all:
	pandoc wdr45.md --citeproc -o /mnt/c/Users/alexi/Documents/out.docx 

	title = {A neurodegeneration gene, {WDR45} , links impaired ferritinophagy to iron accumulation},
	volume = {160},
	url = {https://doi.org/10.1111%2Fjnc.15548},
	doi = {10.1111/jnc.15548},
	number = {3},
	journal = {Journal of Neurochemistry},
	author = {Aring, Luisa and Choi, Eun-Kyung and Kopera, Huira and Lanigan, Thomas and Iwase, Shigeki and Klionsky, Daniel J. and Seo, Young Ah},
	month = dec,
	year = {2021},
	note = {Publisher: Wiley},
	pages = {356--375},
}
	url = {https://doi.org/10.1016%2Fb978-0-444-63233-3.00019-1},
	publisher = {Elsevier},
	pages = {293--305},
	title = {Neurodegeneration with brain iron accumulation},
}
	volume = {91},
	url = {https://doi.org/10.1016%2Fj.ajhg.2012.10.019},
	doi = {10.1016/j.ajhg.2012.10.019},
	number = {6},
	journal = {The American Journal of Human Genetics},
	author = {Haack, Tobias B. and Hogarth, Penelope and Kruer, Michael C. and Gregory, Allison and Wieland, Thomas and Schwarzmayr, Thomas and Graf, Elisabeth and Sanford, Lynn and Meyer, Esther and Kara, Eleanna and Cuno, Stephan M. and Harik, Sami I. and Dandu, Vasuki H. and Nardocci, Nardo and Zorzi, Giovanna and Dunaway, Todd and Tarnopolsky, Mark and Skinner, Steven and Frucht, Steven and Hanspal, Era and Schrander-Stumpel, Connie and Héron, Delphine and Mignot, Cyril and Garavaglia, Barbara and Bhatia, Kailash and Hardy, John and Strom, Tim M. and Boddaert, Nathalie and Houlden, Henry H. and Kurian, Manju A. and Meitinger, Thomas and Prokisch, Holger and Hayflick, Susan J.},
	month = dec,
	year = {2012},
	note = {Publisher: Elsevier BV},
	pages = {1144--1149},
}
	title = {Iron {Accumulation} and {Changes} in {Cellular} {Organelles} in {WDR45} {Mutant} {Fibroblasts}},
	volume = {22},
	url = {https://doi.org/10.3390%2Fijms222111650},
	doi = {10.3390/ijms222111650},
	number = {21},
	journal = {IJMS},
	author = {Lee, Hye Eun and Jung, Min Kyo and Noh, Seul Gi and Choi, Hye Bin and Chae, Se hyun and Lee, Jae Hyeok and Mun, Ji Young},
	month = oct,
	year = {2021},
	pages = {11650},
}
	volume = {185},
	url = {https://doi.org/10.1002%2Fajmg.a.62442},
	doi = {10.1002/ajmg.a.62442},
	number = {12},
	journal = {Am J Med Genet},
	author = {Lee, Jae-Hyeok and Nam, Sang Ook and Kim, Eun Kyoung and Shin, Jin-Hong and Oh, Seung Hwan and Ryu, Dongryeol and Lee, Hye Eun and Mun, Ji Young},
	month = jul,
	year = {2021},
	pages = {3866--3871},
}
	volume = {31},
	number = {8},
	pages = {1666--1677.e6},
}
	volume = {185},
	number = {2},
	pages = {579--583},
}
	title = {Clinical and genetic delineation of neurodegeneration with brain iron accumulation},
	volume = {46},
	doi = {10.1136/jmg.2008.061929},
	abstract = {Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive neurodegenerative disorders characterised by high brain iron and the presence of axonal spheroids, usually limited to the central nervous system. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase associated neurodegeneration (PKAN). More recently, it was found that mutations in the PLA2G6 gene cause both infantile neuroaxonal dystrophy (INAD) and, more rarely, an atypical neuroaxonal dystrophy that overlaps clinically with other forms of NBIA. High brain iron is also present in a portion of these cases. Clinical assessment, neuroimaging, and molecular genetic testing all play a role in guiding the diagnostic evaluation and treatment of NBIA.},
}
	volume = {8},
	url = {https://doi.org/10.1002%2Fmgg3.1499},
	doi = {10.1002/mgg3.1499},
	number = {11},
}
	volume = {11},
	url = {https://doi.org/10.1038%2Fs41598-021-02123-3},
	doi = {10.1038/s41598-021-02123-3},
	number = {1},
}
	doi = {10.1016/j.seizure.2019.08.002},
	pages = {245--246},
}
	doi = {10.1007/s12017-018-08522-6},
	number = {1},
	journal = {Neuromol Med},
	author = {Akçakaya, Nihan Hande and Salman, Barış and Görmez, Zeliha and Argüden, Yelda Tarkan and Çırakoğlu, Ayşe and Çakmur, Raif and Çolakoğlu, Berril Dönmez and Hacıhanefioğlu, Seniha and Özbek, Uğur and Yapıcı, Zuhal and Uğur {\textbackslash}.Işeri, Sibel Aylin},
	month = jan,
	year = {2019},
	note = {Publisher: Springer Science and Business Media LLC},
	pages = {54--59},
}
	volume = {131},
	url = {https://doi.org/10.4103%2F0366-6999.247216},
	doi = {10.4103/0366-6999.247216},
	number = {24},
	journal = {Chinese Medical Journal},
	author = {Liu, Wan-Ting and Chen, Qian and Gao, Zhi-Jie and Ji, Xin-Na and Xu, Ke-Ming and Cao, Yan-Yan},
	month = dec,
	year = {2018},
	note = {Publisher: Ovid Technologies (Wolters Kluwer Health)},
	pages = {2991--2992},
}
	volume = {8},
	url = {https://doi.org/10.1111%2Fncn3.12427},
	doi = {10.1111/ncn3.12427},
	number = {5},
	journal = {Neurology \& Clinical Neurosc},
	author = {Umehara, Fujio and Iwama, Kazuhiro and Mizuguchi, Takeshi and Matsumoto, Naomichi},
	month = jul,
	year = {2020},
	note = {Publisher: Wiley},
	pages = {332--334},
}
	volume = {27},
	url = {https://doi.org/10.1007%2Fs00062-017-0605-9},
	doi = {10.1007/s00062-017-0605-9},
	number = {4},
	journal = {Clin Neuroradiol},
	author = {Hattingen, Elke and Handke, Nikolaus and Cremer, Kirsten and Hoffjan, Sabine and Kukuk, Guido Matthias},
	month = jun,
	year = {2017},
	note = {Publisher: Springer Science and Business Media LLC},
	pages = {481--483},
}
	doi = {10.1684/epd.2016.0840},
	number = {3},
	journal = {Epileptic Disorders},
	author = {Xixis, Kathryn I. and Mikati, Mohamad A.},
	month = sep,
	year = {2016},
	note = {Publisher: John Libbey Eurotext},
	pages = {336--336},
}
	volume = {5},
	url = {https://doi.org/10.1111%2Fncn3.12132},
	doi = {10.1111/ncn3.12132},
	number = {4},
	journal = {Neurology \& Clinical Neurosc},
	author = {Endo, Hironobu and Uenaka, Takeshi and Satake, Wataru and Suzuki, Yutaka and Tachibana, Hisatsugu and Chihara, Norio and Ueda, Takehiro and Sekiguchi, Kenji and Mariko, Taniguchi-Ikeda and Kowa, Hisatomo and Kanda, Fumio and Toda, Tatsushi},
	month = jun,
	year = {2017},
	note = {Publisher: Wiley},
	pages = {131--133},
}
@article{spiegel_severe_2016,
	title = {Severe infantile male encephalopathy is a result of early post-zygotic {WDR45} somatic mutation},
	volume = {90},
	issn = {1399-0004},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/cge.12849},
	doi = {10.1111/cge.12849},
	language = {en},
	number = {6},
	urldate = {2022-04-16},
	journal = {Clinical Genetics},
	author = {Spiegel, R. and Shalev, S. and Bercovich, D. and Rabinovich, D. and Khayat, M. and Shaag, A. and Elpeleg, O.},
	year = {2016},
	note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/cge.12849},
	pages = {560--562},
	file = {Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\68N593JK\\cge.html:text/html},
}
@article{redon_intragenic_2017,
	title = {Intragenic deletion of the {WDR45} gene in a male with encephalopathy, severe psychomotor disability, and epilepsy},
	volume = {173},
	issn = {1552-4833},
	doi = {10.1002/ajmg.a.38180},
	language = {eng},
	number = {5},
	journal = {American Journal of Medical Genetics. Part A},
	author = {Redon, Sylvia and Benech, Caroline and Schutz, Sacha and Despres, Aurore and Gueguen, Paul and Le Berre, Pauline and Le Marechal, Cédric and Peudenier, Sylviane and Meriot, Philippe and Parent, Philippe and Ferec, Claude},
	month = may,
	year = {2017},
	pmid = {28371320},
	keywords = {Alleles, Brain, Brain Diseases, Carrier Proteins, Child, Codon, Epilepsy, Genotype, Humans, Magnetic Resonance Imaging, Male, Phenotype, Psychomotor Disorders, Sequence Deletion, Severity of Illness Index},
	pages = {1444--1446},
}
}
@article{seibler_iron_2018-1,
	title = {Iron overload is accompanied by mitochondrial and lysosomal dysfunction in {WDR45} mutant cells},
	volume = {141},
	issn = {0006-8950},
	url = {https://doi.org/10.1093/brain/awy230},
	doi = {10.1093/brain/awy230},
	abstract = {Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.},
	number = {10},
	urldate = {2022-04-18},
	journal = {Brain},
	author = {Seibler, Philip and Burbulla, Lena F and Dulovic, Marija and Zittel, Simone and Heine, Johanne and Schmidt, Thomas and Rudolph, Franziska and Westenberger, Ana and Rakovic, Aleksandar and Münchau, Alexander and Krainc, Dimitri and Klein, Christine},
	month = oct,
	year = {2018},
	pages = {3052--3064},
	file = {Full Text PDF:C\:\\Users\\alexi\\Zotero\\storage\\5UDT5GV4\\Seibler et al. - 2018 - Iron overload is accompanied by mitochondrial and .pdf:application/pdf;Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\L6DFFNWC\\5087794.html:text/html},
}
@incollection{hayflick_chapter_2018,
	series = {Neurogenetics, {Part} {I}},
	title = {Chapter 19 - {Neurodegeneration} with brain iron accumulation},
	volume = {147},
	url = {https://www.sciencedirect.com/science/article/pii/B9780444632333000191},
	abstract = {Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A2-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor–Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). Together, these genes account for disease in approximately 85\% of patients diagnosed with an NBIA disorder. New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.},
	language = {en},
	urldate = {2022-04-24},
	booktitle = {Handbook of {Clinical} {Neurology}},
	publisher = {Elsevier},
	author = {Hayflick, Susan J. and Kurian, Manju A. and Hogarth, Penelope},
	editor = {Geschwind, Daniel H. and Paulson, Henry L. and Klein, Christine},
	month = jan,
	year = {2018},
	doi = {10.1016/B978-0-444-63233-3.00019-1},
	keywords = {BPAN, INAD, infantile neuroaxonal dystrophy, MPAN, NBIA, neurodegeneration with brain iron accumulation, pantothenate kinase, PKAN, PLAN},
	pages = {293--305},
	file = {ScienceDirect Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\HB5STVSJ\\B9780444632333000191.html:text/html},
}
@article{belohlavkova_clinical_2020,
	title = {Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration},
	volume = {28},
	issn = {1090-3798},
	url = {https://www.sciencedirect.com/science/article/pii/S1090379820301549},
	doi = {10.1016/j.ejpn.2020.07.010},
	abstract = {Background
Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7\% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism.
