Clinical Focus


  • Autoimmune Diseases of the Nervous System
  • Adrenoleukodystrophy
  • Multiple Sclerosis
  • Autoimmune encephalitis
  • MOGAD
  • Leukodystrophies
  • Neurology with Special Qualifications in Child Neurology

Academic Appointments


Honors & Awards


  • Excellence in Clinical Neurology, Stanford Dept of Neurology (2021)
  • Ann Moser Award for Science & Humanism, ALD Connect (2020)
  • Finalist, DP2 New Innovator Award, NIH (2019)
  • Morgridge Endowed Faculty Scholar in Pediatric Translational Medicine, Stanford Maternal & Child Health Research Institute (2019)
  • K23 Clinician-Scientist Training Award, NIH/NINDS (2015)
  • PERF-CNF Scientific Award, Child Neurology Foundation (2011)
  • Chief Resident, Stanford Dept Neurology (2009)
  • Medical Student Teaching Award, Stanford Dept Neurology (2009)
  • Commencement Speaker, University of Rochester School of Medicine (2005)
  • Inductee, Arnold Gold Humanism Honor Society (2004)
  • Moore Award, Honorable Mention, American Association of Neuropathology (2003)

Boards, Advisory Committees, Professional Organizations


  • Founding Member, ALD Connect (2014 - Present)
  • Founding Member, The Global Leukodystrophy Initiative (GLIA) (2014 - Present)

Professional Education


  • Board Certification: American Board of Psychiatry and Neurology, Neurology with Special Qualifications in Child Neurology (2010)
  • BA, College of the Holy Cross, Chemistry (1999)
  • MD, University of Rochester School of Medicine, Medicine (2005)
  • PGY1-2 Pediatrics, Massachusetts General Hospital, Pediatrics (2007)
  • PGY3-5 Neurology, Stanford University Hospitals & Clinics, Child & Adult Neurology (2010)
  • Fellowship, Stanford University Hospital & Clinics, Neuroimmunology (2012)
  • Post-doc, Steinman & Robinson Labs, Stanford University, Neuroimmunology (2014)

Current Research and Scholarly Interests


Our lab explores the nexus of metabolic failure and inflammation. Our approach is unique. We leverage insights from neurologic disorders with known single-gene mutations to unravel the molecular mechanisms of human neuroinflammation.

Genetic disorders offer an unparalleled vantage point for understanding human biology. Immunogenetic are particularly unique because immune tissue is both accessible and modifiable. These disorders offer a unique window into basic molecular mechanisms and make exceptional targets for stem cell and gene therapies.

Our team's goals are to:
1. build foundational knowledge in human biology
2. develop transformational therapies for each disorder we study
3. train the next generation of translational scientists

Our team draws purpose and inspiration from children and adults affected by neurodegenerative disorders. We are particularly focused on genetic and autoimmune disorders that cause damage to the myelin (the fatty insulation around the nerves) of the brain and spinal cord. X-linked adrenoleukodystrophy (genetic) and multiple sclerosis (autoimmune) are the prototypical examples of degenerative disorders of myelin; these are the two disorders we study most intensively.

One of the great obstacles to understanding and treating MS is its pathological heterogeneity. MS is currently defined solely by clinical and radiological criteria. Although MS diagnostic criteria have improved over time, abundant evidence suggests that pathophysiologic "subtypes" of MS remain clinically indistinguishable. This pathophysiologic heterogeneity poses a major confounder to the development of new therapies. To combat this heterogeneity, we use ALD as a genetic model for MS.

ALD is a rare (~1:17,00), monogenetic, X-linked disorder involving a gene (ABCD1) that encodes a peroxisomal protein. The biochemical hallmark of the disease is an accumulation of very-long chain fatty acids in several tissues, including myelin and blood. The ABCD1 mutation yields a variety of neuroendocrine symptoms, but the most feared manifestation is an inflammatory cerebral demyelinating syndrome known as "cerebral ALD" that affects ~40% of ALD boys. The absence of a clear genotype-phenotype correlation for cerebral ALD suggests a role for environmental modifiers, similar to MS.

Despite the clinical and pathogenic similarities of MS and ALD, one question stands out: Why would a metabolic disorder like ALD yield a syndrome that so closely resembles MS, the prototypic neuroimmune disorder? This is the central questions animating our lab's current work.

Clinical Trials


  • A Pilot Study of Vitamin D in Boys With X-linked Adrenoleukodystrophy Not Recruiting

    In this pilot study, the investigators will assess the safety of two high-dose regimens of oral vitamin D supplementation and measure the effects of vitamin D supplementation on markers of oxidative stress and inflammation in the blood and brain of study participants before, during, and after taking vitamin D supplements. The goal of the study is to establish research measures (i.e. biomarkers) and an optimal dose for vitamin D supplementation in boys with the X-linked adrenoleukodystrophy (ALD) genotype.

    Stanford is currently not accepting patients for this trial.

    View full details

2023-24 Courses


Stanford Advisees


All Publications


  • A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy. Neurology. Genetics Van Haren, K. P., Cunanan, K., Awani, A., Gu, M., Peña, D., Chromik, L. C., Považan, M., Rossi, N. C., Goodman, J., Sundaram, V., Winterbottom, J., Raymond, G. V., Cowan, T., Enns, G. M., Waubant, E., Steinman, L., Barker, P. B., Spielman, D., Fatemi, A. 2023; 9 (2): e200061

    Abstract

    There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD.In this open-label, multicenter, phase 1 study, we recruited boys and young men with ALD without brain lesions to a 12-month study of daily oral vitamin D3 supplementation. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80 ng/mL) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in the brain, measured with magnetic resonance spectroscopy, and blood, measured via mass spectrometry. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. After a midstudy safety assessment, we modified the dosing regimen, so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily.Between October 2016 and June 2019, we enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels in the brain, but not the blood, increased significantly between baseline and 12 months.Our vitamin D dosing regimens were well tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels warrant further study as a biomarker for vitamin D and ALD.This study provides Class IV evidence that fixed or weight-stratified vitamin D supplementation achieved target levels of 25-hydroxyvitamin D in boys and young men with X-ALD without brain lesions.

    View details for DOI 10.1212/NXG.0000000000200061

    View details for PubMedID 37090939

    View details for PubMedCentralID PMC10117697

  • Effect of vitamin D supplementation on cerebral blood flow in male patients with adrenoleukodystrophy. Journal of neuroscience research Zhao, M. Y., Dahlen, A., Ramirez, N. J., Moseley, M., Van Haren, K., Zaharchuk, G. 2023

    Abstract

    One-third of boys with X-linked adrenoleukodystrophy (ALD) develop inflammatory demyelinating lesions, typically at the splenium. These lesions share similarities with multiple sclerosis, including cerebral hypoperfusion and links to vitamin D insufficiency. We hypothesized that increasing vitamin D levels would increase cerebral blood flow (CBF) in ALD boys. We conducted an exploratory analysis of vitamin D supplementation and CBF using all available data from participants enrolled in a recent single-arm interventional study of vitamin D supplementation in boys with ALD. We measured whole brain and splenium CBF using arterial spin labeling (ASL) from three study time points (baseline, 6 months, and 12 months). We used linear generalized estimating equations to evaluate CBF changes between time points and to test for an association between CBF and vitamin D. ASL data were available for 16 participants, aged 2-22 years. Mean vitamin D levels increased by 72.7% (p < .001) after 6 months and 88.6% (p < .01) after 12 months. Relative to baseline measures, mean CBF of the whole brain (6 months: +2.5%, p = .57; 12 months: +6.1%, p = .18) and splenium (6 months: +1.2%, p = .80; 12 months: +7.4%, p = .058) were not significantly changed. Vitamin D levels were positively correlated with CBF in the splenium (slope = .59, p < .001). In this exploratory analysis, we observed a correlation between vitamin D levels and splenial CBF in ALD boys. We confirm the feasibility of measuring CBF in this brain region and population, but further work is needed to establish a causal role for vitamin D in modulating CBF.

    View details for DOI 10.1002/jnr.25187

    View details for PubMedID 36967233

  • Peripheral T-Cells, B-Cells, and Monocytes from Multiple Sclerosis Patients Supplemented with High-Dose Vitamin D Show Distinct Changes in Gene Expression Profiles. Nutrients Kim, D., Witt, E. E., Schubert, S., Sotirchos, E., Bhargava, P., Mowry, E. M., Sachs, K., Bilen, B., Steinman, L., Awani, A., He, Z., Calabresi, P. A., Van Haren, K. 2022; 14 (22)

    Abstract

    Vitamin D is a steroid hormone that has been widely studied as a potential therapy for multiple sclerosis and other inflammatory disorders. Pre-clinical studies have implicated vitamin D in the transcription of thousands of genes, but its influence may vary by cell type. A handful of clinical studies have failed to identify an in vivo gene expression signature when using bulk analysis of all peripheral immune cells. We hypothesized that vitamin D's gene signature would vary by immune cell type, requiring the analysis of distinct cell types. Multiple sclerosis patients (n = 18) were given high-dose vitamin D (10,400 IU/day) for six months as part of a prospective clinical trial (NCT01024777). We collected peripheral blood mononuclear cells from participants at baseline and again after six months of treatment. We used flow cytometry to isolate three immune cell types (CD4+ T-cells, CD19+ B-cells, CD14+ monocytes) for RNA microarray analysis and compared the expression profiles between baseline and six months. We identified distinct sets of differentially expressed genes and enriched pathways between baseline and six months for each cell type. Vitamin D's in vivo gene expression profile in the immune system likely differs by cell type. Future clinical studies should consider techniques that allow for a similar cell-type resolution.

    View details for DOI 10.3390/nu14224737

    View details for PubMedID 36432424

  • Nocturnal hypoventilation as a respiratory complication of acute flaccid myelitis. The Journal of pediatrics Aziz-Bose, R., Bhargava, S., Buu, M., Bove, R., van Haren, K. 2022

    Abstract

    Detailed accounts of long-term respiratory complications among children with acute flaccid myelitis have not been systematically reported. We describe respiratory complications and outcomes in a single-center cohort of 19 children with acute flaccid myelitis. Significantly, 3 of the 19 children had a prolonged course of nocturnal hypoventilation that required intervention.

    View details for DOI 10.1016/j.jpeds.2022.05.032

    View details for PubMedID 35605645

  • Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurology(R) neuroimmunology & neuroinflammation Cellucci, T., Van Mater, H., Graus, F., Muscal, E., Gallentine, W., Klein-Gitelman, M. S., Benseler, S. M., Frankovich, J., Gorman, M. P., Van Haren, K., Dalmau, J., Dale, R. C. 2020; 7 (2)

    Abstract

    OBJECTIVE: Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes.METHODS: A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers.RESULTS: Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis.CONCLUSIONS: Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.

    View details for DOI 10.1212/NXI.0000000000000663

    View details for PubMedID 31953309

  • Subacute Neuropsychiatric Syndrome in Girls With SHANK3 Mutations Responds to Immunomodulation. Pediatrics Bey, A. L., Gorman, M. P., Gallentine, W. n., Kohlenberg, T. M., Frankovich, J. n., Jiang, Y. H., Van Haren, K. n. 2020; 145 (2)

    Abstract

    Phenotypic and biological characterization of rare monogenic disorders represents 1 of the most important avenues toward understanding the mechanisms of human disease. Among patients with SH3 and multiple ankyrin repeat domains 3 (SHANK3) mutations, a subset will manifest neurologic regression, psychosis, and mood disorders. However, which patients will be affected, when, and why are important unresolved questions. Authors of recent studies suggest neuronal SHANK3 expression is modulated by both inflammatory and hormonal stimuli. In this case series, we describe 4 independent clinical observations of an immunotherapy responsive phenotype of peripubertal-onset neuropsychiatric regression in 4 girls with pathogenic SHANK3 mutations. Each child exhibited a history of stable, mild-to-moderate lifelong developmental disability until 12 to 14 years of age, at which time each manifested a similar, subacute-onset neurobehavioral syndrome. Symptoms included mutism, hallucinations, insomnia, inconsolable crying, obsessive-compulsive behaviors, loss of self-care, and urinary retention and/or incontinence. Symptoms were relatively refractory to antipsychotic medication but improved after immunomodulatory treatment. All 4 patients exhibited chronic relapsing courses during a period of treatment and follow-up ranging from 3 to 6 years. Two of the 4 girls recovered their premorbid level of functioning. We briefly review the scientific literature to offer a conceptual and molecular framework for understanding these clinical observations. Future clinical and translational investigations in this realm may offer insights into mechanisms and therapies bridging immune function and human behavior.

