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Phenotypic and Imaging Spectrum Associated With WDR45 - 23/07/20

Doi : 10.1016/j.pediatrneurol.2020.03.005 
Laura A. Adang, MD, PhD a, , Amy Pizzino, GC a, Alka Malhotra, PhD b, Holly Dubbs, GC a, Catherine Williams, BS a, Omar Sherbini, MPH a, Anna-Kaisa Anttonen, MD, PhD c, d, Gaetan Lesca, MD, PhD e, Tarja Linnankivi, MD, PhD d, Chloé Laurencin, MD f, Matthieu Milh, MD, PhD g, Charles Perrine, MD h, Christian P. Schaaf, MD, PhD i, Anne-Lise Poulat, MD j, Dorothee Ville, MD j, Tanner Hagelstrom, PhD, MBA b, Denise L. Perry, MS, CGC b, Ryan J. Taft, PhD b, Amy Goldstein, MD k, Arastoo Vossough, MD l, Ingo Helbig, MD a, m, Adeline Vanderver, MD a
a Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 
b Illumina Clinical Services Laboratory, Illumina, Inc., San Diego, California 
c Folkhälsan Research Center, Helsinki, Finland 
d Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 
e Department of Medical genetics, Lyon University Hospital, Bron, France 
f Hôpital Neurologique Pierre Wertheimer, Bron, France 
g Aix-Marseille Université, Marseille, France 
h Hôpital de La Salpêtrière, Paris, France 
i Institute of Human Genetics, Heidelberg University, Heidelberg, Germany 
j Department of Pediatric Neurology, Lyon University Hospital, Bron, France 
k Division of Metabolism, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 
l Division of Neuroradiology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 
m The Epilepsy NeuroGenetics Initiative (ENGIN), Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 

Communications should be addressed to: Dr. Adang; Division of Neurology; Children’s Hospital of Philadelphia; Philadelphia, PA.Division of NeurologyChildren’s Hospital of PhiladelphiaPhiladelphiaPA

Abstract

Background

Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain.

Methods

We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected.

Results

Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age.

Conclusions

WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.

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Keywords : Hypomyelination, Epileptic encephalopathy, WDR45, Developmental delay


Plan


 Conflicts of interest: A.M., D.L.P., R.J.T., and T.H. are Illumina employees.
 Funding disclosures: L.A.: Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001879, and research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K23NS114113. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.V.: Supported by the Kamens endowed chair for Translational Neurotherapeutics and the Myelin Disorders Bioregistry Project.


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Vol 109

P. 56-62 - août 2020 Retour au numéro
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