Material and methods
We present a cohort of paediatric patients with pathogenic variants of WD-Repeat Domain 45 gene (WDR45). The diagnosis was established by targeted panel sequencing of genes associated with epileptic encephalopathies (n = 9) or by Sanger sequencing of WDR45 (n = 1). Data on clinical characteristics, molecular-genetic findings and other performed investigations were gathered from all participating centres. Markers of iron metabolism were analysed in 6 patients.
Results
Ten children (3 males, 7 females, median age 8.4 years) from five centres (Prague, Berlin, Vogtareuth, Tubingen and Cologne) were enrolled in the study. All patients manifested first symptoms (e.g. epilepsy, developmental delay) between 2 and 31 months (median 16 months). Seven patients were seizure-free (6 on antiepileptic medication, one drug-free) at the time of data collection. Neurological findings were non-specific with deep tendon hyperreflexia (n = 4) and orofacial dystonia (n = 3) being the most common. Soluble transferrin receptor/log ferritin ratio was elevated in 5/6 examined subjects; other parameters of iron metabolism were normal.
Conclusion
Severity of epilepsy often gradually decreases in BPAN patients. Elevation of soluble transferrin receptor/log ferritin ratio could be another biochemical marker of the disease and should be explored by further studies.},
	language = {en},
	urldate = {2022-04-24},
	journal = {European Journal of Paediatric Neurology},
	author = {Belohlavkova, Anezka and Sterbova, Katalin and Betzler, Cornelia and Burkhard, Stuve and Panzer, Axel and Wolff, Markus and Lassuthova, Petra and Vlckova, Marketa and Kyncl, Martin and Benova, Barbora and Jahodova, Alena and Kudr, Martin and Goerg, Maria and Dusek, Petr and Seeman, Pavel and Kluger, Gerhard and Krsek, Pavel},
	month = sep,
	year = {2020},
	keywords = {Beta-propeller protein-associated neurodegeneration, Neurodegeneration with brain iron accumulation  BPAN, Targeted gene panel sequencing},
	pages = {81--88},
	file = {ScienceDirect Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\J6FVAWV7\\S1090379820301549.html:text/html},
}
@article{takano_elevation_2016,
	title = {Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: {Additional} case report and review of the literature},
	volume = {170},
	issn = {1552-4833},
	shorttitle = {Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.37432},
	doi = {10.1002/ajmg.a.37432},
	abstract = {Beta-propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), is a subtype of neurodegeneration with brain iron accumulation (NBIA). BPAN is caused by mutations in an X-linked gene WDR45 that is involved in autophagy. BPAN is characterized by developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. Brain magnetic resonance imaging (MRI) shows iron deposition in the bilateral globus pallidus (GP) and substantia nigra (SN). Clinical manifestations and laboratory findings in early childhood are limited. We report a 3-year-old girl with BPAN who presented with severe developmental delay and characteristic facial features. In addition to chronic elevation of serum aspartate transaminase, lactate dehydrogenase, creatine kinase, and soluble interleukin-2 receptor, she had persistent elevation of neuron specific enolase (NSE) in serum and cerebrospinal fluid. MRI using susceptibility-weighted imaging (SWI) demonstrated iron accumulation in the GP and SN bilaterally. Targeted next-generation sequencing identified a de novo splice-site mutation, c.831-1G{\textgreater}C in WDR45, which resulted in aberrant splicing evidenced by reverse transcriptase-PCR. Persistent elevation of NSE and iron deposition on SWI may provide clues for diagnosis of BPAN in early childhood. © 2015 Wiley Periodicals, Inc.},
	language = {en},
	number = {2},
	urldate = {2022-04-24},
	journal = {American Journal of Medical Genetics Part A},
	author = {Takano, Kyoko and Shiba, Naoko and Wakui, Keiko and Yamaguchi, Tomomi and Aida, Noriko and Inaba, Yuji and Fukushima, Yoshimitsu and Kosho, Tomoki},
	year = {2016},
	note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajmg.a.37432},
	keywords = {autophagy, beta-propeller protein-associated neurodegeneration (BPAN), developmental delay, intellectual disability, neurodegeneration with brain iron accumulation (NBIA), neuron specific enolase (NSE), static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), susceptibility-weighted imaging (SWI), WDR45},
	pages = {322--328},
	file = {Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\VZJVAZEZ\\ajmg.a.html:text/html},
}
@article{zarate_lessons_2016,
	title = {Lessons from a pair of siblings with {BPAN}},
	volume = {24},
	copyright = {2016 Macmillan Publishers Limited},
	issn = {1476-5438},
	url = {https://www.nature.com/articles/ejhg2015242},
	doi = {10.1038/ejhg.2015.242},
	abstract = {Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for {\textasciitilde}7\% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161\_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year-old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered.},
	language = {en},
	number = {7},
	urldate = {2022-04-24},
	journal = {European Journal of Human Genetics},
	author = {Zarate, Yuri A. and Jones, Julie R. and Jones, Melanie A. and Millan, Francisca and Juusola, Jane and Vertino-Bell, Annette and Schaefer, G. Bradley and Kruer, Michael C.},
	month = jul,
	year = {2016},
	note = {Number: 7
Publisher: Nature Publishing Group},
	keywords = {Genetic counselling, Genetic testing, Neurodegenerative diseases},
	pages = {1080--1083},
	file = {Full Text PDF:C\:\\Users\\alexi\\Zotero\\storage\\QYK5IM6X\\Zarate et al. - 2016 - Lessons from a pair of siblings with BPAN.pdf:application/pdf;Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\U42G8ZQB\\ejhg2015242.html:text/html},
}
@article{saffari_quantitative_2021,
	title = {Quantitative retrospective natural history modeling of {WDR45}-related developmental and epileptic encephalopathy – a systematic cross-sectional analysis of 160 published cases},
	volume = {0},
	issn = {1554-8627},
	url = {https://doi.org/10.1080/15548627.2021.1990671},
	doi = {10.1080/15548627.2021.1990671},
	abstract = {WDR45-related neurodevelopmental disorder (NDD) is a clinically-heterogenous congenital disorder of macroautophagy/autophagy. The natural history of this ultra-orphan disease remains incompletely understood, leading to delays in diagnosis and lack of quantifiable outcome measures. In this cross-sectional study, we model quantitative natural history data for WDR45-related NDD using a standardized analysis of 160 published cases, representing the largest cohort to date. The primary outcome of this study was survival. Age at disease onset, diagnostic delay and geographic distribution were quantified as secondary endpoints. Our tertiary aim was to explore and quantify the spectrum of WDR45-related phenotypes. Survival estimations showed low mortality until 39 years of age. Median age at onset was 10 months, with a median diagnostic delay of 6.2 years. Geographic distribution appeared worldwide with clusters in North America, East Asia, Western Europe and the Middle East. The clinical spectrum was highly variable with a bi-phasic evolution characterized by early-onset developmental and epileptic encephalopathy during childhood followed by a progressive dystonia-parkinsonism syndrome along with cognitive decline during early adulthood. Female individuals showed milder disease severity. The majority of pathogenic WDR45 variants were predicted to result in a loss of WDR45 expression, without clear genotype-phenotype associations. Our results provide clinical and epidemiological data that may facilitate an earlier diagnosis, enable anticipatory guidance and counseling of affected families and provide the foundation for endpoints for future interventional trials.Abbreviations: BPAN: beta-propeller protein-associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NDD: neurodevelopmental disorder; NGS: next-generation sequencing; WDR45/WIPI4: WD repeat domain 45},
	number = {0},
	urldate = {2022-04-16},
	journal = {Autophagy},
	author = {Saffari, Afshin and Schröter, Julian and Garbade, Sven F. and Alecu, Julian E. and Ebrahimi-Fakhari, Darius and Hoffmann, Georg F. and Kölker, Stefan and Ries, Markus and Syrbe, Steffen},
	month = nov,
	year = {2021},
	pmid = {34818117},
	note = {Publisher: Taylor \& Francis
\_eprint: https://doi.org/10.1080/15548627.2021.1990671},