    View details for DOI 10.1542/peds.2019-1490

    View details for PubMedID 32015180

  • Measuring early lesion growth in boys with cerebral demyelinating adrenoleukodystrophy NEUROLOGY van Haren, K., Engelen, M., Wolf, N. 2019; 92 (15): 691–93
  • Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology Sotirchos, E. S., Bhargava, P., Eckstein, C., Van Haren, K., Baynes, M., Ntranos, A., Gocke, A., Steinman, L., Mowry, E. M., Calabresi, P. A. 2016; 86 (4): 382-390

    Abstract

    To study the safety profile and characterize the immunologic effects of high- vs low-dose cholecalciferol supplementation in patients with multiple sclerosis (MS).In this double-blind, single-center randomized pilot study, 40 patients with relapsing-remitting MS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months. Assessments were performed at baseline and 3 and 6 months.Mean increase of 25-hydroxyvitamin D levels from baseline to final visit was larger in the high-dose group (34.9 ng/mL; 95% confidence interval [CI] 25.0-44.7 ng/mL) than in the low-dose group (6.9 ng/mL; 95% CI 1.0-13.7 ng/mL). Adverse events were minor and did not differ between the 2 groups. Two relapses occurred, one in each treatment arm. In the high-dose group, we found a reduction in the proportion of interleukin-17(+)CD4(+) T cells (p = 0.016), CD161(+)CD4(+) T cells (p = 0.03), and effector memory CD4(+) T cells (p = 0.021) with a concomitant increase in the proportion of central memory CD4(+) T cells (p = 0.018) and naive CD4(+) T cells (p = 0.04). These effects were not observed in the low-dose group.Cholecalciferol supplementation with 10,400 IU daily is safe and tolerable in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects in MS, which include reduction of interleukin-17 production by CD4(+) T cells and decreased proportion of effector memory CD4(+) T cells with concomitant increase in central memory CD4(+) T cells and naive CD4(+) T cells.This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects.

    View details for DOI 10.1212/WNL.0000000000002316

    View details for PubMedID 26718578

  • Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015. JAMA Van Haren, K., Ayscue, P., Waubant, E., Clayton, A., Sheriff, H., Yagi, S., Glenn-Finer, R., Padilla, T., Strober, J. B., Aldrovandi, G., Wadford, D. A., Chiu, C. Y., Xia, D., Harriman, K., Watt, J. P., Glaser, C. A. 2016; 314 (24): 2663-71

    Abstract

    There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology.To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury.Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing.Case incidence and infectious agent association.Fifty-nine cases were identified. Median age was 9 years (interquartile range [IQR], 4-14 years; 50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41). Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis. During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100,000 person-years) compared with other monitoring periods (0.028 cases per 100,000 person-years; P <.001).In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.

    View details for DOI 10.1001/jama.2015.17275

    View details for PubMedID 26720027

  • Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing- remitting multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) Van Haren, K., Tomooka, B. H., Kidd, B. A., Banwell, B., Bar-Or, A., Chitnis, T., Tenembaum, S. N., Pohl, D., Rostasy, K., Dale, R. C., O'Connor, K. C., Hafler, D. A., Steinman, L., Robinson, W. H. 2013; 19 (13): 1726-1733

    Abstract

    BACKGROUND AND OBJECTIVE: Acute disseminated encephalomyelitis (ADEM) and relapsing-remitting multiple sclerosis (RRMS) share overlapping clinical, radiologic and laboratory features at onset. Because autoantibodies may contribute to the pathogenesis of both diseases, we sought to identify autoantibody biomarkers that are capable of distinguishing them. METHODS: We used custom antigen arrays to profile anti-myelin-peptide autoantibodies in sera derived from individuals with pediatric ADEM (n = 15), pediatric multiple sclerosis (Ped MS; n = 11) and adult MS (n = 15). Using isotype-specific secondary antibodies, we profiled both IgG and IgM reactivities. We used Statistical Analysis of Microarrays software to confirm the differences in autoantibody reactivity profiles between ADEM and MS samples. We used Prediction Analysis of Microarrays software to generate and validate prediction algorithms, based on the autoantibody reactivity profiles. RESULTS: ADEM was characterized by IgG autoantibodies targeting epitopes derived from myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein, and alpha-B-crystallin. In contrast, MS was characterized by IgM autoantibodies targeting myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein and oligodendrocyte-specific protein. We generated and validated prediction algorithms that distinguish ADEM serum (sensitivity 62-86%; specificity 56-79%) from MS serum (sensitivity 40-87%; specificity 62-86%) on the basis of combined IgG and IgM anti-myelin autoantibody reactivity to a small number of myelin peptides. CONCLUSIONS: Combined profiles of serum IgG and IgM autoantibodies identified myelin antigens that may be useful for distinguishing MS from ADEM. Further studies are required to establish clinical utility. Further biological assays are required to delineate the pathogenic potential of these antibodies.

    View details for DOI 10.1177/1352458513485653

    View details for PubMedID 23612879

  • Identification of Naturally Occurring Fatty Acids of the Myelin Sheath That Resolve Neuroinflammation SCIENCE TRANSLATIONAL MEDICINE Ho, P. P., Kanter, J. L., Johnson, A. M., Srinagesh, H. K., Chang, E., Purdy, T. M., Van Haren, K., Wikoff, W. R., Kind, T., Khademi, M., Matloff, L. Y., Narayana, S., Hur, E. M., Lindstrom, T. M., He, Z., Fiehn, O., Olsson, T., Han, X., Han, M. H., Steinman, L., Robinson, W. H. 2012; 4 (137)

    Abstract

    Lipids constitute 70% of the myelin sheath, and autoantibodies against lipids may contribute to the demyelination that characterizes multiple sclerosis (MS). We used lipid antigen microarrays and lipid mass spectrometry to identify bona fide lipid targets of the autoimmune response in MS brain, and an animal model of MS to explore the role of the identified lipids in autoimmune demyelination. We found that autoantibodies in MS target a phosphate group in phosphatidylserine and oxidized phosphatidylcholine derivatives. Administration of these lipids ameliorated experimental autoimmune encephalomyelitis by suppressing activation and inducing apoptosis of autoreactive T cells, effects mediated by the lipids' saturated fatty acid side chains. Thus, phospholipids represent a natural anti-inflammatory class of compounds that have potential as therapeutics for MS.

    View details for DOI 10.1126/scitranslmed.3003831

    View details for PubMedID 22674551

  • A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis. bioRxiv : the preprint server for biology Hashemi, E., Narain Srivastava, I., Aguirre, A., Tilahan Yoseph, E., Kaushal, E., Awani, A., Kyu Ryu, J., Akassoglou, K., Talebian, S., Chu, P., Pisani, L., Musolino, P., Steinman, L., Doyle, K., Robinson, W. H., Sharpe, O., Cayrol, R., Orchard, P., Lund, T., Vogel, H., Lenail, M., Han, M. H., Bonkowsky, J. L., Van Haren, K. P. 2023

    Abstract

    We sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues.ALD is caused by mutations in the gene ABCD1 encoding a peroxisomal transporter. More than half of males with an ABCD1 mutation develop the cerebral phenotype (cALD). Incomplete penetrance and absence of a genotype-phenotype correlation imply a role for environmental triggers. Mechanistic studies have been limited by the absence of a cALD phenotype in the Abcd1-null mouse.We generated a cALD phenotype in 8-week-old, male Abcd1-null mice by deploying a two-hit method that combines cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) models. We employed in vivo MRI and post-mortem immunohistochemistry to evaluate myelin loss, astrogliosis, blood-brain barrier (BBB) disruption, immune cell infiltration, fibrin deposition, oxidative stress, and Nlrp3 inflammasome activation in mice. We used bead-based immunoassay and immunohistochemistry to evaluate IL-18 in CSF and post-mortem human cALD brain tissue.MRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. Both human and mouse cALD lesions shared common histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-null mice had more severe cerebral inflammation, demyelination, fibrin deposition, oxidative stress, and IL-18 activation. IL-18 immunoreactivity co-localized with macrophages/microglia in the perivascular region of both human and mouse brain tissue.This novel mouse model of cALD suggests loss of Abcd1 function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in humans with cALD. We expect this model to enable long-sought investigations into cALD mechanisms and accelerate development of candidate therapies for lesion prevention, cessation, and remyelination.

    View details for DOI 10.1101/2023.11.07.564025

    View details for PubMedID 37986739

    View details for PubMedCentralID PMC10659266

  • Immunotherapy in Autoimmune Encephalitis: So Many Options, So Few Guidelines. Neurology Srivastava, I., Van Haren, K. 2023

    View details for DOI 10.1212/WNL.0000000000208026

    View details for PubMedID 37879941

  • Clinical Outcomes in Aicardi Goutieres Syndrome: A Natural History Study Modesti, N. B., Barcelos, I., Jan, A. K., Isaacs, D., Gavazzi, F., Sevagamoorthy, A., Woidill, S., D'Aiello, R., Muirhead, K., Schmidt, J., Pizzino, A., Van Haren, K., Keller, S., Eichler, F., Emrick, L., Fraser, J., Shults, J., Vanderver, A., Adang, L. WILEY. 2023: S210
  • Brain Magnetic Resonance Imaging Abnormalities in Acute Flaccid Myelitis. Pediatric neurology Caceres, J. A., Saucier, L., Murphy, O. C., Gordon-Lipkin, E. M., Santoro, J. D., Van Haren, K., Pardo, C. A., Hopkins, S. 2023; 149: 56-62

    Abstract

    Acute flaccid myelitis (AFM) presents with acute onset of flaccid paralysis with involvement of the gray matter on magnetic resonance imaging (MRI) of the spinal cord. Studies have reported brain MRI abnormalities, but the characteristics have not been fully defined. In this multicenter study, we assessed the acute features and evolution of brain MRI abnormalities in AFM.We reviewed brain MRIs of patients with AFM who presented to four referral hospitals between 2012 and 2018. Cases met established criteria for AFM. We analyzed the initial and follow-up brain MRIs. Areas were divided into supratentorial, infratentorial, and subdivisions within those regions.A total of 66 patients were included. Brain MRI abnormalities were present in 34 (52%). Infratentorial abnormalities were more common, occurring in 33 (97%) cases with the dorsal pons being the most frequently affected area (88%). Abnormalities were also present in the medulla (74%), cerebellum (41%), and midbrain (38%). Nine subjects (26%) exhibited both supratentorial and infratentorial abnormalities, whereas isolated supratentorial changes were present in only one (3%). Contrast-enhancing abnormalities were encountered in 9% of cases and meningeal involvement in 6%. On follow-up, most abnormalities, 20 of 24 (83%), were stable, improving, or had resolved.Brain MRI abnormalities occur in about half of the cases of AFM and commonly resolve with time. Dorsal pontine involvement is a characteristic MRI feature, whereas isolated supratentorial abnormalities are rare. Clinicians should consider that brain imaging abnormalities do not exclude a diagnosis of AFM in patients with typical presentations.

