk of cerebral palsy including among premature infants, suggesting a potentially broader neuroprotective role for magnesium. Our objective was to determine whether magnesium could be protective against autism spectrum disorders in premature infants. A cohort of 4855 preterm children was identified, magnesium levels from 24 to 48 hours of life recorded, and subsequent autism spectrum disorder status determined. Adjusted relative risk of autism spectrum disorder with each 1 mg/dL increase in neonatal magnesium level was 1.15 (95% confidence interval: 0.86-1.53). Analysis of variance indicated that magnesium levels varied by gestational age and maternal antenatal magnesium supplementation, but not autism spectrum disorder status ( = 1.43, = .23). We found that neonatal magnesium levels were not associated with decreased autism spectrum disorder risk. Future research into autism spectrum disorder risks and treatments in premature infants is needed.
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http://dx.doi.org/10.1177/2329048X18800566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144497PMC
September 2018

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy.

NPJ Genom Med 2018 13;3:22. Epub 2018 Aug 13.

1Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT USA.

Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.
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http://dx.doi.org/10.1038/s41525-018-0061-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089881PMC
August 2018

Novel Mutations Identified With Next-Generation Sequencing Expand the Spectrum of PLP1-Associated Leukodystrophy Clinical Phenotypes.

Child Neurol Open 2018 23;5:2329048X18789282. Epub 2018 Jul 23.

Pediatric Motor Disorders Research Program, Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.

Next-generation sequencing was performed for 2 families with an undiagnosed neurologic disease. Analysis revealed X-linked mutations in the () gene, which is associated with X-linked Pelizaeus-Merzbacher disease and Spastic Paraplegia type 2. In family A, the novel missense mutation c.617T>A (p.M206K) was hemizygous in the 2 affected male children and heterozygous in the mother. In family B, the novel frameshift mutation c.359_369del (p.G120fs) was hemizygous in the affected male child. Although mutations have been reported to cause an increasingly wide range of phenotypes inclusive of the dystonia, spastic paraparesis, motor neuronopathy, and leukodystrophy observed in our patients, atypical features included the cerebrospinal fluid deficiency of neurotransmitter and pterin metabolites and the delayed appearance of myelin abnormalities on neuroimaging studies. Next-generation sequencing studies provided a diagnosis for these families with complex leukodystrophy disease phenotypes, which expanded the spectrum of PLP1-associated leukodystrophy clinical phenotypes.
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http://dx.doi.org/10.1177/2329048X18789282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056774PMC
July 2018

The Midline Axon Crossing Decision Is Regulated through an Activity-Dependent Mechanism by the NMDA Receptor.

eNeuro 2018 Mar-Apr;5(2). Epub 2018 Apr 17.

Department of Pediatrics.

Axon guidance in vertebrates is controlled by genetic cascades as well as by intrinsic activity-dependent refinement of connections. Midline axon crossing is one of the best studied pathfinding models and is fundamental to the establishment of bilaterally symmetric nervous systems. However, it is not known whether crossing requires intrinsic activity in axons, and what controls that activity. Further, a mechanism linking neuronal activity and gene expression has not been identified for axon pathfinding. Using embryonic zebrafish, we found that the NMDA receptor (NMDAR) NR1.1 subunit () is expressed in commissural axons. Pharmacological inhibition of , hypoxia exposure reduction of expression, or CRISPR knock-down of leads to defects in midline crossing. Inhibition of neuronal activity phenocopies the effects of loss on midline crossing. By combining pharmacological inhibition of the NMDAR with optogenetic stimulation to precisely restore neuronal activity, we observed rescue of midline crossing. This suggests that the NMDAR controls pathfinding by an activity-dependent mechanism. We further show that the NMDAR may act, via modulating activity, on the transcription factor (mammalian ), a known regulator of midline pathfinding. These findings uncover a novel role for the NMDAR in controlling activity to regulate commissural pathfinding and identify as a key link between the genetic and activity-dependent regulation of midline axon guidance.
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http://dx.doi.org/10.1523/ENEURO.0389-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952305PMC
January 2019

Rapid clinical diagnostic variant investigation of genomic patient sequencing data with web tools.

J Clin Transl Sci 2017 Dec;1(6):381-386

Department of Human Genetics, USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.

Introduction: Computational analysis of genome or exome sequences may improve inherited disease diagnosis, but is costly and time-consuming.

Methods: We describe the use of , a web-based tool suite for intuitive, real-time genome diagnostic analyses.

Results: We used to identify the disease-causing variant in a patient with early infantile epileptic encephalopathy with prior nondiagnostic genetic testing.

Conclusions: tools can be used by clinicians to rapidly identify disease-causing variants from genomic patient sequencing data.
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http://dx.doi.org/10.1017/cts.2017.311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915807PMC
December 2017

An automated system for rapid cellular extraction from live zebrafish embryos and larvae: Development and application to genotyping.

PLoS One 2018 15;13(3):e0193180. Epub 2018 Mar 15.

Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.