	keywords = {Beta-propeller protein-associated neurodegeneration, BPAN, congenital disorder of autophagy, DEE, NBIA, NBIA5, NDD, WDR45, WIPI4},
	pages = {1--13},
	file = {Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\SDB2GYAF\\15548627.2021.html:text/html},
}
@article{kulikovskaja_wdr45_2018,
	title = {{WDR45} mutations may cause a {MECP2} mutation-negative {Rett} syndrome phenotype},
	volume = {4},
	copyright = {Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.},
	issn = {2376-7839},
	url = {https://ng.neurology.org/content/4/2/e227},
	doi = {10.1212/NXG.0000000000000227},
	abstract = {Mutations in the autophagy-related WD domain repeat 45 ( WDR45 ) gene cause beta-propeller protein-associated neurodegeneration (BPAN), a distinct form of neurodegeneration with brain iron accumulation (NBIA).1,2 Clinical and imaging features comprise childhood-onset global developmental delay with further regression in early adulthood, progressive dystonia, parkinsonism, stereotypies, and iron deposition in the basal ganglia. Female and the few existing male patients show similar phenotypes, probably because of somatic mosaicism in males and skewed X-chromosome inactivation (XCI) in females, as WDR45 is located on Xp11.23. To date, about 60 cases have been reported, many of whom had a different initial clinical diagnosis.3 Hyperkinetic movements and stereotypies overlap with Rett syndrome features, another X-linked disorder most commonly caused by MECP2 mutations. Indeed, for 7\% of the reported cases of BPAN, the initial diagnosis was Rett syndrome,3 prompting us to perform the first mutational screen of the WDR45 gene in a large cohort of MECP2 mutation-negative Rett syndrome patients.},
	language = {en},
	number = {2},
	urldate = {2022-04-16},
	journal = {Neurology Genetics},
	author = {Kulikovskaja, Leonora and Sarajlija, Adrijan and Savic-Pavicevic, Dusanka and Dobricic, Valerija and Klein, Christine and Westenberger, Ana},
	month = apr,
	year = {2018},
	note = {Publisher: Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
Section: Clinical/Scientific Notes},
	file = {Full Text PDF:C\:\\Users\\alexi\\Zotero\\storage\\9MZ5B4NW\\Kulikovskaja et al. - 2018 - WDR45 mutations may cause a MECP2 mutation-negativ.pdf:application/pdf;Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\ESG3IN9S\\e227.html:text/html},
}
@article{long_novel_2015,
	title = {Novel {WDR45} {Mutation} and {Pathognomonic} {BPAN} {Imaging} in a {Young} {Female} {With} {Mild} {Cognitive} {Delay}},
	volume = {136},
	issn = {0031-4005},
	url = {https://doi.org/10.1542/peds.2015-0750},
	doi = {10.1542/peds.2015-0750},
	abstract = {β-propeller protein-associated neurodegeneration (BPAN) is a recently identified X-linked dominant form of neurodegeneration with brain iron accumulation caused by mutations in the WDR45 gene. BPAN commonly presents as global developmental delay in childhood with rapid onset of parkinsonism and dementia in early adulthood and associated pathognomonic changes seen on brain MRI. In this case report, we present a pediatric patient with mild cognitive delay and pathognomonic MRI changes indicative of BPAN preceding neurologic deterioration who is found to have a novel de novo mutation in the WDR45 gene.},
	number = {3},
	urldate = {2022-04-16},
	journal = {Pediatrics},
	author = {Long, Michelle and Abdeen, Nishard and Geraghty, Michael T. and Hogarth, Penelope and Hayflick, Susan and Venkateswaran, Sunita},
	month = sep,
	year = {2015},
	pages = {e714--e717},
}
@article{ji_bpan_2021,
	title = {The {BPAN} and intellectual disability disease proteins {WDR45} and {WDR45B} modulate autophagosome-lysosome fusion},
	volume = {17},
	issn = {1554-8627},
	url = {https://doi.org/10.1080/15548627.2021.1924039},
	doi = {10.1080/15548627.2021.1924039},
	abstract = {WDR45 and WDR45B are β-propeller proteins belonging to the WIPI (WD repeat domain, phosphoinositide interacting) family. Mutations in WDR45 and WDR45B are genetically linked with beta-propeller protein-associated neurodegeneration (BPAN) and intellectual disability (ID), respectively. WDR45 and WDR45B are homologs of yeast Atg18. Atg18 forms a complex with Atg2 for autophagosome biogenesis, probably by transferring lipids from the ER to phagophores. We revealed that WDR45 and WDR45B are critical for autophagosome-lysosome fusion in neural cells. WDR45 and WDR45B, but not their disease-related mutants, bind to the tether protein EPG5 and facilitate its targeting to late endosomes/lysosomes. In Wdr45 Wdr45b-deficient cells, the formation of tether-SNARE fusion machinery is compromised. The macroautophagy/autophagy deficiency in wdr45 wdr45b DKO cells is ameliorated by suppression of O-GlcNAcylation, which promotes autophagosome maturation. Thus, our results provide insights into the pathogenesis of WDR45- and WDR45B-related neurological diseases.},
	number = {7},
	urldate = {2022-04-16},
	journal = {Autophagy},
	author = {Ji, Cuicui and Zhao, Yan G.},
	month = jul,
	year = {2021},
	pmid = {34105435},
	note = {Publisher: Taylor \& Francis
\_eprint: https://doi.org/10.1080/15548627.2021.1924039},
	keywords = {autophagosome maturation, Autophagy, BPAN, ID, WDR45, WDR45B},
	pages = {1783--1784},
	file = {Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\8Y3QM6A8\\15548627.2021.html:text/html},
}
@article{carvill_severe_2018,
	title = {Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene {WDR45}},
	volume = {59},
	issn = {1528-1167},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.13957},
	doi = {10.1111/epi.13957},
	abstract = {Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66\% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.},
	language = {en},
	number = {1},
	urldate = {2022-04-16},
	journal = {Epilepsia},
	author = {Carvill, Gemma L. and Liu, Aijie and Mandelstam, Simone and Schneider, Amy and Lacroix, Amy and Zemel, Matthew and McMahon, Jacinta M. and Bello-Espinosa, Luis and Mackay, Mark and Wallace, Geoffrey and Waak, Michaela and Zhang, Jing and Yang, Xiaoling and Malone, Stephen and Zhang, Yue-Hua and Mefford, Heather C. and Scheffer, Ingrid E.},
	year = {2018},
	note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/epi.13957},
	keywords = {de novo variant, DEE, genetics, magnetic resonance imaging},
	pages = {e5--e13},
	file = {Full Text PDF:C\:\\Users\\alexi\\Zotero\\storage\\NMISLX7K\\Carvill et al. - 2018 - Severe infantile onset developmental and epileptic.pdf:application/pdf;Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\3DLECNC7\\epi.html:text/html},
}
@article{chen_early_2019-1,
	title = {Early onset developmental delay and epilepsy in pediatric patients with {WDR45} variants},
	volume = {62},
	issn = {1769-7212},
	url = {https://www.sciencedirect.com/science/article/pii/S1769721217308790},
	doi = {10.1016/j.ejmg.2018.07.002},
	abstract = {Background
Developmental delay (DD) is a neurological disorder that presents with defects in gross motor, fine motor, language and cognition functions. WD repeat domain 45 (WDR45) is one of the disease-causing genes of DD. Previously, WDR45 de novo mutations were reported in certain adult and pediatric patients due to iron accumulation.
Clinical report
We report five pediatric female patients with DD and epilepsy. Their ages were below 3 years at the first consultation, and precise diagnoses were difficult based on the available clinical information and phenotype.
Methods
Children with DD and/or epilepsy presenting to the molecular diagnostic center of Children's Hospital of Fudan University between May 2016 and May 2017 were enrolled. The patients and their parents were subjected to whole-exome sequencing (WES), and we characterized the phenotypes of the patients carrying WDR45 variants. Furthermore, we overexpressed the candidate variants in HeLa cells and evaluated their effect on autophagy through Western blot and immunofluorescence staining with confocal microscopy.
Results
Five WDR45 de novo mutations, namely, c.19C {\textgreater} T (p.Arg7*), c.401G {\textgreater} C (p.Arg134Pro), c.503G {\textgreater} A (p.Gly168Glu), c.700C {\textgreater} T (p.Arg234*), and c.912delT (p.Ala305Leufs*25), were detected in 623 enrolled pediatric patients (274 females; 487 patients younger than 6 years). All five patients with WDR45 variants presented with DD and epilepsy. Compared with the control HeLa cells, the cells with the p. Arg134Pro and p. Gly168Glu missense mutations showed accumulation of LC3-containing autophagic structures and an abnormally enlarged cell volume, and Western blotting revealed a significant increase in LC3II/GAPDH.