    View details for DOI 10.1016/j.pediatrneurol.2023.08.021

    View details for PubMedID 37797356

  • Developmental delay can precede neurologic regression in metachromatic leukodystrophy Adang, L. A., Groeschel, S., Grzyb, C., Eichler, F. S., Fraser, J. L., Emrick, L., Van Haren, K., Keller, S., Poe, M., Bernat, J., Bonkowsky, J. L., Bernard, G., Stutterd, C., Orchard, P. J., Gupta, A., Ljungberg, M., Gronborg, S., Fumagalli, F., Elgun, S., Kehrer, C., Shults, J., Vanderver, A., Escolar, M. L. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2023: 3
  • Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial LANCET NEUROLOGY Koehler, W., Engelen, M., Eichler, F., Lachmann, R., Fatemi, A., Sampson, J., Salsano, E., Gamez, J., Molnar, M., Pascual, S., Rovira, M., Vila, A., Pina, G., Martin-Ugarte, I., Mantilla, A., Pizcueta, P., Rodriguez-Pascau, L., Traver, E., Vilalta, A., Pascual, M., Martinell, M., Meya, U., Mochel, F., Adv Study Grp 2023; 22 (2): 127-136
  • Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial. The Lancet. Neurology Kohler, W., Engelen, M., Eichler, F., Lachmann, R., Fatemi, A., Sampson, J., Salsano, E., Gamez, J., Molnar, M. J., Pascual, S., Rovira, M., Vila, A., Pina, G., Martin-Ugarte, I., Mantilla, A., Pizcueta, P., Rodriguez-Pascau, L., Traver, E., Vilalta, A., Pascual, M., Martinell, M., Meya, U., Mochel, F., ADVANCE Study Group, Mc Govern, E., Yazbeck, E., Barbier, M., Luton, M., Pousset, F., Hogrel, J., Adanyeguh, I., Then Bergh, F., Bergner, C., Unterlauft, A., Roicke, H., Hoffmann, K., Scherlach, C., Kalb, A., Meilick, B., Reuschel, M., Fenu, S., Mauro, E., Murphy, E., Krishna, G., Beyene, T., Sierra, A., Quinoa, S., Belen Canovas, A., Grosz, Z., Gyorgyi, B., van de Stadt, S. I., Huffnagel, I. C., van Ballegoij, W. J., Voermans, M. M., Seyedsadjadi, R., Corre, C., Godbole, N., Grant, N. R., Brito Pires, C. M., Trovato, M., Yeh, N., Goodman, J., Keller, J., Joseph, C., Van Haren, K., Sakamuri, S., Duong, T., Perrone, L., Tran, S., Dunaway Young, S., Hashmi, S. 2023; 22 (2): 127-136

    Abstract

    BACKGROUND: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.METHODS: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 mug·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.FINDINGS: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group.INTERPRETATION: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.FUNDING: Minoryx Therapeutics.

    View details for DOI 10.1016/S1474-4422(22)00495-1

    View details for PubMedID 36681445

  • Pulmonological issues. Current problems in pediatric and adolescent health care Perez, G., Young, L., Kravitz, R., Sheehan, D., Adang, L., Van Haren, K., Lin, J. L., Jaffe, N. N., Kuo, D., Ball, L., Keller, J., Sank, J., DiVito, D., Naime, S. 2022: 101313

    Abstract

    Pediatric leukodystrophies are rare neurodegenerative diseases involving multiple systems. Each form has unique neurologic features but are characterized by encephalopathy with accompanying impairments evidenced in reflexes, muscle tone and movement control. Weakness of expiratory, inspiratory, and upper airway muscles may lead to impaired airway secretion clearance resulting in recurrent respiratory infections, dysphagia, sleep-disordered breathing, restrictive lung disease, and ultimately chronic respiratory insufficiency.

    View details for DOI 10.1016/j.cppeds.2022.101313

    View details for PubMedID 36470809

  • A Novel Mouse Model of Cerebral Demyelination in X-Linked Adrenoleukodystrophy Highlights NLRP3 Activation in Lesion Pathogenesis Srivastava, I., Van Haren, K., Hashemi, E., Kaushal, E., Han, M., Lund, T., Bonkowsky, J., Yoseph, E. WILEY. 2022: S174
  • A retrospective investigation of MOG-IgG titers in relapse and disability prediction in adult and pediatric myelin oligodendrocyte glycoprotein antibody-associated disease patients McDonald, J., Santoro, J. D., Sattarnezhad, N., Tomczak, A., Sumera, J., Van Haren, K., Corwin, N., Kipp, L., Lock, C., Dunn, J., Hinman, J., Nelson, L., Han, M. SAGE PUBLICATIONS LTD. 2022: 427-428
  • Developmental Delay Can Precede Neurologic Regression in Metachromatic Leukodystrophy Adang, L. A., Groeschel, S., Grzyb, C., D'Aiello, R., Sherbini, O., Bronner, N., Patel, A., Vincent, A., Jin, D., Eichler, F., Fraser, J. L., Emrick, L., Van Haren, K., Ruzhnikov, M., Keller, S., Fatemi, A., Uebergang, E., Poe, M., Yazdani, P., Bernat, J., Lindstrom, K., Bonkowsky, J., Bernard, G., Stutterd, C., Orchard, P., Gupta, A., Ljungberg, M., Gronborg, S., Facchini, M., Locatelli, S., Fumagalli, F., Elguen, S., Kehrer, C., Kraegeloh-Mann, I., Shults, J., Vanderver, A., Escolar, M. WILEY. 2022: S164
  • International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach. Neurology Engelen, M., van Ballegoij, W. J., Mallack, E. J., Van Haren, K. P., Köhler, W., Salsano, E., van Trotsenburg, A. S., Mochel, F., Sevin, C., Regelman, M. O., Tritos, N. A., Halper, A., Lachmann, R. H., Davison, J., Raymond, G. V., Lund, T., Orchard, P. J., Kuehl, J. S., Lindemans, C. A., Caruso, P., Turk, B. R., Moser, A. B., Vaz, F. M., Ferdinandusse, S., Kemp, S., Fatemi, A., Eichler, F. S., Huffnagel, I. C. 2022

    Abstract

    Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by three core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals, and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age of onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary.We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of ALD patients. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoeitic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses as well as presymptomatic individuals is increasing due to newborn screening and greater availability of next generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerges. This knowledge gap should direct future research and illustrates once again that international collaboration amongst physicians, researchers and patients is essential to improving care.

    View details for DOI 10.1212/WNL.0000000000201374

    View details for PubMedID 36175155

  • Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy: Timing and Treatment. Neurology Mallack, E. J., Van Haren, K. P., Torrey, A., van de Stadt, S., Engelen, M., Raymond, G. V., Fatemi, A., Eichler, F. S. 2022

    Abstract

    BACKGROUND AND OBJECTIVES: We sought to characterize the natural history and standard of care practices between the radiologic appearance of brain lesions, the appearance of lesional enhancement, and treatment with hematopoietic stem cell transplant or gene therapy among boys diagnosed with presymptomatic childhood-onset cerebral adrenoleukodystrophy (CCALD).METHODS: We analyzed a multi-center, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score [NFS] = 0, Loes Score [LS] = 0.5 - 9.0, Age < 13 years old). Two time-to-event survival analyses were conducted: (1) Time from CCALD lesion-onset-to-lesional enhancement, (2) Time from enhancement-to-treatment. The analysis was repeated in the subset of patients with (1) the earliest evidence of CCALD, defined as an MRI LS < 1, and (2) patients diagnosed between 2016 - 2021.RESULTS: Seventy-one boys were diagnosed with presymptomatic cerebral lesions at a median age of 6.4yo [2.4 - 12.1] with a LS of 1.5 [0.5 - 9.0]. Fifty percent of patients had lesional enhancement at diagnosis. In the remaining 50%, the median KM-estimate of time from diagnosis-to-lesional enhancement was 6.0 months [95%CI 3.6 - 17.8]. The median KM-estimate of time from enhancement-to-treatment is 3.8 months [95%CI 2.8 - 5.9]; two patients (4.2%) developed symptoms prior to treatment. Patients with a diagnostic LS < 1 were younger (5.8yo [2.4 - 11.5]), had a time-to-enhancement of 4.7mo [95%CI 2.7 - 9.30], and were treated in 3.8mo [95%CI 3.1 - 7.1]; no patients developed symptoms prior to treatment. Time from CCALD diagnosis-to-treatment decreased over the course of the study (rho = -0.401, p = 0.003).CONCLUSION: Our findings offer a more refined understanding of the timing of lesion formation, enhancement, and treatment among boys with presymptomatic CCALD. These data offer benchmarks for standardizing clinical care and designing future clinical trials.

    View details for DOI 10.1212/WNL.0000000000200571

    View details for PubMedID 35609989

  • Inadequate Vaccine Responses in Children with Multiple Sclerosis Santoro, J. D., Saucier, L. E., Tanna, R., Pagarkar, D., Tempchin, A. G., Khoshnood, M., Ahsan, N., Van Haren, K. SAGE PUBLICATIONS LTD. 2022: 204-205
  • Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene. Genes van de Stadt, S. I., Mooyer, P. A., Dijkstra, I. M., Dekker, C. J., Vats, D., Vera, M., Ruzhnikov, M. R., van Haren, K., Tang, N., Koop, K., Willemsen, M. A., Hui, J., Vaz, F. M., Ebberink, M. S., Engelen, M., Kemp, S., Ferdinandusse, S. 1800; 12 (12)

    Abstract

    Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D3-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal SS-oxidation capacity (as measured by the D3-C16:0/D3-C22:0 ratio in the D3-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected.

    View details for DOI 10.3390/genes12121930

    View details for PubMedID 34946879

  • A variant of uncertain significance in SDHAF1, the succinate dehydrogenase chaperone protein, in an adult patient with spastic paraparesis and leukoencephalopathy. Multiple sclerosis and related disorders Vlahovic, L., Lock, C. B., Han, M. H., Van Haren, K., Sampson, J. B. 2021; 54: 103132

    Abstract

    Succinate dehydrogenase (SDH), or respiratory complex II, consists of four nuclear-encoded subunits. The chaperone protein succinate dehydrogenase assembly factor 1 (SDHAF1) plays an essential role in the assembly of SDH, and in the incorporation of iron-sulfur clusters into the SDHB subunit. SDHB couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. Previously reported mutations in SDHAF1 have been associated with infantile leukoencephalopathy. We report an adult case with a homozygous variant of uncertain significance (VUS) mutation in SDHAF1, presenting with dementia, spastic paraparesis, and cardiomyopathy, initially diagnosed as multiple sclerosis.

    View details for DOI 10.1016/j.msard.2021.103132

    View details for PubMedID 34289436

  • Gastrostomy Tubes Placed in Children With Neurologic Impairment: Associated Morbidity and Mortality. Journal of child neurology Lin, J. L., Rigdon, J. n., Van Haren, K. n., Buu, M. n., Saynina, O. n., Bhattacharya, J. n., Owens, D. K., Sanders, L. M. 2021: 8830738211000179

    Abstract

    Gastrostomy tube (G-tube) placement for children with neurologic impairment with dysphagia has been suggested for pneumonia prevention. However, prior studies demonstrated an association between G-tube placement and increased risk of pneumonia. We evaluate the association between timing of G-tube placement and death or severe pneumonia in children with neurologic impairment.We included all children enrolled in California Children's Services between July 1, 2009, and June 30, 2014, with neurologic impairment and 1 pneumonia hospitalization. Prior to analysis, children with new G-tubes and those without were 1:2 propensity score matched on sociodemographics, medical complexity, and severity of index hospitalization. We used a time-varying Cox proportional hazard model for subsequent death or composite outcome of death or severe pneumonia to compare those with new G-tubes vs those without, adjusting for covariates described above.A total of 2490 children met eligibility criteria, of whom 219 (9%) died and 789 (32%) had severe pneumonia. Compared to children without G-tubes, children with new G-tubes had decreased risk of death (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.39-0.55) but increased risk of the composite outcome (HR 1.21, CI 1.14-1.27). Sensitivity analyses using varied time criteria for definitions of G-tube and outcome found that more recent G-tube placement had greater associated risk reduction for death but increased risk of severe pneumonia.Recent G-tube placement is associated with reduced risk of death but increased risk of severe pneumonia. Decisions to place G-tubes for pulmonary indications in children with neurologic impairment should weigh the impact of severe pneumonia on quality of life.