Zebrafish are a valuable model organism in biomedical research. Their rapid development, ability to model human diseases, utility for testing genetic variants identified from next-generation sequencing, amenity to CRISPR mutagenesis, and potential for therapeutic compound screening, has led to their wide-spread adoption in diverse fields of study. However, their power for large-scale screens is limited by the absence of automated genotyping tools for live animals. This constrains potential drug screen options, limits analysis of embryonic and larval phenotypes, and requires raising additional animals to adulthood to ensure obtaining an animal of the desired genotype. Our objective was to develop an automated system that would rapidly obtain cells and DNA from zebrafish embryos and larvae for genotyping, and that would keep the animals alive. We describe the development, testing, and validation of a zebrafish embryonic genotyping device, termed "ZEG" (Zebrafish Embryo Genotyper). Using microfluidic harmonic oscillation of the animal on a roughened glass surface, the ZEG is able to obtain genetic material (cells and DNA) for use in genotyping, from 24 embryos or larvae simultaneously in less than 10 minutes. Loading and unloading of the ZEG is performed manually with a standard pipette tip or transfer pipette. The obtained genetic material is amplified by PCR and can be used for subsequent analysis including sequencing, gel electrophoresis, or high-resolution melt-analysis. Sensitivity of genotyping and survival of animals are both greater than 90%. There are no apparent effects on body morphology, development, or motor behavior tests. In summary, the ZEG device enables rapid genotyping of live zebrafish embryos and larvae, and animals are available for downstream applications, testing, or raising.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193180PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854293PMC
June 2018

A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination.

Hum Mol Genet 2017 09;26(18):3600-3614

Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.

X-linked adrenoleukodystrophy (ALD) is a devastating inherited neurodegenerative disease caused by defects in the ABCD1 gene and affecting peripheral and central nervous system myelin. ABCD1 encodes a peroxisomal transmembrane protein required for very long chain fatty acid (VLCFA) metabolism. We show that zebrafish (Danio rerio) Abcd1 is highly conserved at the amino acid level with human ABCD1, and during development is expressed in homologous regions including the central nervous system and adrenal glands. We used TALENs to generate five zebrafish abcd1 mutant allele lines introducing premature stop codons in exon 1, as well as obtained an abcd1 allele from the Zebrafish Mutation Project carrying a point mutation in a splice donor site. Similar to patients with ALD, zebrafish abcd1 mutants have elevated VLCFA levels. Interestingly, we found that CNS development of the abcd1 mutants is disrupted, with hypomyelination in the spinal cord, abnormal patterning and decreased numbers of oligodendrocytes, and increased cell death. By day of life five abcd1 mutants demonstrate impaired motor function, and overall survival to adulthood of heterozygous and homozygous mutants is decreased. Expression of human ABCD1 in oligodendrocytes rescued apoptosis in the abcd1 mutant. In summary, we have established a zebrafish model of ALD that recapitulates key features of human disease pathology and which reveals novel features of underlying disease pathogenesis.
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http://dx.doi.org/10.1093/hmg/ddx249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886093PMC
September 2017

Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.

Mol Genet Metab 2017 09 20;122(1-2):18-32. Epub 2017 Aug 20.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Translational Science, Children's National Medical Center, Washington, DC, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.
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http://dx.doi.org/10.1016/j.ymgme.2017.08.006DOI Listing
September 2017

Comprehensive population-based determination of pediatric multiple sclerosis health care costs.

Neurol Neuroimmunol Neuroinflamm 2017 Jan 19;4(1):e314. Epub 2016 Dec 19.

School of Medicine (M.A.W.), Study Design and Biostatistics Center (T.B.), Department of Biostatistics (T.B.), and Department of Pediatrics, Division of Pediatric Neurology (J.L.B., M.S.C.), University of Utah; and Intermountain Healthcare (E.K.K.), Salt Lake City.

Objective: To determine the health care costs associated with pediatric multiple sclerosis (MS).

Methods: We performed a retrospective analysis of all patients with MS 18 years of age or younger who were diagnosed or treated between 2002 and 2012 in a population-based cohort. Demographics and health care costs were extracted from the Intermountain Healthcare Enterprise Data Warehouse. Patients were divided into high-cost (>84th percentile) and low-cost groups and differences in health care utilization between the groups were analyzed.

Results: Fifty-seven pediatric patients with MS were identified. Health care costs for the cohort totaled more than $1.5 million over the 10-year period, with the top 16th percentile of patients contributing nearly two-thirds. Outpatient visits represented the majority of health care encounters and expenditures, accounting for 83.1% of total costs. Costs per encounter were highest for inpatient stays, averaging $2,924 per stay.

Conclusions: The burden of health care expenses for pediatric patients with MS is significant. Expenditures related to outpatient visits were the largest contributor to costs, but inpatient stays were the most costly per encounter. A small proportion of patients incurred the bulk of costs and spent significantly more time receiving care compared to the majority of patients. Avoidance of inpatient treatment and efficient outpatient management are potential areas for health care cost reduction and improvement in care.
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http://dx.doi.org/10.1212/NXI.0000000000000314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173349PMC
January 2017