Conclusion
The identification of WDR45 mutations provides further evidence that WES plays an important role in the diagnosis of neurological disorders with common phenotypes and that WDR45 mutations are associated with neurological disorders and are not very rare in Chinese female pediatric patients with DD and/or epilepsy. The diagnosis of patients with WDR45 mutations would enable more precise genetic counseling for the parents of these children.},
	language = {en},
	number = {2},
	urldate = {2022-04-16},
	journal = {European Journal of Medical Genetics},
	author = {Chen, Hongbo and Qian, Yanyan and Yu, Sha and Xiao, Deyong and Guo, Xiao and Wang, Qing and Hao, Lili and Yan, Kai and Lu, Yulan and Dong, Xinran and Zhou, Wenhao and Wu, Bingbing and Zhou, Shuizhen and Wang, Huijun},
	month = feb,
	year = {2019},
	keywords = {Developmental delay, Early onset, Epilepsy, Pediatric},
	pages = {149--160},
	file = {ScienceDirect Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\65BQLSKV\\S1769721217308790.html:text/html},
}
@article{xiong_functional_2019-1,
	title = {Functional evidence for a de novo mutation in {WDR45} leading to {BPAN} in a {Chinese} girl},
	volume = {7},
	issn = {2324-9269},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/mgg3.858},
	doi = {10.1002/mgg3.858},
	abstract = {Background Beta-propeller protein-associated neurodegeneration (BPAN, OMIM 300894) is an X-linked neurodegenerative disorder caused by mutations in WDR45. WDR45 is required for autophagy, defect in WDR45 impaired autophagy which contributes for the pathogenesis of BPAN. Previously, we reported a novel de novo mutation (c.1040\_1041del, p.Glu347GlyfsTer7) in WDR45 (NM\_007075) in a 3-year-old Chinese girl with BPAN. Methods The protein structure was constructed using SWISS-MODEL and the isoelectric point (pI) was predicted by the online pI/Mw tool at ExPASy. The functional effects of this mutation were predicted by two online software programs: PROVEN and MutationTaster. Stable overexpression of Flag-tagged wild-type or mutant WDR45 in HeLa cells was constructed. Protein levels of LC3 and p62 were analyzed by western blot upon treatment with/without autophagy inhibitor Bafilomycin A1, the formation of LC3 puncta were analyzed in HeLa cells transfected with mCherry-LC3 by confocal microscopy. Results The mutation resulted in a shift of pI from 6.74 to 8.84 and was predicted to be pathogenic. The protein levels of LC3-II and p62 were increased in cells overexpression of wild-type and mutant WDR45 while the protein levels were not increased in cells overexpression of mutant WDR45 upon treatment with autophagy inhibitor Bafilomycin A1. Results from confocal microscopy revealed that LC3-positive puncta were increased in cells expressing both wild-type and mutant WDR45 while the number of LC3-positive puncta was not increased in cells expressing mutant WDR45 upon treatment with Bafilomycin A1. Conclusion Our study evidenced that this novel mutation in WDR45 impaired autophagy in cells thus this mutation is the cause for BPAN in this patient.},
	language = {en},
	number = {9},
	urldate = {2022-04-16},
	journal = {Molecular Genetics \& Genomic Medicine},
	author = {Xiong, Qiuhong and Li, Wenjing and Li, Ping and Zhao, Zhonghua and Wu, Changxin and Xiao, Han},
	year = {2019},
	note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/mgg3.858},
	keywords = {autophagy, BPAN, novel mutation, WDR45},
	pages = {e858},
	file = {Full Text PDF:C\:\\Users\\alexi\\Zotero\\storage\\JAH8UYRZ\\Xiong et al. - 2019 - Functional evidence for a de novo mutation in WDR4.pdf:application/pdf;Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\N8MM7R6T\\mgg3.html:text/html},
}
@article{ozawa_novel_2014-1,
	title = {A novel {WDR45} mutation in a patient with static encephalopathy of childhood with neurodegeneration in adulthood ({SENDA})},
	volume = {164},
	issn = {1552-4833},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.36635},
	doi = {10.1002/ajmg.a.36635},
	abstract = {Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is an X-linked dominant neurodegenerative disorder, and is classified as a subtype of neurodegeneration with brain iron accumulation. Recently, de novo heterozygous mutations in WDR45 at Xp11.23 have been reported in patients with SENDA. We report the clinical and neuroradiological findings of a patient with SENDA with a novel c.322del mutation in WDR45. In this patient, characteristic MRI findings were useful for diagnosis. © 2014 The Authors. American Journal of Medical Genetics published by Wiley Periodicals, Inc.},
	language = {en},
	number = {9},
	urldate = {2022-04-16},
	journal = {American Journal of Medical Genetics Part A},
	author = {Ozawa, Tadashi and Koide, Reiji and Nakata, Yasuhiro and Saitsu, Hirotomo and Matsumoto, Naomichi and Takahashi, Kazushi and Nakano, Imaharu and Orimo, Satoshi},
	year = {2014},
	note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajmg.a.36635},
	keywords = {magnetic resonance imaging (MRI), static encephalopathy of childhood with neurodegenartion in adulthood (SENDA), WDR45},
	pages = {2388--2390},
	file = {Full Text PDF:C\:\\Users\\alexi\\Zotero\\storage\\QNRAM7NS\\Ozawa et al. - 2014 - A novel WDR45 mutation in a patient with static en.pdf:application/pdf;Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\BS8BRP33\\ajmg.a.html:text/html},
}
@article{morikawa_clinical_2017-1,
	title = {Clinical features of a female with {WDR45} mutation complicated by infantile spasms: a case report and literature review},
	volume = {39},
	issn = {0387-7604},
	shorttitle = {Clinical features of a female with {WDR45} mutation complicated by infantile spasms},
	url = {https://www.sciencedirect.com/science/article/pii/S0387760417301432},
	doi = {10.1016/j.braindev.2017.05.003},
	abstract = {We present a 3-year-old girl with beta-propeller protein-associated neurodegeneration (BPAN) who had a de novo heterozygous splice-site mutation of c.831-1G{\textgreater}C in WDR45 and developed infantile spasms; her onset age of infantile spasms was relatively late. Her infantile spasms and hypsarrhythmia disappeared promptly by adrenocorticotropic hormone therapy (CORTROSYN®Z, 0.0125mg/kg/day daily for 2weeks intramuscularly), though the administration of pyridoxal phosphate and valproic acid had poor efficacy. BPAN is known to be associated with various types of seizures, but there are few reports on infantile spasms, especially in females. To date, only 5 patients with BPAN have been reported to develop infantile spasms, and our patient is the second case in females. In this report, we showed that female patients with BPAN had milder phenotypic features than males: males developed intractable infantile spasms in early infancy, while females had treatable infantile spasms in late infancy.},
	language = {en},
	number = {9},
	urldate = {2022-04-16},
	journal = {Brain and Development},
	author = {Morikawa, Manami and Takano, Kyoko and Motobayashi, Mitsuo and Shiba, Naoko and Kosho, Tomoki and Nakazawa, Yozo and Inaba, Yuji},
	month = oct,
	year = {2017},
	keywords = {Adrenocorticotropic hormone therapy, Beta-propeller protein-associated neurodegeneration, Infantile spasms, West syndrome},
	pages = {804--807},
	file = {ScienceDirect Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\NUYWD386\\S0387760417301432.html:text/html},
}
@article{hermann_case_2017,
	title = {A {Case} of {Beta}-propeller {Protein}-associated {Neurodegeneration} due to a {Heterozygous} {Deletion} of {WDR45}},
	volume = {7},
	issn = {2160-8288},
	url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656753/},
	doi = {10.7916/D8251WB0},
	abstract = {Background
Static encephalopathy of childhood with neurodegeneration in adulthood is a phenotypically distinctive, X-linked dominant subtype of neurodegeneration with brain iron accumulation (NBIA). WDR45 mutations were recently identified as causal. WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, and the disease has been renamed beta-propeller protein-associated neurodegeneration (BPAN).
Case Report
Here we describe a female patient suffering from a classical BPAN phenotype due to a novel heterozygous deletion of WDR45. An initial gene panel and Sanger sequencing approach failed to uncover the molecular defect. Based on the typical clinical and neuroimaging phenotype, quantitative polymerase chain reaction of the WDR45 coding regions was undertaken, and this showed a reduction of the gene dosage by 50\% compared with controls.