    View details for DOI 10.1177/08830738211000179

    View details for PubMedID 33750232

  • Inadequate Vaccine Responses in Children With Multiple Sclerosis. Frontiers in pediatrics Santoro, J. D., Saucier, L. E., Tanna, R., Wiegand, S. E., Pagarkar, D., Tempchin, A. F., Khoshnood, M., Ahsan, N., Van Haren, K. 2021; 9: 790159

    Abstract

    Objective: Immunizations against Hepatitis B virus (HBV) and Varicella Zoster virus (VZV), are recommended for patients with pediatric onset multiple sclerosis (POMS) and may be required prior to initiation of some disease modifying therapies. However, the efficacy of routine vaccine administration in POMS has never been studied. We sought to assess the humoral mediated vaccine response to HBV and VZV in children with POMS. Methods: A multi-center retrospective chart-based review of 62 patients with POMS was performed. Clinical data and antibody titers against HBV and VZV were collected prior to initiation of disease modifying therapy or steroids and compared to institutional control data, using t-test and chi squared analysis. Results: There were low rates of immunity against both HBV and VZV (33 and 25% respectively) among individuals with POMS. Fifteen individuals (24%) were non-immune to both. Compared to institutional control data, individuals with POMS were significantly less likely to be immune to and HBV (p = 0.003, 95% CI: 0.22-0.75) and VZV (p < 0.001, 95% CI: 0.09-0.39). Interpretation: Individuals with POMS have low rates of antibody-mediated immunity against HBV and VZV, despite receiving the appropriate vaccinations. This suggests an association between POMS and systemic immune dysregulation although further study is needed.

    View details for DOI 10.3389/fped.2021.790159

    View details for PubMedID 34926358

    View details for PubMedCentralID PMC8678906

  • Acute flaccid myelitis: cause, diagnosis, and management. Lancet (London, England) Murphy, O. C., Messacar, K., Benson, L., Bove, R., Carpenter, J. L., Crawford, T., Dean, J., DeBiasi, R., Desai, J., Elrick, M. J., Farias-Moeller, R., Gombolay, G. Y., Greenberg, B., Harmelink, M., Hong, S., Hopkins, S. E., Oleszek, J., Otten, C., Sadowsky, C. L., Schreiner, T. L., Thakur, K. T., Van Haren, K., Carballo, C. M., Chong, P. F., Fall, A., Gowda, V. K., Helfferich, J., Kira, R., Lim, M., Lopez, E. L., Wells, E. M., Yeh, E. A., Pardo, C. A., AFM working group, Salazar-Camelo, A., Mithal, D., Wilson-Murphy, M., Bauer, A., Watkins, C., Abzug, M., Dominguez, S., Press, C., Yang, M., Ahsan, N., Ramos-Platt, L., Tiongson, E., Seruya, M., Tilton, A., Katz, E., Kirschen, M., Shah, A., Ulloa, E., Yum, S., Mondok, L., Blaufuss, M., Rosenfeld, A., Vargas, W., Zucker, J., Yeshokumar, A., Navis, A., Chao, K., Hagen, K., Melicosta, M., Porter, C., Tunney, M., Scheuermann, R., Duggal, P., Pekosz, A., Bayliss, A., Moore, M., Belzberg, A., Bembea, M., O'Brien, C., Riggs, R., Nance, J., Milstone, A., Rice, J., Garcia-Dominguez, M. A., Flanagan, E., Tillema, J., Bosques, G., Bhatia, S., Gordon-Lipkin, E., Deike, D., Revivo, G., Zlotolow, D., deFiebre, G., Lazerow, P., Lotze, T., Bitnun, A., Davidge, K., Vajsar, J., Moore, A., Konersman, C., Nash, K., Strober, J., Gupta, N., Chiu, C., Sweeney, M., Jackson, W., Simon, D., Thakkar, K., Cheng, J., Luce, J., Das, S., Vogt, M., Vu, N., Gofshteyn, J., Makhani, N., Patel, P. 2020

    Abstract

    Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

    View details for DOI 10.1016/S0140-6736(20)32723-9

    View details for PubMedID 33357469

  • The NLRP3 Inflammasome as a Link Between Metabolic Failure and Cerebral Demyelination in X-linked Adrenoleukodystrophy Aguirre, A., Cayrol, R., Srivastava, I., Vogel, H., Van Haren, K. OXFORD UNIV PRESS INC. 2020: 675
  • Natural history of brain lesions in X-linked adrenoleukodystrophy: On-again, off-again. Neurology Thompson Stone, R., van Haren, K. 2020

    View details for DOI 10.1212/WNL.0000000000009628

    View details for PubMedID 32482840

  • Genetic and phenotypic spectrum associated with IFIH1 gain-of-function. Human mutation Rice, G. I., Park, S. n., Gavazzi, F. n., Adang, L. A., Ayuk, L. A., Van Eyck, L. n., Seabra, L. n., Barrea, C. n., Battini, R. n., Belot, A. n., Berg, S. n., Billette de Villemeur, T. n., Bley, A. E., Blumkin, L. n., Boespflug-Tanguy, O. n., Briggs, T. A., Brimble, E. n., Dale, R. C., Darin, N. n., Debray, F. G., De Giorgis, V. n., Denecke, J. n., Doummar, D. n., Drake Af Hagelsrum, G. n., Eleftheriou, D. n., Estienne, M. n., Fazzi, E. n., Feillet, F. n., Galli, J. n., Hartog, N. n., Harvengt, J. n., Heron, B. n., Heron, D. n., Kelly, D. A., Lev, D. n., Levrat, V. n., Livingston, J. H., Marti, I. n., Mignot, C. n., Mochel, F. n., Nougues, M. C., Oppermann, I. n., Pérez-Dueñas, B. n., Popp, B. n., Rodero, M. P., Rodriguez, D. n., Saletti, V. n., Sharpe, C. n., Tonduti, D. n., Vadlamani, G. n., Van Haren, K. n., Tomas Vila, M. n., Vogt, J. n., Wassmer, E. n., Wiedemann, A. n., Wilson, C. J., Zerem, A. n., Zweier, C. n., Zuberi, S. M., Orcesi, S. n., Vanderver, A. L., Hur, S. n., Crow, Y. J. 2020

    Abstract

    IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and non-penetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/humu.23975

    View details for PubMedID 31898846

  • Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders. Annals of neurology Vanderver, A. n., Bernard, G. n., Helman, G. n., Sherbini, O. n., Boeck, R. n., Cohn, J. n., Collins, A. n., Demarest, S. n., Dobbins, K. n., Emrick, L. n., Fraser, J. n., Masser-Frye, D. n., Hayward, J. n., Karmarkar, S. n., Keller, S. n., Mirrop, S. n., Mitchell, W. n., Pathak, S. n., Sherr, E. n., van Haren, K. n., Waters, E. n., Wilson, J. L., Zhorne, L. n., Schiffmann, R. n., van der Knaap, M. S., Pizzino, A. n., Dubbs, H. n., Shults, J. n., Simons, C. n., Taft, R. J. 2020

    Abstract

    Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied.A prospective time-delayed cross-over design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between 12/01/2015 - 09/27/2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for four months followed by GS.34 individuals were assessed at interim review. The genetic origin of two patient's leukoencephalopathy was resolved before randomization. Nine patients stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the Immediate (5 of 9 [56%] vs. 0 of 9 [0%]; Wild-Seber p < 0.005) and Delayed (control) arms (14 of 23 [61%] vs 5 of 23 [22%]; Wild-Seber p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log rank test, p=0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5% [95% CI = 58.8% to 89.3%]) in less than 4 months, greater than historical norms of less than 50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study.In this study, first-line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence-based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.25757

    View details for PubMedID 32342562

  • MRI Surveillance of Boys with X-linked Adrenoleukodystrophy Identified by Newborn Screening: Meta-analysis and Consensus Guidelines. Journal of inherited metabolic disease Mallack, E. J., Turk, B. R., Yan, H. n., Price, C. n., Mlis, M. D., Moser, A. B., Becker, C. n., Hollandsworth, K. n., Adang, L. n., Vanderver, A. n., Van Haren, K. n., Ruzhnikov, M. n., Kurtzberg, J. n., Maegawa, G. n., Orchard, P. J., Lund, T. C., Raymond, G. V., Regelmann, M. n., Orsini, J. J., Seeger, E. n., Kemp, S. n., Eichler, F. n., Fatemi, A. n. 2020

    Abstract

    Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy.To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus.One hundred twenty-three studies met inclusion criteria yielding 1,285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0 - 9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (1) Obtain an MRI between 12 and 18 months old. (2) Obtain a second MRI 1 year after baseline. (3) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (4) After 12 years, obtain an annual MRI.Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/jimd.12356

    View details for PubMedID 33373467

  • Five men with arresting and relapsing cerebral adrenoleukodystrophy. Journal of neurology Carlson, A. M., Huffnagel, I. C., Verrips, A. n., van der Knaap, M. S., Engelen, M. n., Van Haren, K. n. 2020

    Abstract

    X-linked adrenoleukodystrophy (ALD) is the most common genetic peroxisomal disorder with an estimated prevalence of 1:15,000. Approximately two-thirds of males with ALD manifest the inflammatory demyelinating cerebral phenotype (cALD) at some disease stage, in which focal, inflammatory lesions progress over months to years. Hematopoietic stem-cell transplantation can permanently halt cALD progression, but it is only effective if initiated early. Although most cALD lesions progress relentlessly, a subset may spontaneously arrest; subsequent reactivation of these arrested lesions has not been previously detailed.We describe a novel arresting-relapsing variant of cALD.Salient clinical and radiographic studies were reviewed and summarized for cALD patients with episodic deteriorations.We report a series of five unrelated men with spontaneously arrested cALD lesions that subsequently manifested signs of clinical and radiologic lesion progression during longitudinal follow-up. In three of five patients, functional status was too poor to attempt transplant by the time the recurrence was identified. One patient experienced reactivation followed by another period of spontaneous arrest.These cases emphasize the need for continued clinical and radiologic vigilance for adult men with ALD to screen for evidence of new or reactivated cALD lesions to facilitate prompt treatment evaluation.

    View details for DOI 10.1007/s00415-020-10225-7

    View details for PubMedID 32995952

  • Incidence, Risk Factors and Outcomes Among Children With Acute Flaccid Myelitis: A Population-based Cohort Study in a California Health Network Between 2011 and 2016 PEDIATRIC INFECTIOUS DISEASE JOURNAL Kane, M. S., Sonne, C., Zhu, S., Malhotra, A., Van Haren, K., Messacar, K., Glaser, C. A. 2019; 38 (7): 667–72
  • Safety, tolerability, and efficacy of fluoxetine as an antiviral for acute flaccid myelitis NEUROLOGY Messacar, K., Sillau, S., Hopkins, S. E., Otten, C., Wilson-Murphy, M., Wong, B., Santoro, J. D., Treister, A., Bains, H. K., Torres, A., Zabrocki, L., Glanternik, J. R., Hurst, A. L., Martin, J. A., Schreiner, T., Makhani, N., DeBiasi, R. L., Kruer, M. C., Tremoulet, A. H., Van Haren, K., Desai, J., Benson, L. A., Gorman, M. P., Abzug, M. J., Tyler, K. L., Dominguez, S. R. 2019; 92 (18): E2118–E2126
  • Incidence, Risk Factors and Outcomes Among Children With Acute Flaccid Myelitis: A Population-based Cohort Study in a California Health Network Between 2011 and 2016. The Pediatric infectious disease journal Kane, M. S., Sonne, C., Zhu, S., Malhotra, A., Van Haren, K., Messacar, K., Glaser, C. A. 2019

    Abstract

    BACKGROUND: Acute flaccid myelitis (AFM) is defined as an acute onset of limb weakness with longitudinal spinal gray matter lesions. Reporting bias and misdiagnosis confound epidemiologic studies of AFM. We mitigated these confounders by using a large data set to assess AFM incidence, risk factors and outcomes in a fixed population.METHODS: A retrospective cohort study was conducted within Kaiser Permanente Northern California population among children 1-18 years. Cases met radiographic and clinical criteria for AFM and were confirmed by two clinicians. Clinical and demographic data were assessed.RESULTS: A total of 28 patients met study criteria for AFM between January 1, 2011 and December 31, 2016, an overall rate of 1.46 per 100,000 person-years. Incidence increased from 0.30 to 1.43 cases/per 100,000 person-years between 2011 and 2016, respectively. Median age was 9 years. Risk factors included male sex, Asian ancestry and history of asthma, atopic dermatitis or head injury. Risk factors associated with poliomyelitis were absent. Prodromal illness was common; enterovirus was the most common pathogen detected (n = 5). Among the 27 patients with 12-month follow-up, most demonstrated some improvement, 11 (41.0%) had full recovery, but several had significant deficits with one death reported after the study period.CONCLUSIONS: We employed a closed-population study to generate AFM incidence, risk and outcome data. Our findings support previous reports of male sex and atopy as risk factors. Interval increase in incidence, predisposing Asian ancestry and history of head injury were unique findings to this study. Overall prognosis was better than prior reports, but recovery was incomplete in several patients.

    View details for PubMedID 30985511

  • Consensus Guidelines: MRI surveillance of Children with Presymptomatic Adrenoleukodystrophy Turk, B., Mallack, E., Adang, L., Becker, C., Eichler, F., Van Haren, K., Hollandsworth, K., Kurtzberg, J., Kwon, J., Lund, T., Maegawa, G., Moser, A., Orchard, P., Orsini, J., Rauner, B., Raymond, G., Regelman, M., Ruzhnikov, M., Salzman, A., Vanderver, A., Seeger, E., Fatemi, S. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Measuring early lesion growth in boys with cerebral demyelinating adrenoleukodystrophy. Neurology van Haren, K., Engelen, M., Wolf, N. 2019

    View details for PubMedID 30902909

  • Clinical Subpopulations in a Sample of North American Children Diagnosed With Acute Flaccid Myelitis, 2012-2016 JAMA PEDIATRICS Elrick, M. J., Gordon-Lipkin, E., Crawford, T. O., Van Haren, K., Messacar, K., Thornton, N., Dee, E., Voskertchian, A., Nance, J. R., Munoz, L. S., Gorman, M. P., Benson, L. A., Thomas, D. L., Pardo, C. A., Milstone, A. M., Duggal, P. 2019; 173 (2): 134–39
  • Allogeneic HSCT for adult-onset leukoencephalopathy with spheroids and pigmented glia. Brain : a journal of neurology Gelfand, J. M., Greenfield, A. L., Barkovich, M. n., Mendelsohn, B. A., Van Haren, K. n., Hess, C. P., Mannis, G. N. 2019

    Abstract

    Adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) is an autosomal dominant leukoencephalopathy caused by mutations in colony stimulating factor 1 receptor (CSF1R). Here we report clinical and imaging outcomes following allogeneic haematopoietic stem cell transplantation (HSCT) in two patients with ALSP at the University of California, San Francisco between January 2016 and December 2017. Patient 1 proceeded to transplantation at age 53 with a haplo-identical sibling donor. Patient 2, whose sister and mother had died of the disease, proceeded to transplantation at age 49 with a 12/12 human leukocyte antigen-matched unrelated donor. Both patients received reduced intensity conditioning regimens. At 28 and 26 months post-HSCT, respectively, both patients were alive, without evidence of graft-versus-host disease, with major infection at 1 year in one and new-onset seizures in the other. In both cases, neurological worsening continued post-HSCT; however, the progression in cognitive deficits, overall functional status and gait impairment gradually stabilized. There was continued progression of parkinsonism in both patients. On brain MRI, within 1 year there was stabilization of T2/FLAIR abnormalities, and after 2 years there was complete resolution of abnormal multifocal reduced diffusion. In summary, after >2 years of follow-up, allogeneic HSCT in ALSP led to interval resolution of diffusion MRI abnormalities, stabilization of T2/FLAIR MRI abnormalities, and partial clinical stabilization, supportive of treatment response. Allogeneic HSCT may be beneficial in ALSP by providing a supply of bone marrow-derived brain-engrafting myeloid cells with donor wild-type CSF1R to repopulate the microglial niche.

    View details for DOI 10.1093/brain/awz390

    View details for PubMedID 31840744

  • Pneumonia Prevention Strategies for Children With Neurologic Impairment. Pediatrics Lin, J. L., Van Haren, K. n., Rigdon, J. n., Saynina, O. n., Song, H. n., Buu, M. C., Thakur, Y. n., Srinivas, N. n., Asch, S. M., Sanders, L. M. 2019

    Abstract

    Children with neurologic impairment (NI) face high risk of recurrent severe pneumonia, with prevention strategies of unknown effectiveness. We evaluated the comparative effectiveness of secondary prevention strategies for severe pneumonia in children with NI.We included children enrolled in California Children's Services between July 1, 2009, and June 30, 2014, with NI and 1 pneumonia hospitalization. We examined associations between subsequent pneumonia hospitalization and expert-recommended prevention strategies: dental care, oral secretion management, gastric acid suppression, gastrostomy tube placement, chest physiotherapy, outpatient antibiotics before index hospitalization, and clinic visit before or after index hospitalization. We used a 1:2 propensity score matched model to adjust for covariates, including sociodemographics, medical complexity, and severity of index hospitalization.Among 3632 children with NI and index pneumonia hospitalization, 1362 (37.5%) had subsequent pneumonia hospitalization. Only dental care was associated with decreased risk of subsequent pneumonia hospitalization (adjusted odds ratio [aOR]: 0.64; 95% confidence interval [CI]: 0.49-0.85). Exposures associated with increased risk included gastrostomy tube placement (aOR: 2.15; 95% CI: 1.63-2.85), chest physiotherapy (aOR: 2.03; 95% CI: 1.29-3.20), outpatient antibiotics before hospitalization (aOR: 1.42; 95% CI: 1.06-1.92), clinic visit before (aOR: 1.30; 95% CI: 1.11-1.52), and after index hospitalization (aOR: 1.72; 95% CI: 1.35-2.20).Dental care was associated with decreased recurrence of severe pneumonia. Several strategies, including gastrostomy tube placement, were associated with increased recurrence, possibly due to unresolved confounding by indication. Our results support a clinical trial of dental care to prevent severe pneumonia in children with NI.

    View details for DOI 10.1542/peds.2019-0543

    View details for PubMedID 31537634

  • Clinical Subpopulations in a Sample of North American Children Diagnosed With Acute Flaccid Myelitis, 2012-2016. JAMA pediatrics Elrick, M. J., Gordon-Lipkin, E., Crawford, T. O., Van Haren, K., Messacar, K., Thornton, N., Dee, E., Voskertchian, A., Nance, J. R., Munoz, L. S., Gorman, M. P., Benson, L. A., Thomas, D. L., Pardo, C. A., Milstone, A. M., Duggal, P. 2018

    Abstract

    Importance: Acute flaccid myelitis (AFM) is an emerging poliolike illness of children whose clinical spectrum and associated pathogens are only partially described. The case definition is intentionally encompassing for epidemiologic surveillance to capture all potential AFM cases. Defining a restrictive, homogenous subpopulation may aid our understanding of this emerging disease.Objective: To evaluate the extent to which the US Centers for Disease Control and Prevention (CDC) case definition of AFM incorporates possible alternative diagnoses and to assess the plausibility of a case definition that enriches the biological homogeneity of AFM for inclusion in research studies.Design, Setting, and Participants: Retrospective case analysis of children younger than 18 years diagnosed as having AFM between 2012 and 2016 using the CDC case definition. Group 1 included patients recruited from the United States and Canada based on the CDC case definition of AFM. Group 2 included patients referred to the Johns Hopkins Transverse Myelitis Center for evaluation of suspected AFM. Patients' records and imaging data were critically reviewed by 3 neurologists to identify those cases with definable alternative diagnoses, and the remaining patients were categorized as having restrictively defined AFM (rAFM). Clinical characteristics were compared between patients with rAFM (cases) and those with alternative diagnoses, and a case description distinguishing these AFM groups was identified. Interrater reliability of this description was confirmed for a subset of cases by a fourth neurologist. Data were analyzed between May 2017 and November 2018.Main Outcomes and Measures: Proportion of patients with possible alternative diagnosis.Results: Of the 45 patients who met the CDC AFM case definition and were included, the mean age was 6.1 years; 27 were boys (60%); and 37 were white (82%), 3 were Asian (7%), 1 was Hispanic (2%), and 4 were mixed race/ethnicity (9%). Of the included patients, 34 were classified as having rAFM, and 11 had alternate diagnoses (including transverse myelitis, other demyelinating syndromes, spinal cord stroke, Guillain-Barre syndrome, Chiari I myelopathy, and meningitis). Factors differing between groups were primarily asymmetry of weakness, lower motor neuron signs, preceding viral syndrome, symptoms evolving over hours to days, absence of sensory deficits, and magnetic resonance imaging findings. A case description was able to reliably define the rAFM group.Conclusions and Relevance: We present an approach for defining a homogeneous research population that may more accurately reflect the pathogenesis of the prototypical poliomyelitis-like subgroup of AFM. The definition of rAFM forms a blueprint for inclusion criteria in future research efforts, but more work is required for refinement and external validation.

    View details for PubMedID 30500056

  • Safety, tolerability, and efficacy of fluoxetine as an antiviral for acute flaccid myelitis. Neurology Messacar, K., Sillau, S., Hopkins, S. E., Otten, C., Wilson-Murphy, M., Wong, B., Santoro, J. D., Treister, A., Bains, H. K., Torres, A., Zabrocki, L., Glanternik, J. R., Hurst, A. L., Martin, J. A., Schreiner, T., Makhani, N., DeBiasi, R. L., Kruer, M. C., Tremoulet, A. H., Van Haren, K., Desai, J., Benson, L. A., Gorman, M. P., Abzug, M. J., Tyler, K. L., Dominguez, S. R. 2018

    Abstract

    OBJECTIVE: To determine the safety, tolerability, and efficacy of fluoxetine for proven or presumptive enterovirus (EV) D68-associated acute flaccid myelitis (AFM).METHODS: A multicenter cohort study of US patients with AFM in 2015-2016 compared serious adverse events (SAEs), adverse effects, and outcomes between fluoxetine-treated patients and untreated controls. Fluoxetine was administered at the discretion of treating providers with data gathered retrospectively. The primary outcome was change in summative limb strength score (SLSS; sum of Medical Research Council strength in all 4 limbs, ranging from 20 [normal strength] to 0 [complete quadriparesis]) between initial examination and latest follow-up, with increased SLSS reflecting improvement and decreased SLSS reflecting worsened strength.RESULTS: Fifty-six patients with AFM from 12 centers met study criteria. Among 30 patients exposed to fluoxetine, no SAEs were reported and adverse effect rates were similar to unexposed patients (47% vs 65%, p = 0.16). The 28 patients treated with >1 dose of fluoxetine were more likely to have EV-D68 identified (57.1% vs 14.3%, p < 0.001). Their SLSS was similar at initial examination (mean SLSS 12.9 vs 14.3, p = 0.31) but lower at nadir (mean SLSS 9.25 vs 12.82, p = 0.02) and latest follow-up (mean SLSS 12.5 vs 16.4, p = 0.005) compared with the 28 patients receiving 1 (n = 2) or no (n = 26) doses. In propensity-adjusted analysis, SLSS from initial examination to latest follow-up decreased by 0.2 (95% confidence interval [CI] -1.8 to +1.4) in fluoxetine-treated patients and increased by 2.5 (95% CI +0.7 to +4.4) in untreated patients (p = 0.015).CONCLUSION: Fluoxetine was well-tolerated. Fluoxetine was preferentially given to patients with AFM with EV-D68 identified and more severe paralysis at nadir, who ultimately had poorer long-term outcomes.CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with EV-D68-associated AFM, fluoxetine is well-tolerated and not associated with improved neurologic outcomes.