Discussion
An extended search for deletions should be performed in apparently WDR45-negative cases presenting with features of NBIA and should also be considered in young patients with predominant intellectual disabilities and hypertonia/parkinsonism/dystonia.},
	urldate = {2022-04-16},
	journal = {Tremor and Other Hyperkinetic Movements},
	author = {Hermann, Andreas and Kitzler, Hagen H. and Pollack, Tobias and Biskup, Saskia and Krüger, Stefanie and Funke, Claudia and Terrile, Caterina and Haack, Tobias B.},
	month = aug,
	year = {2017},
	pmid = {29082105},
	pmcid = {PMC5656753},
	pages = {465},
}
@article{khalifa_exome_2015,
	title = {Exome sequencing reveals a novel {WDR45} frameshift mutation and inherited {POLR3A} heterozygous variants in a female with a complex phenotype and mixed brain {MRI} findings},
	volume = {58},
	issn = {1769-7212},
	url = {https://www.sciencedirect.com/science/article/pii/S1769721215001135},
	doi = {10.1016/j.ejmg.2015.05.009},
	abstract = {WDR45 and POLR3A are newly recognized genes; each is associated with a distinct neurodegenerative disease. WDR45 is an X-linked gene associated with a dominant form of Neurodegeneration with Brain Iron Accumulation (NBIA), manifested by progressive disabilities, dystonia, cognitive decline, spastic paraplegia, neuropsychiatric abnormalities and iron deposition in the basal ganglia on brain imaging. POLR3A, on the other hand, is an autosomal gene, and its mutations cause a recessive form of a hypomyelination with leukodystrophy disease, also known as 4H syndrome, characterized by congenital Hypomyelination with thinning of the corpus callosum, Hypodontia and Hypogonadotropic Hypogonadism. We report on a female child with severe intellectual disability, aphasia, short stature, ataxia, failure to thrive and structural brain abnormalities. Brain MRI obtained in late infancy showed hypomyelination involving the central periventricular white matter and thinning of the corpus callosum with no evidence of iron accumulation. Brain MRI obtained in childhood showed stable hypomyelination, with progressive iron accumulation in the basal ganglia, in particular in the globus pallidus and substantia nigra. Whole Exome Sequencing (WES) identified a novel WDR45 frameshift deleterious mutation in Exon 9 (c.587-588del) and also revealed three POLR3A missense heterozygous variants. The first is a maternally inherited novel missense variant in exon 4 (c.346A {\textgreater} G). Exon 13 carried two heterozygous missense variants, a maternally inherited variant (c.1724A {\textgreater} T) and a paternally inherited variant (1745G {\textgreater} A). These variants are considered likely damaging. The patient's complex clinical phenotype and mixed brain MRI findings might be attributed to the confounding effects of the expression of these two mutant genes.},
	language = {en},
	number = {8},
	urldate = {2022-04-16},
	journal = {European Journal of Medical Genetics},
	author = {Khalifa, Mohamed and Naffaa, Lena},
	month = aug,
	year = {2015},
	keywords = {4H syndrome, Demyelinating disease, Leukodystrophy, NBIA, Whole exome sequencing},
	pages = {381--386},
}
@article{wynn_novel_2017,
	title = {A novel {WDR45} mutation in a patient with β-propeller protein-associated neurodegeneration},
	volume = {3},
	copyright = {Copyright © 2016 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.},
	issn = {2376-7839},
	url = {https://ng.neurology.org/content/3/1/e124},
	doi = {10.1212/NXG.0000000000000124},
	abstract = {Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic diseases characterized by progressive extrapyramidal symptoms and focal iron accumulation in the basal ganglia. β-Propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood or NBIA 5, is an X-linked dominant subtype of NBIA.1 Brain MRI studies consistently demonstrate iron accumulation in the globus pallidus and substantia nigra with a subset of patients also demonstrating a halo of hyperintense signal surrounding a thin region of hypointense signal in the substantia nigra on T1-weighted imaging.2 The majority of patients with BPAN are female, but several affected males with identical phenotypes have been described, most likely harboring postzygotic mutations leading to somatic mosaicism.3 BPAN has been shown to be caused by heterozygous mutations in WDR45 at Xp11.23. To date, all mutations have been de novo, with no affected relatives.1,3,4 We report here on a patient with BPAN with a novel c.597\_598 deletion mutation in WDR45.},
	language = {en},
	number = {1},
	urldate = {2022-04-16},
	journal = {Neurology Genetics},
	author = {Wynn, DonRaphael P. and Pulst, Stefan M.},
	month = feb,
	year = {2017},
	note = {Publisher: Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
Section: Clinical/Scientific Notes},
	file = {Full Text PDF:C\:\\Users\\alexi\\Zotero\\storage\\84FSAWGA\\Wynn and Pulst - 2017 - A novel WDR45 mutation in a patient with β-propell.pdf:application/pdf;Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\9H3FUK4F\\e124.html:text/html},
}
@article{ryu_beta-propeller-protein-associated_2015,
	title = {Beta-{Propeller}-{Protein}-{Associated} {Neurodegeneration}: {A} {Case} of {Mutation} in {WDR45}},
	volume = {11},
	shorttitle = {Beta-{Propeller}-{Protein}-{Associated} {Neurodegeneration}},
	url = {https://synapse.koreamed.org/articles/1047886},
	doi = {10.3988/jcn.2015.11.3.289},
	number = {3},
	urldate = {2022-04-16},
	journal = {Journal of Clinical Neurology},
	author = {Ryu, Sook Won and Kim, Jang Su and Lee, Seung-Hwan},
	month = jul,
	year = {2015},
	note = {Publisher: Korean Neurological Association},
	pages = {289--291},
	file = {Full Text PDF:C\:\\Users\\alexi\\Zotero\\storage\\9C4ZFQ7S\\Ryu et al. - 2015 - Beta-Propeller-Protein-Associated Neurodegeneratio.pdf:application/pdf;Snapshot:C\:\\Users\\alexi\\Zotero\\storage\\56842YQH\\1047886.html:text/html},
}
@article{biagosch_comprehensive_2021,
	title = {A comprehensive phenotypic characterization of a whole-body {Wdr45} knock-out mouse},
	volume = {32},
	issn = {1432-1777},
	url = {https://doi.org/10.1007/s00335-021-09875-3},
	doi = {10.1007/s00335-021-09875-3},
	abstract = {Pathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegeneration (BPAN). BPAN represents one of the four most common forms of Neurodegeneration with Brain Iron Accumulation (NBIA). In the current study, we generated and characterized a whole-body Wdr45 knock-out (KO) mouse model. The model, developed using TALENs, presents a 20-bp deletion in exon 2 of Wdr45. Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, specific haematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency. Overall, the systemic Wdr45 KO described here complements the two mouse models previously reported in the literature (PMIDs: 26,000,824, 31,204,559) and represents an additional robust model to investigate the pathophysiology of BPAN and to test therapeutic strategies for the disease.},
	language = {en},
	number = {5},
	urldate = {2022-04-16},
	journal = {Mammalian Genome},
	author = {Biagosch, Caroline A. and Vidali, Silvia and Faerberboeck, Michael and Hensler, Svenja-Viola and Becker, Lore and Amarie, Oana V. and Aguilar-Pimentel, Antonio and Garrett, Lillian and Klein-Rodewald, Tanja and Rathkolb, Birgit and Zanuttigh, Enrica and Calzada-Wack, Julia and da Silva-Buttkus, Patricia and Rozman, Jan and Treise, Irina and Fuchs, Helmut and Gailus-Durner, Valerie and de Angelis, Martin Hrabě and Janik, Dirk and Wurst, Wolfgang and Mayr, Johannes A. and Klopstock, Thomas and Meitinger, Thomas and Prokisch, Holger and Iuso, Arcangela},
	month = oct,
	year = {2021},
	pages = {332--349},
	file = {Full Text PDF:C\:\\Users\\alexi\\Zotero\\storage\\PMBAGL9Q\\Biagosch et al. - 2021 - A comprehensive phenotypic characterization of a w.pdf:application/pdf},
}
@article{araujo_novel_2017,
	title = {Novel {WDR45} mutation causing beta-propeller protein associated neurodegeneration ({BPAN}) in two monozygotic twins},
	volume = {264},
	issn = {1432-1459},
	url = {https://doi.org/10.1007/s00415-017-8475-2},
	doi = {10.1007/s00415-017-8475-2},
	language = {en},
	number = {5},
	urldate = {2022-04-16},
	journal = {Journal of Neurology},
	author = {Araújo, Rui and Garabal, Ana and Baptista, Mariana and Carvalho, Sílvia and Pinho, Crisbety and de Sá, Joaquim and Vasconcelos, Mónica},
	month = may,
	year = {2017},
	keywords = {Cerebral Peduncle, Halo Sign, Intellectual Disability, Risperidone, Substantia Nigra},
	pages = {1020--1022},
}
@article{christoforou_early-onset_2020,
	title = {Early-onset presentation of a new subtype of β-{Propeller} protein-associated neurodegeneration ({BPAN}) caused by a de novo {WDR45} deletion in a 6 year-old female patient},
	volume = {63},
	issn = {1769-7212},
	url = {https://www.sciencedirect.com/science/article/pii/S1769721219302253},
	doi = {10.1016/j.ejmg.2019.103765},
	abstract = {Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare genetic disorders characterized by progressive extrapyramidal and other neurological symptoms due to focal iron accumulation in the basal ganglia (Adidi et al., 2016). β-Propeller protein-associated neurodegeneration (BPAN) is the most recently identified subtype of NBIA caused by heterozygous variants in WDR45 (OMIM: *300526) at Xp11.23. We report the clinical neurophysiological and neuro-imaging findings of a new subtype of BPAN in a 6 year-old female patient, who was identified to have a large de novo WDR45 deletion who presented in the first year of life with early onset global developmental delay, severe cognitive impairment, generalized hypotonia and a corticosteroid responsive epileptic encephalopathy.},
	language = {en},
	number = {3},
	urldate = {2022-04-16},
	journal = {European Journal of Medical Genetics},
	author = {Christoforou, Stephanie and Christodoulou, Kyproula and Anastasiadou, Violetta and Nicolaides, Paola},
	month = mar,
	year = {2020},
	keywords = {BPAN, deletion, Developmental delay, Epileptic encephalopathy, ESES, NBIA},