    View details for PubMedID 30413631

  • Natural History of Vanishing White Matter ANNALS OF NEUROLOGY Hamilton, E. C., van der Lei, H. W., Vermeulen, G., Gerver, J. M., Lourenco, C. M., Naidu, S., Mierzewska, H., Gemke, R. J., de Vet, H. W., Uitdehaag, B. J., Lissenberg-Witte, B. I., van der Knaap, M. S., VWM Res Grp 2018; 84 (2): 274-288

    Abstract

    To comprehensively describe the natural history of vanishing white matter (VWM), aiming at improving counseling of patients/families and providing natural history data for future therapeutic trials.We performed a longitudinal multicenter study among 296 genetically confirmed VWM patients. Clinical information was obtained via disease-specific clinical questionnaire, Health Utilities Index and Guy's Neurological Disability Scale assessments, and chart review.First disease signs occurred at a median age of 3 years (mode = 2 years, range = before birth to 54 years); 60% of patients were symptomatic before the age of 4 years. The nature of the first signs varied for different ages of onset. Overall, motor problems were the most common presenting sign, especially in children. Adolescent and adult onset patients were more likely to exhibit cognitive problems early after disease onset. One hundred two patients were deceased. Multivariate Cox regression analysis revealed a positive relation between age at onset and both preservation of ambulation and survival. Absence of stress-provoked episodes and absence of seizures predicted more favorable outcome. In patients with onset before 4 years, earlier onset was associated with more severe disability and higher mortality. For onset from 4 years on, disease course was generally milder, with a wide variation in severity. There were no significant differences for sex or for the 5 eIF2B gene groups. The results confirm the presence of a genotype-phenotype correlation.The VWM disease spectrum consists of a continuum with extremely wide variability. Age at onset is a strong predictor for disease course. Ann Neurol 2018;84:274-288.

    View details for DOI 10.1002/ana.25287

    View details for Web of Science ID 000444576400012

    View details for PubMedID 30014503

    View details for PubMedCentralID PMC6175238

  • MRI Brain Abnormalities in Acute Flaccid Myelitis: Characteristics and Differentiation from Acute Disseminated Encephalomyelitis Hopkins, S., Gordon-Lipkin, E., Van Haren, K., Santoro, J., Munoz-Arcos, L., Matesanz, S., Pardo-Villamizar, C., Banwell, B. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Pediatric Bickerstaff brainstem encephalitis: a systematic review of literature and case series JOURNAL OF NEUROLOGY Santoro, J., Lazzareschi, D. V., Campen, C., Van Haren, K. P. 2018; 265 (1): 141–50

    Abstract

    To characterize the phenotype of pediatric Bickerstaff's brainstem encephalitis (BBE) and evaluate prognostic features in the clinical course, diagnostic studies, and treatment exposures.We systematically reviewed PubMed, Web of Science, and SCOPUS databases as well as medical records at the Lucile Packard Children's Hospital to identify cases of pediatric BBE. Inclusion required all of the following criteria: age ≤ 20 years, presence of somnolence or alterations in mental status at the time of presentation or developed within 7 days of presentation, ataxia, and ophthalmoplegia.We reviewed 682 manuscripts, identifying a total of 47 pediatric BBE cases. We also describe five previously unreported cases. The phenotype of these pediatric patients was similar to previously published literature. Sixty-eight percent of patients demonstrated positive anti-GQ1b antibody titers, yet the presence of these antibodies was not associated with longer times to recovery. Patients with neuroimaging abnormalities featured a longer median time to recovery, but this was not statistically significant (p = 0.124). Overall, patients treated with any form of immunotherapy (intravenous immunoglobulin, steroids, or plasmapheresis) demonstrated shorter median time to resolution of symptoms compared to supportive therapy, although this trend was not statistically significant (p = 0.277). Post-hoc t tests revealed a trend towards use of immunotherapy against supportive care alone (p = 0.174).Our study identified clinical, radiologic, and treatment features that may hold prognostic value for children with BBE. The role of immunotherapy remains under investigation but may prove of utility with further, randomized controlled studies in this rare disease.

    View details for PubMedID 29177548

  • Neonatal detection of Aicardi Goutieres Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots MOLECULAR GENETICS AND METABOLISM Armangue, T., Orsini, J. J., Takanohashi, A., Gavazzi, F., Conant, A., Ulrick, N., Morrissey, M. A., Nahhas, N., Helman, G., Gordish-Dressman, H., Orcesi, S., Tonduti, D., Stutterd, C., van Haren, K., Toro, C., Iglesias, A. D., van der Knaap, M. S., Mansky, R., Moser, A. B., Jones, R. O., Vanderver, A. 2017; 122 (3): 134–39
  • Neonatal detection of Aicardi Goutières Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots. Molecular genetics and metabolism Armangue, T., Orsini, J. J., Takanohashi, A., Gavazzi, F., Conant, A., Ulrick, N., Morrissey, M. A., Nahhas, N., Helman, G., Gordish-Dressman, H., Orcesi, S., Tonduti, D., Stutterd, C., van Haren, K., Toro, C., Iglesias, A. D., van der Knaap, M. S., Goldbach Mansky, R., Moser, A. B., Jones, R. O., Vanderver, A. 2017; 122 (3): 134-139

    Abstract

    Aicardi Goutières Syndrome (AGS) is a heritable interferonopathy associated with systemic autoinflammation causing interferon (IFN) elevation, central nervous system calcifications, leukodystrophy and severe neurologic sequelae. An infant with TREX1 mutations was recently found to have abnormal C26:0 lysophosphatidylcholine (C26:0 Lyso-PC) in a newborn screening platform for X-linked adrenoleukodystrophy, prompting analysis of this analyte in retrospectively collected samples from individuals affected by AGS.In this study, we explored C26:0 Lyso-PC levels and IFN signatures in newborn blood spots and post-natal blood samples in 19 children with a molecular and clinical diagnosis of AGS and in the blood spots of 22 healthy newborns. We used Nanostring nCounter™ for IFN-induced gene analysis and a high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS) newborn screening platform for C26:0 Lyso-PC analysis.Newborn screening cards from patients across six AGS associated genes were collected, with a median disease presentation of 2months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>0.4μM), that would have resulted in a second screen being performed in a two tier screening system for X-linked adrenoleukodystrophy (X-ALD). The median (95%CI) of first tier C26:0 Lyso-PC values in AGS individuals (0.43μM [0.37-0.48]) was higher than that seen in controls (0.21μM [0.21-0.21]), but lower than X-ALD individuals (0.72μM [0.59-0.84])(p<0.001). Fourteen of 19 children had elevated expression of IFN signaling on blood cards relative to controls (Sensitivity 73.7%, 95%CI 51-88%, Specificity 95%, 95% CI 78-99%) including an individual with delayed disease presentation (36months of age). All five AGS patients with negative IFN signature at birth had RNASEH2B mutations. Consistency of agreement between IFN signature in neonatal and post-natal samples was high (0.85).This suggests that inflammatory markers in AGS can be identified in the newborn period, before symptom onset. Additionally, since C26:0 Lyso-PC screening is currently used in X-ALD newborn screening panels, clinicians should be alert to the fact that AGS infants may present as false positives during X-ALD screening.

    View details for DOI 10.1016/j.ymgme.2017.07.006

    View details for PubMedID 28739201

    View details for PubMedCentralID PMC5722655

  • 26:0 Lysophophatidylcholine Elevations in Newborn Screening Spots in Aicardi Goutieres Syndrome Armangue, T., Orsini, J., Gavazzi, F., Conant, A., Ulrick, N., Morrissey, M., Nahhas, N., Helman, G., Gordish-Dressman, H., Orcesi, S., Tonduti, D., Stutterd, C., van Haren, K., Toro, C., Iglesias, A., van der Knapp, M., Mansky, G. R., Moser, A., Jones, R., Vanderver, A. WILEY. 2017: S302
  • Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings JOURNAL OF CHILD NEUROLOGY Song, H., Haeri, S., Vogel, H., van der Knaap, M., Van Haren, K. 2017; 32 (10): 867–70

    Abstract

    We describe 2 male siblings with a severe, prenatal phenotype of vanishing white matter disease and the impact of whole exome sequencing on their diagnosis and clinical care.The 2 children underwent detailed clinical characterization, through clinical and laboratory testing, as well as prenatal and postnatal imaging. Biobanked blood from the 2 siblings was submitted for whole exome sequencing at Baylor Laboratories.Both male children had abnormal prenatal neuroimaging and suffered precipitous, fatal neurologic decline. Neuropathologic findings included subependymal pseudocysts, microcalcifications, and profound lack of brain myelin and sparing of peripheral nerve myelin. A novel homozygous mutation in the EIF2B3 gene (c.97A>G [p.Lys33Glu]) was found in both children; both parents were heterozygous carriers. The family subsequently conceived a healthy child via in vitro fertilization with preimplantation mutation screening.These histories expand the prenatal phenotype of eIF2b-related disorders and poignantly illustrate the impact that unbiased genomic sequencing can have on the diagnosis and medical decision making for families affected by childhood neurodegenerative disorders.

    View details for PubMedID 28597716

  • Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies MOLECULAR GENETICS AND METABOLISM Adang, L. A., Sherbini, O., Ball, L., Bloom, M., Darbari, A., Amartino, H., DiVito, D., Eichler, F., Escolar, M., Evans, S. H., Fatemi, A., Fraser, J., Hollowell, L., Jaffe, N., Joseph, C., Karpinski, M., Keller, S., Maddock, R., Mancilla, E., McClary, B., Mertz, J., Morgart, K., Langan, T., Leventer, R., Parikh, S., Pizzino, A., Prange, E., Renaud, D. L., Rizzo, W., Shapiro, J., Suhr, D., Suhr, T., Tonduti, D., Waggoner, J., Waldman, A., Wolf, N. I., Zerem, A., Bonkowsky, J. L., Bernard, G., van Haren, K., Vanderver, A., Global Leukodtystrophy Initiative 2017; 122 (1-2): 18–32

    Abstract

    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.

    View details for PubMedID 28863857

  • Decision Making in Adrenoleukodystrophy: When Is a Good Outcome Really a Good Outcome? JAMA neurology Van Haren, K., Engelen, M. 2017

    View details for DOI 10.1001/jamaneurol.2017.0095

    View details for PubMedID 28418445

  • Arresting and Relapsing Cerebral Adrenoleukodystrophy, A Treatable Mimic of Multiple Sclerosis Carlson, A. M., Huffnagel, I. C., Engelen, M., Van Haren, K. SAGE PUBLICATIONS LTD. 2017: 27
  • The Effect of Vitamin D on Markers of Oxidative Stress in X-linked Adrenoleukodystrophy Van Haren, K., Waubant, E., Enns, G., Mowry, E., Raymond, G., Aubourg, P., Steinman, L. WILEY-BLACKWELL. 2016: S244
  • Acute flaccid myelitis: A clinical review of US cases 2012-2015. Annals of neurology Messacar, K., Schreiner, T. L., Van Haren, K., Yang, M., Glaser, C. A., Tyler, K. L., Dominguez, S. R. 2016; 80 (3): 326-338

    Abstract

    This review highlights clinical features of the increasing cases of acute flaccid paralysis associated with anterior myelitis noted in the United States from 2012 to 2015. Acute flaccid myelitis refers to acute flaccid limb weakness with spinal cord gray matter lesions on imaging or evidence of spinal cord motor neuron injury on electrodiagnostic testing. Although some individuals demonstrated improvement in motor weakness and functional deficits, most have residual weakness a year or more after onset. Epidemiological evidence and biological plausibility support an association between enterovirus D68 and the recent increase in acute flaccid myelitis cases in the United States. Ann Neurol 2016.