	pages = {103765},
}
@article{willoughby_functional_2018,
	title = {Functional {mRNA} analysis reveals aberrant splicing caused by novel intronic mutation in {WDR45} in {NBIA} patient},
	volume = {176},
	issn = {1552-4833},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.38656},
	doi = {10.1002/ajmg.a.38656},
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}
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}
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	volume = {22},
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	doi = {10.3390/ijms222111650},
	number = {21},
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@article{cong_wdr45_2021,
	title = {{WDR45}, one gene associated with multiple neurodevelopmental disorders},
	volume = {17},
	issn = {1554-8627},
	url = {https://doi.org/10.1080/15548627.2021.1899669},
	doi = {10.1080/15548627.2021.1899669},
	abstract = {The WDR45 gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ß-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat β-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in WDR45 can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders.Abbreviations: ATG/Atg: autophagy related; BPAN: ß-propeller protein associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; EEG: electroencephalograph; ENO2/neuron-specific enolase, enolase 2; EOEE: early-onset epileptic encephalopathy; ER: endoplasmic reticulum; ID: intellectual disability; IDR: intrinsically disordered region; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NCOA4: nuclear receptor coactivator 4; PtdIns3P: phosphatidylinositol-3-phosphate; RLS: Rett-like syndrome; WDR45: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting},
	number = {12},
	urldate = {2022-03-09},
	journal = {Autophagy},
	author = {Cong, Yingying and So, Vincent and Tijssen, Marina A. J. and Verbeek, Dineke S. and Reggiori, Fulvio and Mauthe, Mario},
	month = dec,
	year = {2021},
	pmid = {33843443},
	note = {Publisher: Taylor \& Francis
\_eprint: https://doi.org/10.1080/15548627.2021.1899669},
	keywords = {Autophagy, beta-propeller protein-associated neurodegeneration, brain iron accumulation, endoplasmic reticulum, mitochondria},
	pages = {3908--3923},
	file = {Full Text:C\:\\Users\\alexi\\Zotero\\storage\\6SZ8GQZS\\Cong et al. - 2021 - WDR45, one gene associated with multiple neurodeve.pdf:application/pdf},
}
@article{aring_neurodegeneration_2021,

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		Sex	Method of molecular diagnosis	DNA change	Amino Acid change	Source
1		Male	Whole Exome Sequencing	c.830+1G>A	IVS10+1G>A in intron 10
2	*	Female	Whole Genome Sequencing	c.1020_1023delTGAT	p.Asp341Glufsext69
3		Female	Whole Genome Sequencing	c.700C>T	p.Arg234Ter
4	*	Female	Targeted	c.519+2 T>C
5		Female	UK	chrX:48934349 A>G	p.Phe100Ser
6	*	Female	Whole Genome Sequencing	c.728+2T>A
7		Female	Whole Exome Sequencing	c.729-1G>A	IV59-1G>A
8		Male	UK	c.19C>T	p.Arg7*
9	*	Female	UK	c.2T>A
10	*	Male	UK	c.442_446delCTCTG	p.Leu148*
11		Male	UK	19.9-kb Deletion in Xp11.23		261739689
12	*	Female	UK	c.944_953del	p.Arg315
13		Female	UK	c.830+1G>A
14	*	Female	UK	c.412G>T
15	*	Male	Whole Genome Sequencing	c.14_20dupCACTTCG	p.Gly8ThrfsTer65
16	*	Female	Whole Exome Sequencing	c.52C>T	p.Gln18Ter
17	*	Female	Whole Exome Sequencing	c.718dupA	p.T240Nfs*6
18	*	Male	Targeted	c.729-1G>A
19		Female	UK	c.868C>T	p.Gln290Ter	3163285820
20		Female	Targeted	chrX:g.48,930,034_ 48,935,858del (hg19) deletion		3153683121
21		Female	Targeted	c.830 +1G>A	fs premature termination codon at position 278	3150568822
22		Male	Whole Exome Sequencing	c.197 T > A	p.V66E	3146601023
23		Female	Whole Exome Sequencing	c.1040_1041del	p.Glu347GlyfsTer7	*24, 3133296025
24		Female	Targeted	c.761_762insAG	p.Cys254Ter	3129389626
25		Female	Targeted	c.614G > A	p.Gly205Asp	31293896 26, 2917101313
26		Female	Targeted	c.830+1G > A		3129389626
27		Female	Targeted	c.299T>C	p.Phe100Ser	3129389626
28		Female	Whole Exome Sequencing	c.830+1G > C		3129389626
29		Female	UK	c.629delG 	p.Ser210X	2917101313
30		Female	UK	c.1007_1008del	p.Tyr336CysfsX5 	2917101313
31		Female	UK	c.700C>T	p.Arg234X 	2917101313
32		Female	UK	c.627del	p.Ser210GlnfsX78	2917101313
33		Female	UK	c.454delT	p.Cys152AlafsX9	2917101313
34		Female	UK	c.726C>G	p.Tyr242X	2917101313
35		Female	UK	c.921delA	p.Ala308Leufs*22	3074641627
36		Female	Targeted	c.479T>G	p.Leu160Arg	3074641627
37		Female	Targeted	c.251delA	p.Asp84Alafs*34	3074641627
38		Female	Targeted	c.344 + 1G>A		3074641627
				c.100G>A	p.Val34Met
39		Male	Whole Exome Sequencing	c.873C>G	p.Tyr291*	3061224728
40		Male	UK	c.977 1 C>T		2917101313
41		Female	UK	c.439+2T>G		3045515629
42		Female	UK	c.411dupT (c.412insT)	p.Glu138*	3045515629
43		Female	UK	c.729-2 A>G		3045515629
44		Female	UK	UK	UK	3034127530
45		Female	UK	c.19C > T	p.Arg7*	2998185231
46		Female	UK	c.401G > C	p.Arg134Pro	2998185231
47		Female	UK	c.700C > T	p.Arg234*	2998185231
48		Female	UK	c.503G > A	p.Gly168Glu	2998185231
49		Female	UK	c.912delT	p.Ala305Leufs*25	2998185231
50		Female	Whole Exome Sequencing	c.1007_1008del	p.Tyr336Cysfs ∗5 	231768204
51		Female	Whole Exome Sequencing	c.38G>C	p.Arg13Pro	231768204
52		Female	Whole Exome Sequencing	c.-1_5del	p.Met1?	231768204
53		Female	Whole Exome Sequencing	c.293T>C	p.Leu98Pro	231768204
54		Female	Whole Exome Sequencing	c.476del	p.Leu159Argfs ∗2	231768204
55		Female	Whole Exome Sequencing	c.19C>T	p.Arg7 ∗	231768204
56		Female	Whole Exome Sequencing	c.56-1G>A	splicing defect	231768204
57		Female	Whole Exome Sequencing	c.700C>T	p.Arg234 ∗	231768204
58		Female	Whole Exome Sequencing	c.400C>T	p.Arg134 ∗	231768204
59		Male	Whole Exome Sequencing	c.228_229del	p.Glu76Aspfs ∗38 	231768204
60		Female	Whole Exome Sequencing	c.405_409del	p.Lys135Asnfs ∗2	231768204
61		Female	Whole Exome Sequencing	c.359dup	p.Lys121Glufs ∗18 	231768204
62		Female	Whole Exome Sequencing	c.830+1G>A	splicing defect	231768204
63		Male	Whole Exome Sequencing	c.19dup	p.Arg7Profs ∗64	231768204
64		Female	Whole Exome Sequencing	c.235+1G>A	splicing defect	231768204
65		Female	Whole Exome Sequencing	c.1007_1008del	p.Tyr336Cysfs ∗5 	231768204
66		Female	Whole Exome Sequencing	c.694_703del	p.Leu232Alafs ∗53	231768204
67		Female	Whole Exome Sequencing	c.183C>A	p.Asn61Lys	231768204
68		Male	Whole Exome Sequencing	c.1025_1034del insACATATTT	p.Gly342Aspfs ∗12 	231768204
69		Female	Whole Exome Sequencing	c.55+1G>C	splicing defect	231768204
70		Female	Whole Exome Sequencing	c.C19T	p.Arg7*	2535689932
71		Female	Targeted	c.319_320delCT	p.Leu107Phefs*7	2960027433
72		Female	Targeted	c.20G>A	p.Arg7Gln	2960027433
73		Female	Targeted	c.64DeIT	p.Cys22Alafs*16	2887872834
74		Male	Whole Exome Sequencing	c.131-1G>A		2703014615
75		Male	Whole Exome Sequencing	c.248G>A	p.Trp83	2703014615
76		Male	Whole Exome Sequencing	c.400C>T	p.Arg134	2703014615
77		Female	Whole Exome Sequencing	c.400C>T	p.Arg134	2703014615
78		Male	Whole Exome Sequencing	c.161_163delTGG	p.Val54del	2657704135
79		Female	Whole Exome Sequencing	c.161_163delTGG	p.Val54del	2657704135
80		Female	Targeted	c.235+1G>T	Splice site	2968245336
81		Female	Whole Exome Sequencing	c.236-18A>G	intronic	2968110837
82		Female	UK	c.251A>G	p.Asp84Gly	262402097
83		Female	UK	c.969_970insT	p.V324CfsX18	2574462338
84		Female	UK	c.587_588delTA	p.I196SfsX26	2574462338
85		Female	UK	c.414_419delGTTGA	p.E138_F139del	2574462338
86		Female	UK	c.628T>C	p.S210P	2574462338
87		Female	UK	c.400C>T	p.R134X	2574462338
88		Female	UK	c.587_588delT	p.I196SfsX26	2574462338
89		Female	UK	c.293T>C	p.L98P	2574462338
90		Female	UK	c.322del	p.Ser108Leufs*10	2504465539
91		Female	Whole Exome Sequencing	c.342-2A>C	splice site	2461025519
92		Female	Targeted	c.345-1G>A	r.345_439del	2602246340
93		Female	Targeted	c.400G > A	p.R134Ter	2685981841
94		Female	Whole Exome Sequencing	c.400C>T	p.R134X	2660973042
95		Female	Whole Exome Sequencing	c.439+1G>T	p.Gly147Val; Val147_Leu148ins8	234350868, 2339012143
96		Female	Whole Exome Sequencing	c.516G>C	p.Asp174Valfs*29 	234350868
97		Female	Whole Exome Sequencing	c.437dupA	p.Leu148Alafs*3	234350868, 2289218944
98		Female	Whole Exome Sequencing	c.637C>T	p.Gln213*	234350868
99		Female	Whole Exome Sequencing	c.1033_1034dupAA	p.Asn345Lysfs*67	234350868
100		Female	Targeted	c.440-2 A > G	splice site	2679096045
101		Female	Targeted	c.447_448del	p.Cys149*	2836125546
102		Female	Targeted	c.447_448del	p.Cys149*	2836125546
103		Female	UK	c.488del C	p.Pro163Argfs*34	2530122746
104		Female	UK	c.51911_51913del	splice site	2479080247
105		Female	Whole Exome Sequencing	c.551delC	p.S184LfsX13	2513162248
106		Female	Targeted	c.597_598	p.Leuo201Lysfs*21	2795754849
107		Female	UK	c.626C > A	p.Ala209Asp	2559241150
108		Female	UK	c.662_663del	p.Phe221*	2436817651
109		Female	Targeted	c.752_754del	p.Ser251del	2436817651
110		Female	Whole Exome Sequencing	c.1030del	p.Cys344fs	2436817651
111		Female	Whole Exome Sequencing	c.700 C>T	p.Arg 234*	2893239552
112		Male	Whole Exome Sequencing	c.752_754delCCT	p.Ser251del	2837132053
113		Female	Whole Exome Sequencing	p.T260Lfs*27		2715902854
114		Female	Whole Exome Sequencing	c.795delT		2907562214
115		Female	Whole Exome Sequencing	c.830+1G>A	Splice site	2462158455
116		Male	Whole Exome Sequencing	c.830+1G > A	splice site	2871174056
117		Female	UK	c.830 + 2 T > C	splice site	2734908557
118		Female	Whole Exome Sequencing	c.831‐1G>C	splice site	2648185217
119		Female	Whole Exome Sequencing	c.C868T	p.Q290X	2526306158
120		Male	Whole Exome Sequencing	c.1007_1008delAT	p.Tyr336Cys*5	2768147059
121		Female	Whole Exome Sequencing	c.1007_1008del	p.Y336Cfs*5	2944547760
122		Female	Targeted	c.1056C>G 	p.Tyr352*	3071389361
123		Female	Targeted	heterozygous deletion of WDR45 gene		2908210562

---
title: WDR45 missense variants in males
subtitle: Two male patients with WDR45 mutation and a mild phenotype
bibliography: wdr45.bib
---
Asgarov Fatima^1^, Cecilia Altuzarra^2^, Daniel Amsallem^2^ , Bénédicte
Gérard^3^, Patricia Fergelot^4^, Alain Verloes^5^, Juliette Piard
^1,\ 6^.
Compléter les affiliations
1- Centre de Génétique Humaine, Université de Franche-Comté, CHU,
Besançon, France
2- Service de Neuropédiatrie, CHU, Besançon, France
3-
4-
5-
6- Unité de recherche en neurosciences intégratives et cognitives EA481,
Université de Franche-Comté, Besançon, France
Corresponding author
Dr. Juliette Piard, Centre de Génétique Humaine, Centre Hospitalier et
Universitaire
2, place Saint-Jacques, 25000 Besançon, France
E-mail:
[[jpiard\@chu-besancon.fr]{.underline}](mailto:jpiard@chu-besancon.fr)
Abstract
Introduction 
=============
Neurodegeneration with brain iron accumulation (NBIA) is a group of
inherited neurologic disorders characterized by abnormal accumulation of
iron in the basal ganglia. (Gregory and Hayflick, 2013).
NBIA includes the diagnoses of pantothenate kinase-associated
neurodegeneration (PKAN), phospholipase-associated neurodegeneration
(PLAN), fatty acid hydroxylase-associated neurodegeneration (FAHN),
mitochondrial protein-associated neurodegeneration (MPAN), Kufor Rakeb
syndrome, aceruloplasminemia, neuroferritinopathy, and beta-propeller
protein-associated neurodegeneration (BPAN).
BPAN is an X-linked condition due to pathogenic variants in *WDR45*
which encodes the WD repeat domain phosphoinositide-interacting protein
4 (WIPI4) (Kaleka et al.). WDR45 protein functions as a beta-propeller
scaffold and plays a putative role in autophagy through its interaction
with phospholipids and autophagy-related proteins. Loss of WDR45
function has been linked to defects in autophagic flux in patient and
animal cells. However, the role of WDR45 in iron homeostasis remains
elusive (Seibler et al., 2018).
Main clinical signs of BPAN are seizures, developmental delay,
intellectual disability with absent to limited expressive language and
behavioral disturbances with Rett syndrome-like features (Gregory and
Hayflick, 2013).**Seizures** are common during childhood, often starting
as febrile seizures then multiform [@nishioka2015]. During
adolescence and early adulthood seizures tend to become less prominent,
while cognitive decline, progressive parkinsonism and dystonia emerge as
characteristic findings.
A clear female predominance has been described in patients with BPAN and
lethality for males with germline hemizygous variants was initially
suggested The description of few male cases was attributed to somatic
mosaicism. However, observations of affected male patients recently
described with germline variants inherited from their asymptomatic or
pauci-symptomatic mother were challenging this hypothesis.
Here, we report two unrelated male patients with missense variants in
*WDR45* and a moderate phenotype. While two siblings (brother and
sister) and their mother shared the first variant, the second variant
occurred *de novo*.
Material and methods
====================
Participants
============
Written informed consent was obtained from all participants.
============================================================
Methods
=======
NGS (Family 1)
==============
NGS (family 2)
==============
Sanger sequencing
=================
Functional study (?)
====================
Results
=======
Clinical features
=================
**[Family 1 ]{.underline}**
**Patient 1** was the first child of non-consanguineous parents of
French origin (figure 1). The pregnancy was uncomplicated. He was born
at 36 weeks of gestation with a birth weight of 3010 g ( +1,5 SD), a
birth length of 48 cm (+0,5 SD) and a birth
occipito-frontal-circumference of 34 cm (-1 SD). In the neonatal period,
he had poor suckling and two episodes of neonatal bronchiolitis
requiring hospitalization. The initial motor development was
satisfactory. Autonomous walking was acquired at 17 months. A language
delay and fine motor difficulties were noted at kindergarten. At the age
of nine, the language was still very poor. He said a dozen of words
without association. Toilet training was not acquired at night. He was
oriented in a specialized school at the age of 6. He can't read or
write. Fine motor skills remain difficult (image 1(A)). Clinical
examination showed an overlapping of left toes, a mild hypertonia of
lower limbs, and mild dysmorphic features with bilateral epicanthus and
hooded eyelids. He had no epilepsy. The metabolic screening did not show
any abnormalities. Ophthalmologic examination and hearing test were all
normal. A brain MRI at age 7 showed bilateral and symmetric hypersignal
of dentate nucleus in T2 with no signs of iron deposition (figure 2).
**Patient 2** is the sister of P1. She was born at 38 weeks of gestation
with a birth weight of 2760 g (+1 SD), a birth length of 50 cm (-0.5 SD)
and a birth occipito-frontal-circumference of 32.5 cm (-1.5 SD). She
walked at 14 months. She presented a language delay and learning
difficulties. She is monitored in speech therapy. Toilet training of
night was acquired at the age of 9. Clinical examination showed a round
face, thick hair, short forehead and a right preaurical fistula. She has
corrective glasses for hyperopia and astigmatism (image 1(B)).
**Patient 3** is the mother of patient 1 and 2. She presented learning
difficulty at school and an episode of depression. She is completely
autonomous in daily life but her level of education is very inferior to
that of her two healthy brothers. A brain MRI realized after transient
visual disturbances indicated a left cerebellar lesion without expansive
character.
### [Family 2]{.underline}
**Patient 4** was the second child of healthy non-consanguineous parents
of Algerian and French origins. He had three healthy siblings.He was
born at 38 weeks of gestation with a birth weight of 3110 g ( -2.5 SD),
a birth length of 50,5 cm (-1 SD) and a birth
occipito-frontal-circumference of 34 cm (-1 SD). Suckling difficulties
and generalized hypotonia were noted in the neonatal period. .
Psychomotor milestones were delayed : head control was obtained at 4-5
months, sitting at 10 months and standing with support at 18 months of
age. At age 4, he was not ambulatory and had no speech. A gluten-free
diet was set up for gluten intolerance No seizure was reported. When
examined at age 4, he weighed 13.6 kg (-2SD), was 79 cm tall (-1SD) and
had an OFC of 47.5 cm (-3SD). There were no dysmorphic features.
Neurological examination showed axial hypotonia, pyramidal syndrome in
the lower limbs, mild peripheral hypertonia and bilateral nystagmus.
Biological workup included normal blood parameters, hepatic enzymes,
renal and metabolic screening. Ophthalmologic examination, hearing test,
EEG, and cardiac ultrasound were all normal. A brain MRI, performed at
age four, showed delayed myelination, ventricular and pericerebral
spaces enlargement, bilateral hypersignal of dentate nucleus in T2 and
bilateral hypersignal of subcortical white matter in the temporal
regions. Brain MRI repeated at age 6 showed additional cerebellar
atrophy, symmetrical T1 hyposignal and T2 hypersignal of dentate
nucleus. There were no signs of iron deposition.
Genetics studies
================
**[Family 1]{.underline}**
Karyotype, array-CGH and fragile X study didn't show any abnormalities.
High-throughput sequencing study identified the hemizygous c.697C\> T ;
p.(Arg233Cys) variant in *WDR45.*Extensive family segregation study
showed that the variant was present at the heterozygous state in his
mother and his sister and was absent in his maternal uncles and maternal
grand-parents. ( Figure 1). Thus, the variant occurred *de novo* in his
mother.
**[Family 2]{.underline}**
Karyotype, array-CGH and fragile X study didn't show any abnormalities.
NGS study revealed the presence of the hemizygous (NM\_007075.3):
c.698G\>T ;p.(Arg233Leu) variation in *WDR45*. Parental study indicated
that the variant occurred *de novo*.