    View details for DOI 10.1002/ana.24730

    View details for PubMedID 27422805

  • Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome. Neurology Pohl, D., Alper, G., Van Haren, K., Kornberg, A. J., Lucchinetti, C. F., Tenembaum, S., Belman, A. L. 2016; 87 (9): S38-45

    Abstract

    Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating CNS disorder with predilection to early childhood. ADEM is generally considered a monophasic disease. However, recurrent ADEM has been described and defined as multiphasic disseminated encephalomyelitis. ADEM often occurs postinfectiously, although a causal relationship has never been established. ADEM and multiple sclerosis are currently viewed as distinct entities, generally distinguishable even at disease onset. However, pathologic studies have demonstrated transitional cases of yet unclear significance. ADEM is clinically defined by acute polyfocal neurologic deficits including encephalopathy. MRI typically demonstrates reversible, ill-defined white matter lesions of the brain and often also the spinal cord, along with frequent involvement of thalami and basal ganglia. CSF analysis may reveal a mild pleocytosis and elevated protein, but is generally negative for intrathecal oligoclonal immunoglobulin G synthesis. In the absence of a specific diagnostic test, ADEM is considered a diagnosis of exclusion, and ADEM mimics, especially those requiring a different treatment approach, have to be carefully ruled out. The role of biomarkers, including autoantibodies like anti-myelin oligodendrocyte glycoprotein, in the pathogenesis and diagnosis of ADEM is currently under debate. Based on the presumed autoimmune etiology of ADEM, the current treatment approach consists of early immunotherapy. Outcome of ADEM in pediatric patients is generally favorable, but cognitive deficits have been reported even in the absence of other neurologic sequelae. This review summarizes the current knowledge on epidemiology, pathology, clinical presentation, neuroimaging features, CSF findings, differential diagnosis, therapy, and outcome, with a focus on recent advances and controversies.

    View details for DOI 10.1212/WNL.0000000000002825

    View details for PubMedID 27572859

  • Magnetic Resonance Imaging Spectrum of Succinate Dehydrogenase-Related Infantile Leukoencephalopathy ANNALS OF NEUROLOGY Helman, G., Caldovic, L., Whitehead, M. T., Simons, C., Brockmann, K., Edvardson, S., Bai, R., Moroni, I., Taylor, J. M., Van Haren, K., Taft, R. J., Vanderver, A., van der Knaap, M. S. 2016; 79 (3): 379-386

    Abstract

    Succinate dehydrogenase-deficient leukoencephalopathy is a complex II-related mitochondrial disorder for which the clinical phenotype, neuroimaging pattern, and genetic findings have not been comprehensively reviewed.Nineteen individuals with succinate dehydrogenase deficiency-related leukoencephalopathy were reviewed for neuroradiological, clinical, and genetic findings as part of institutional review board-approved studies at Children's National Health System (Washington, DC) and VU University Medical Center (Amsterdam, the Netherlands).All individuals had signal abnormalities in the central corticospinal tracts and spinal cord where imaging was available. Other typical findings were involvement of the cerebral hemispheric white matter with sparing of the U fibers, the corpus callosum with sparing of the outer blades, the basis pontis, middle cerebellar peduncles, and cerebellar white matter, and elevated succinate on magnetic resonance spectroscopy (MRS). The thalamus was involved in most studies, with a predilection for the anterior nucleus, pulvinar, and geniculate bodies. Clinically, infantile onset neurological regression with partial recovery and subsequent stabilization was typical. All individuals had mutations in SDHA, SDHB, or SDHAF1, or proven biochemical defect.Succinate dehydrogenase deficiency is a rare leukoencephalopathy, for which improved recognition by magnetic resonance imaging (MRI) in combination with advanced sequencing technologies allows noninvasive diagnostic confirmation. The MRI pattern is characterized by cerebral hemispheric white matter abnormalities with sparing of the U fibers, corpus callosum involvement with sparing of the outer blades, and involvement of corticospinal tracts, thalami, and spinal cord. In individuals with infantile regression and this pattern of MRI abnormalities, the differential diagnosis should include succinate dehydrogenase deficiency, in particular if MRS shows elevated succinate. Ann Neurol 2016 ANN NEUROL 2016;79:379-386.

    View details for DOI 10.1002/ana.24572

    View details for PubMedID 26642834

  • Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015 JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Van Haren, K., Ayscue, P., Waubant, E., Clayton, A., Sheriff, H., Yagi, S., Glenn-Finer, R., Padilla, T., Strober, J. B., Aldrovandi, G., Wadford, D. A., Chiu, C. Y., Xia, D., Harriman, K., Watt, J. P., Glaser, C. A. 2015; 314 (24): 2663-2671

    Abstract

    There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology.To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury.Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing.Case incidence and infectious agent association.Fifty-nine cases were identified. Median age was 9 years (interquartile range [IQR], 4-14 years; 50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41). Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis. During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100,000 person-years) compared with other monitoring periods (0.028 cases per 100,000 person-years; P <.001).In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.

    View details for DOI 10.1001/jama.2015.17275

    View details for Web of Science ID 000366939800021

  • Statewide Prospective Surveillance of Acute Flaccid Myelitis in California, 2012-2014 Van Haren, K., Ayscue, P. R., Clayton, A., Sheriff, H., Yagi, S., Wadford, D., Harriman, K., Watt, J., Glaser, C. WILEY-BLACKWELL. 2015: S157
  • Emerging Treatments for Pediatric Leukodystrophies PEDIATRIC CLINICS OF NORTH AMERICA Helman, G., Van Haren, K., Escolar, M. L., Vanderver, A. 2015; 62 (3): 649-?

    Abstract

    The leukodystrophies are a heterogeneous group of inherited disorders with broad clinical manifestations and variable pathologic mechanisms. Improved diagnostic methods have allowed identification of the underlying cause of these diseases, facilitating identification of their pathologic mechanisms. Clinicians are now able to prioritize treatment strategies and advance research in therapies for specific disorders. Although only a few of these disorders have well-established treatments or therapies, a number are on the verge of clinical trials. As investigators are able to shift care from symptomatic management of disorders to targeted therapeutics, the unmet therapeutic needs could be reduced for these patients.

    View details for DOI 10.1016/j.pcl.2015.03.006

    View details for PubMedID 26022168

  • A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012-14): a retrospective cohort study LANCET INFECTIOUS DISEASES Greninger, A. L., Naccache, S. N., Messacar, K., Clayton, A., Yu, G., Somasekar, S., Federman, S., Stryke, D., Anderson, C., Yagi, S., Messenger, S., Wadford, D., Xia, D., Watt, J. P., Van Haren, K., Dominguez, S. R., Glaser, C., Aldrovandi, G., Chiu, C. Y. 2015; 15 (6): 671-682

    Abstract

    Enterovirus D68 was implicated in a widespread outbreak of severe respiratory illness across the USA in 2014 and has also been reported sporadically in patients with acute flaccid myelitis. We aimed to investigate the association between enterovirus D68 infection and acute flaccid myelitis during the 2014 enterovirus D68 respiratory outbreak in the USA.Patients with acute flaccid myelitis who presented to two hospitals in Colorado and California, USA, between Nov 24, 2013, and Oct 11, 2014, were included in the study. Additional cases identified from Jan 1, 2012, to Oct 4, 2014, via statewide surveillance were provided by the California Department of Public Health. We investigated the cause of these cases by metagenomic next-generation sequencing, viral genome recovery, and enterovirus D68 phylogenetic analysis. We compared patients with acute flaccid myelitis who were positive for enterovirus D68 with those with acute flaccid myelitis but negative for enterovirus D68 using the two-tailed Fisher's exact test, two-sample unpaired t test, and Mann-Whitney U test.48 patients were included: 25 with acute flaccid myelitis, two with enterovirus-associated encephalitis, five with enterovirus-D68-associated upper respiratory illness, and 16 with aseptic meningitis or encephalitis who tested positive for enterovirus. Enterovirus D68 was detected in respiratory secretions from seven (64%) of 11 patients comprising two temporally and geographically linked acute flaccid myelitis clusters at the height of the 2014 outbreak, and from 12 (48%) of 25 patients with acute flaccid myelitis overall. Phylogenetic analysis revealed that all enterovirus D68 sequences associated with acute flaccid myelitis grouped into a clade B1 strain that emerged in 2010. Of six coding polymorphisms in the clade B1 enterovirus D68 polyprotein, five were present in neuropathogenic poliovirus or enterovirus D70, or both. One child with acute flaccid myelitis and a sibling with only upper respiratory illness were both infected by identical enterovirus D68 strains. Enterovirus D68 viraemia was identified in a child experiencing acute neurological progression of his paralytic illness. Deep metagenomic sequencing of cerebrospinal fluid from 14 patients with acute flaccid myelitis did not reveal evidence of an alternative infectious cause to enterovirus D68.These findings strengthen the putative association between enterovirus D68 and acute flaccid myelitis and the contention that acute flaccid myelitis is a rare yet severe clinical manifestation of enterovirus D68 infection in susceptible hosts.National Institutes of Health, University of California, Abbott Laboratories, and the Centers for Disease Control and Prevention.

    View details for DOI 10.1016/S1473-3099(15)70093-9

    View details for PubMedID 25837569

  • Disease specific therapies in leukodystrophies and leukoencephalopathies MOLECULAR GENETICS AND METABOLISM Helman, G., Van Haren, K., Bonkowsky, J. L., Bernard, G., Pizzino, A., Braverman, N., Suhr, D., Patterson, M. C., Fatemi, S. A., Leonard, J., van der Knaap, M. S., Back, S. A., Damiani, S., Goldman, S. A., Takanohashi, A., Petryniak, M., Rowitch, D., Messing, A., Wrabetz, L., Schiffmann, R., Eichler, F., Escolar, M. L., Vanderver, A. 2015; 114 (4): 527-536

    Abstract

    Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.

    View details for DOI 10.1016/j.ymgme.2015.01.014

    View details for Web of Science ID 000353008900005

    View details for PubMedCentralID PMC4390468

  • Consensus statement on preventive and symptomatic care of leukodystrophy patients MOLECULAR GENETICS AND METABOLISM Van Haren, K., Bonkowsky, J. L., Bernard, G., Murphy, J. L., Pizzino, A., Helman, G., Suhr, D., Waggoner, J., Hobson, D., Vanderver, A., Patterson, M. C. 2015; 114 (4): 516-526

    Abstract

    Leukodystrophies are inherited disorders whose primary pathophysiology consists of abnormal deposition or progressive disruption of brain myelin. Leukodystrophy patients manifest many of the same symptoms and medical complications despite the wide spectrum of genetic origins. Although no definitive cures exist, all of these conditions are treatable. This report provides the first expert consensus on the recognition and treatment of medical and psychosocial complications associated with leukodystrophies. We include a discussion of serious and potentially preventable medical complications and propose several preventive care strategies. We also outline the need for future research to prioritize clinical needs and subsequently develop, validate, and optimize specific care strategies.

    View details for DOI 10.1016/j.ymgme.2014.12.433

    View details for PubMedID 25577286

  • Disease specific therapies in leukodystrophies and leukoencephalopathies. Molecular genetics and metabolism Helman, G., Van Haren, K., Bonkowsky, J. L., Bernard, G., Pizzino, A., Braverman, N., Suhr, D., Patterson, M. C., Ali Fatemi, S., Leonard, J., van der Knaap, M. S., Back, S. A., Damiani, S., Goldman, S. A., Takanohashi, A., Petryniak, M., Rowitch, D., Messing, A., Wrabetz, L., Schiffmann, R., Eichler, F., Escolar, M. L., Vanderver, A. 2015; 114 (4): 527-536

    Abstract

    Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.

    View details for DOI 10.1016/j.ymgme.2015.01.014

    View details for PubMedID 25684057

  • De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment, Spastic Paraparesis, Axonal Neuropathy, and Cerebellar Atrophy HUMAN MUTATION Lee, J., Srour, M., Kim, D., Hamdan, F. F., Lim, S., Brunel-Guitton, C., Decarie, J., Rossignol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., Richardson, R., Nicolai, J., Oberndorff, K. M., Wagner, J. D., Boycott, K. M., Rahikkala, E., Junna, N., Tyynismaa, H., Cuppen, I., Verbeek, N. E., Stumpel, C. T., Willemsen, M. A., de Munnik, S. A., Rouleau, G. A., Kim, E., Kamsteeg, E., Kleefstra, T., Michaud, J. L. 2015; 36 (1): 69-78

    Abstract

    KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

    View details for DOI 10.1002/humu.22709

    View details for Web of Science ID 000347076700011

    View details for PubMedID 25265257

  • Acute Flaccid Paralysis with Anterior Myelitis - California, June 2012-June 2014 MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT Ayscue, P., Van Haren, K., Sheriff, H., Waubant, E., Waldron, P., Yagi, S., Yen, C., Clayton, A., Padilla, T., Pan, C., Reichel, J., Harriman, K., Watt, J., Sejvar, J., Nix, W. A., Feikin, D., Glaser, C. 2014; 63 (40): 903-906

    Abstract

    In August 2012, the California Department of Public Health (CDPH) was contacted by a San Francisco Bay area clinician who requested poliovirus testing for an unvaccinated man aged 29 years with acute flaccid paralysis (AFP) associated with anterior myelitis (i.e., evidence of inflammation of the spinal cord involving the grey matter including anterior horn cell bodies) and no history of international travel during the month before symptom onset. Within 2 weeks, CDPH had received reports of two additional cases of AFP with anterior myelitis of unknown etiology. Testing at CDPH's Viral and Rickettsial Disease Laboratory for stool, nasopharyngeal swab, and cerebrospinal fluid (CSF) did not detect the presence of an enterovirus (EV), the genus of the family Picornaviridae that includes poliovirus. Additional laboratory testing for infectious diseases conducted at the CDPH Viral and Rickettsial Disease Laboratory did not identify a causative agent to explain the observed clinical syndrome reported among the patients. To identify other cases of AFP with anterior myelitis and elucidate possible common etiologies, CDPH posted alerts in official communications for California local health departments during December 2012, July 2013, and February 2014. Reports of cases of neurologic illness received by CDPH were investigated throughout this period, and clinicians were encouraged to submit clinical samples for testing. A total of 23 cases of AFP with anterior myelitis of unknown etiology were identified. Epidemiologic and laboratory investigation did not identify poliovirus infection as a possible cause for the observed cases. No common etiology was identified to explain the reported cases, although EV-D68 was identified in upper respiratory tract specimens of two patients. EV infection, including poliovirus infection, should be considered in the differential diagnosis in cases of AFP with anterior myelitis and testing performed per CDC guidelines.

    View details for Web of Science ID 000342955700006

    View details for PubMedCentralID PMC4584614

  • ALD Connect, An All-inclusive Consortium with the Goal to Eradicate X-linked Adrenoleukodystrophy Eichler, F., Lenail, B., van Haren, K., Fatemi, A., Zackowski, K., Raymond, G., Jamal, L., Salzman, A., Paker, A., Bonkowsky, J., Brown, R., Fink, J., O'Sullivan-Fortin, K., Salzman, R., Sherman, A. WILEY-BLACKWELL. 2014: S192
  • ALD Connect, an All-Inclusive Consortium with the Goal to Eradicate X-Linked Adrenoleukodystrophy Eichler, F., Van Haren, K., Lenail, B., Fatemi, A., Zackowski, K., Raymond, G., Jamal, L., Bonkowsky, J., Fink, J., Brown, R., Salzman, R., Sherman, A. WILEY-BLACKWELL. 2014: S60
  • National Variation in Costs and Mortality for Leukodystrophy Patients in US Children's Hospitals PEDIATRIC NEUROLOGY Brimley, C. J., Lopez, J., Van Haren, K., Wilkes, J., Sheng, X., Nelson, C., Korgenski, E. K., Srivastava, R., Bonkowsky, J. L. 2013; 49 (3): 156-162

    Abstract

    Inherited leukodystrophies are progressive, debilitating neurological disorders with few treatment options and high mortality rates. Our objective was to determine national variation in the costs for leukodystrophy patients and to evaluate differences in their care.We developed an algorithm to identify inherited leukodystrophy patients in deidentified data sets using a recursive tree model based on International Classification of Disease, 9th Edition, Clinical Modification, diagnosis and procedure charge codes. Validation of the algorithm was performed independently at two institutions, and with data from the Pediatric Health Information System (PHIS) of 43 US children's hospitals, for a 7-year period between 2004 and 2010.A recursive algorithm was developed and validated, based on six International Classification of Disease, 9th Edition, Clinical Modification, codes and one procedure code that had a sensitivity up to 90% (range 61-90%) and a specificity up to 99% (range 53-99%) for identifying inherited leukodystrophy patients. Inherited leukodystrophy patients comprise 0.4% of admissions to children's hospitals and 0.7% of costs. During 7 years, these patients required $411 million of hospital care, or $131,000/patient. Hospital costs for leukodystrophy patients varied at different institutions, ranging from two to 15 times more than the average pediatric patient. There was a statistically significant correlation between higher volume and increased cost efficiency. Increased mortality rates had an inverse relationship with increased patient volume that was not statistically significant.We developed and validated a code-based algorithm for identifying leukodystrophy patients in deidentified national datasets. Leukodystrophy patients account for $59 million of costs yearly at children's hospitals. Our data highlight potential to reduce unwarranted variability and improve patient care.

    View details for DOI 10.1016/j.pediatrneurol.2013.06.006

    View details for Web of Science ID 000323588800003

    View details for PubMedID 23953952

    View details for PubMedCentralID PMC3748620

  • Case Report of Subdural Hematoma in a Patient With Sturge-Weber Syndrome and Literature Review: Questions and Implications for Therapy JOURNAL OF CHILD NEUROLOGY Lopez, J., Yeom, K. W., Comi, A., Van Haren, K. 2013; 28 (5): 672-675

    Abstract

    Sturge-Weber syndrome is a neurocutaneous disorder associated with vascular abnormalities in the skin, eye, and brain leading to both acute and chronic cerebral hypoperfusion and, in some affected children, brain injury. Aspirin can reduce stroke-like events and seizure episodes and prevent further brain injuries in these patients. Although a few cases of intracranial hemorrhage in patients with Sturge-Weber syndrome have been reported, prior reports have not discussed this complication with regard to particular therapies. The authors present a toddler with Sturge-Weber syndrome who developed a subdural hematoma in the setting of a mechanical fall with minor head trauma. They discuss the possible role of aspirin in contributing to, or perhaps protecting against, intracranial hemorrhage in patients with Sturge-Weber syndrome. Further data are needed to establish the utility of aspirin in Sturge-Weber syndrome.

    View details for DOI 10.1177/0883073812449514

    View details for PubMedID 22805242

  • Vitamin D Status as a Risk Factor for Cerebral Demyelination in X-Linked Adrenoleukdystrophy Van Haren, K., Mowry, E., Raymond, G., Moser, A., Steinman, L. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Therapeutic Advances in Pediatric Multiple Sclerosis. The Journal of pediatrics 2013

    View details for PubMedID 23726542

  • Fahr's Disease: Pediatric Presentation of a Rare Neurodegenerative Disorder Singhal, N., Van Haren, K., Wu, Y. LIPPINCOTT WILLIAMS & WILKINS. 2012
  • Fahr's Disease: Pediatric Presentation of a Rare Neurodegenerative Disorder Singhal, N., Van Haren, K., Wu, Y. LIPPINCOTT WILLIAMS & WILKINS. 2012
  • Idiopathic Basal Ganglia Calcification: Pediatric Presentation of a Rare Neurodegenerative Disorder Singhal, N. S., Hess, C. P., VanHaren, K., Toro, C., Kilbane, C., Wu, Y. WILEY-BLACKWELL. 2012: S184-S185
  • Immune response in Leukodystrophies PEDIATRIC NEUROLOGY Eichler, F., Van Haren, K. 2007; 37 (4): 235-244

    Abstract

    Although the genetics and biochemistry of leukodystrophies have been extensively explored, the immune response in these disorders has received relatively little attention. Both the disease course and its response to treatment may be highly dependent on the immune system. In this review, we compare three common leukodystrophies, each with a different immune response: (1) X-linked adrenoleukodystrophy, which demonstrates a severe, lymphocytic inflammatory response; (2) metachromatic leukodystrophy, which yields a histiocytic response; and (3) vanishing white-matter disease, in which no inflammation is typically seen. We highlight the biochemical, pathologic, and clinical differences, while focusing on the immune response in each disease. We also review the response of leukodystrophies to immunomodulatory therapies and interventions such as hematopoietic stem-cell transplantation. Future studies may delineate specific inflammatory markers as possible candidates for therapeutic intervention.

    View details for DOI 10.1016/j.pediatrneurol.2007.06.011

    View details for Web of Science ID 000250295000001

    View details for PubMedID 17903666

  • The unfolded protein response in vanishing white matter disease JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY van der Voorn, J. P., van Kollenburg, B., Bertrand, G., Van Haren, K., Scheper, G. C., Powers, J. M., van der Knaap, M. S. 2005; 64 (9): 770-775

    Abstract

    Leukoencephalopathy with vanishing white matter (VWM) is an autosomal-recessive disorder in which febrile infections may provoke major neurologic deterioration. Characteristic pathologic findings include cystic white matter degeneration, foamy oligodendrocytes, dysmorphic astrocytes and oligodendrocytes, oligodendrocytosis, and apoptotic losses of oligodendrocytes. VWM is caused by mutations in eukaryotic initiation factor (eIF) 2B (eIF2B). eIF2B plays an important role in the regulation of protein synthesis. Mutant eIF2B may impair the ability of cells to regulate protein synthesis in response to stress and perhaps even under normal conditions. An overload of misfolded proteins in the endoplasmic reticulum activates the unfolded protein response (UPR), a compensatory mechanism that inhibits synthesis of new proteins and induces both prosurvival and proapoptotic signals. We have studied the activation of the UPR in VWM through the immunohistochemical expression of its upstream components PERK and phosphorylated eIF2alpha (eIF2alphaP) and combined immunohistochemical and Western blot analysis of the downstream effector proteins activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) in 4 VWM brains and 3 age-matched controls. We demonstrate activation of the UPR in glia of patients with VWM. Our findings may point to a possible explanation for the dysmorphic glia, the increased numbers of oligodendrocytes, and the apoptotic loss of oligodendrocytes in VWM.

    View details for Web of Science ID 000231781300004

    View details for PubMedID 16141786

  • The unfolded protein response in vanishing white matter disease van der Voorn, J. P., van Kollenburg, B., Bertrand, G., VanHaren, K., Scheper, G. C., Powers, J. M., van der Knaap, M. S. JOHN WILEY & SONS LTD. 2005: 17
  • The life and death of Oligodendrocytes in vanishing white matter disease 79th Annual Meeting of the American-Association-of-Neuropathologists Van Haren, K., van der Voorn, J. P., PETERSON, D. R., van der Knaap, M. S., Powers, J. M. LIPPINCOTT WILLIAMS & WILKINS. 2004: 618–30

    Abstract

    Vanishing white matter disease (VWM) is a progressive cavitating disease of central white matter due to a deficiency of the translation initiation factor eIF2B. Oligodendrocytes appear to be numerically increased in some white matter areas, while decreased in others. We compared oligodendrocytes of cerebral, cerebellar, and pontine white matter from 5 VWM patients with those of age-matched controls by light microscopy and immunohistochemistry using antibodies to activated caspase-3, bak, bax, bcl-2, survivin, and Ki-67, as well as by the TUNEL technique. Oligodendrocytes were identified morphologically and quantified using an ocular grid. We observed statistically significant increases in their densities at all sites; Ki-67-labeled oligodendrocytes were identified in 2 of 5 patients. Apoptotic oligodendrocytes were documented in 3 of 5 patients, while bcl-2 and survivin labeling was observed in 2 of 5 and 2 of 2 patients, respectively. There was a trend toward an increase in apoptotic labeling of oligodendrocytes that was strongest in the cerebrum, the major locus of VWM, in the youngest and most severely affected patients. These data conclusively demonstrate increased oligodendrocytic densities in VWM; the increase is not an artifact of white matter contraction. Our data also document that oligodendrocytes undergo apoptosis, perhaps in conjunction with major neurologic crises, and that a subset of oligodendrocytes are able to persist and proliferate. Conflicting proliferative, cell-death, and survival signals impact the oligodendrocytes of VWM.

    View details for Web of Science ID 000221897100006

    View details for PubMedID 15217090

  • The life and death of oligodendrocytes in vanishing white matter disease. Van Haren, K. P., van der Voorn, P., van der Knaap, M. S., Powers, J. M. AMER ASSN NEUROPATHOLOGISTS INC. 2003: 580