Neuropsychological assessment
=============================
**Patient 1.** Listening and understanding skills revolve around
understanding multi-part directions. It can make sentences with a
subject and a verb, but the sentence structuring ends there. The lexical
stock articulated and understood by all is limited. He is able to copy
some simple words. He can write his first name from memory. He shows
emerging skills in his socialization. The total psyco\_motor results
indicate that he is limited in his cognitive abilities, with an overall
score that places him in the zone of average impairment.
**Patient 2.** A slight intellectual disability was indeed found during
the initial assessment (M. Campello, November 2018, CHU) while a
multiple learning disability was highlighted on the last assessment.
Discussion
----------
Since the causative gene was first identified in 2012, more than 80
caseshave been published in the literature. The majority of individuals
described to date are severely delayed with prominent expressive speech
impairment, epileptic encephalopathy, autism, and/or a Rett-like
syndrome. However, the phenotype of BPAN is expanding recognize with
milder cases emerging, thus expanding the phenotypic spectrum of this
condition.
Among reported cases, 20 male patients were described. Four of these
patients were mosaic, however they did not show less severe phenotype
compared to others.
Generally, female patients present less severe symptoms compared to
males. Among described cases, 93% of female cases present delayed
development, 53% of them have epilepsy and 57% have parkinsonism.
However all male patients present intellectual deficiency and 70% of
them have epileptic symptoms. Moreover all of these symptoms appears in
early ages in male cases compared to females.
Most of described mutations of WDR45 are *de novo* mutations. 2
inherited male cases were been reported. In 2016 Zarate and al.,
detected a new in-frame deletion in the WDR45 gene (c.161\_163delTGG, p.
(Val54del)) which was in hemizygous, heterozygous and mosaic states in
the brother, sister and mother, respectively. The variant was not found
in the father of the patients. The patient was a 20 year old male with a
history of global developmental delay and epilepsy. He had never been
able to walk independently and relies on the wheelchair. He was
completely dependent on the activities of daily living. He had several
contractures with limited range of motion. At age 20, her brain magnetic
resonance imaging (MRI) revealed severe diffuse brain atrophy and
findings suggesting iron deposition in the globus pallidus and
substantia nigra. His 14-year-old sister presented static
encephalopathy. Developmental problems appeared during the first year of
life. She only knows a few colors and can count to 20. She is able to
dress and undress, use utensils, and speak in short sentences. An MRI of
the brain revealed a deposit of iron in the basal ganglia. The mother of
patients was in good health.
Nakashima et al. have been reported a family with c.400C\> T mutation.
First patient which was a 7-year-old boy and was the first child of
outbred parents. Psychomotor delay was identified by the lack of visual
fixation and ocular follow-up early in the postnatal period. At the age
of 5 months, a retinitis pigmentosa-like eye fundus was noted and
convulsions with spasms began. At 7 months, he presented with cluster
epileptic spasms. Brain MRI showed delayed myelination and generalized
cerebral and cerebellar atrophy at 8 months of age.At 4 years and 5
months, T2-weighted brain MRI did not detect apparent iron deposition,
but l Sensitivity-weighted imaging (SWI) involved iron deposition
(hypointensity) in the globus pallidus and the substantia nigra. At
present, the patient is bedridden and unable to control his head. A
profound intellectual disability has been recognized and he is unable to
pronounce meaningful words. His dizygotic twin sister had developmental
delay and intellectual disability. At 9 and 10 months and 2 years, she
had had complex febrile convulsions. At age 3, his EEG showed frequent
focal spikes or polyspike, but brain MRI at 2 years was normal. She
presented with mild hypotonia and no spasticity. Its development
milestones have been delayed. She could hold out at 2 years and 3 months
of age. She is unable to pronounce meaningful words. The mother of
patients was mosaic for mutation. She was in good health. 3 months of
age.
The principal anatomical indication of BPAN is the accumulation of iron
in in the basal ganglia which could be detected using radiography.
Iron-sensitive sequences, such as SWI, GRE, and T2\*, should be used as
a first-line diagnostic investigation to identify the characteristic
changes in BPAN. By the time clear neurologic features are present, the
brain MRI almost always shows characteristic changes, although iron may
be visible only later in the disease course (Gregory and Hayflick,
2013). MRI in early childhood is nearly always reported normal, although
generalized cerebellar and cerebral atrophy and corpus callosum thinning
have been already described. As the disease progresses, T2w, but mainly
T2\* and susceptibility‐weighted imaging sequences, reveal hypointensity
as a sign of early‐stage iron deposition. Iron accumulates mainly in the
SN and, to a lesser extent, in the GP. Prominent SN hypointensity is
often evident as a thin, dark central band surrounded by a peripheral
hyperintense halo (halo sign) on axial T1w images (Russo et al., 2019).
Neuropathologic findings include axonal spheroids in the CNS and, in
some types, in peripheral nerves. In both of indentified cases in this
study, bilateral and symmetric hypersignal of dentate nucleus in T2 was
observed in childhood without any signs of iron deposition which
correlated with recent data of the literature.
BPAN is an X-linked condition, the existence of milder female cases is
conceivable by way of possible X-inactivation. However, the existence of
these mildly affected individuals could also potentially be reflective
of mutations that have less of a detrimental effect on protein function.
The phenotype of BPAN is expanding and it is important to recognize that
a spectrum of severity with milder cases is emerging. There are three
cases were reported which clearly describe patients with milder BPAN
phenotypes: first, a 17-year-old female who attends a basic stream in
high school, is verbal but has issues with sentence structure, grammar
and articulation, and with no motor delays or seizures, variation
c.251A\>G (p.Asp84Gly) (Long et al., 2015).; the second, a 36-year-old
female with an IQ of 45, who graduated from high school with assistance
and has intelligible speech, and had epilepsy that remitted at menarche
c.64DelT  (p.Cys22Alafs\*16) (Fonderico et al., 2017).; third,
6-year-old girl presented with mild motor delay and moderate speech
delay, who was reported to have had normal development up to 2 and a
half years old. The patient has difficulties in both receptive and
expressive language but can currently say upwards of 500 words and can
speak in sentences. Sequencing of the *WDR45* gene revealed that the
patient is heterozygous for a *de novo* variant c.299T\>C (p.Phe100Ser)
(Chard et al., 2019). These observations suggest that the severity of
the phenotype is dependent on the location and type of mutation which
could modify the protein function more or less. However in general, a
milder phenotype is observed in females with point mutations compared to
deletions, in males any type of mutation results in a severe phenotype.
Here, we reported that a same mutation in male results more severe
phenotype than female by demonstrating the example of the family two
where the mother of the patient 1 was with normal phenotype without any
symptoms. Finally, we could conclude that the both mutations which were
resulted with the change of the same amino acid (233Arg) in the protein
were pathogen in male patients.
References
----------

"diagnosis","variant","inheritance"," ","variant"," ","sex","age","reference"
"BPAN","c.1A>G",,"de novo",,"nonsense","F","31","46"
"BPAN","c.-1_5del",,"de novo",,"nonsense","F","30","49"
"BPAN","c.1_362del",,"unknown",,"nonsense","F","10","54"
"BPAN","c.19C>T",,"de novo",,"nonsense","F","34","49"
"BPAN","c.19dup",,"de novo",,"frame shift","M","31","49"
"BPAN","c.27dup(hemi)",,"inherited",,"frame shift","F","34","112"
"BPAN","c.38G>C",,"de novo",,"missense","F","44","49"
"BPAN","c.55+1G>C",,"de novo",,"splicing defect","F","43","49"
"BPAN","c.55+1G>C",,"unknown",,"splicing defect","M","10 mo","54"
"BPAN","c.56-1G>A",,"de novo",,"splicing defect","F","22","49"
"BPAN","c.64del",,"de novo",,"frameshift","F","36","113, 114"
"BPAN","c.125dup",,"unknown",,"frameshift","F","2","115, 116"
"BPAN","c.131-2A>G",,"de novo",,"splicing defect","F","15","54"
"BPAN","c.161_163del",,"inherited",,"deletion","M","20","57"
"BPAN","c.161_163del",,"inherited",,"deletion","F","14","57"
"BPAN","c.183C>A",,"de novo",,"missense","F","17","49"
"BPAN","c.186del",,"de novo",,"frameshift","F","16","46"
"BPAN","c.224C>A",,"unknown",,"nonsense","F","1","116"
"BPAN","c.228_229del",,"de novo",,"frameshift","M","37","49"
"BPAN","c.235+1G>A",,"de novo",,"splicing defect","F","35","49"
"BPAN","c.236-18A>G",,"de novo",,"splicing defect","F","6","117"
"BPAN","c.249G>A",,"de novo",,"nonsense","F","29","118"
"BPAN","c.251A>G",,"de novo",,"missense","F","18","119"
"BPAN","c.293T>C",,"de novo",,"missense","F","29","49"
"BPAN","c.293T>C",,"de novo",,"missense","F","41","120"
"BPAN","c.299T>C",,"de novo",,"missense","F","6","60"
"BPAN","c.305dup",,"de novo",,"frame shift","M","44","121"
"BPAN","c.322del",,"de novo",,"frameshift","F","39","122"
"BPAN","c.342-2A>C",,"de novo",,"splicing defect","F","15","123"
"BPAN","c.344+4A>C",,"de novo",,"splicing defect","M","10","54"
"BPAN","c.344+5G>A",,"de novo",,"splicing defect","F","N.A.","124"
"BPAN","c.345-1G>A",,"unknown",,"frameshift","F","38","125"
"BPAN","c.359dup",,"de novo",,"frameshift","F","45","49"
"BPAN","c.400C>T",,"de novo",,"nonsense","F","35","120"
"BPAN","c.400C>T",,"de novo",,"nonsense","F","49","49"
"BPAN","c.400C>T",,"de novo",,"nonsense","F","5","126"
"BPAN","c.400C>T",,"de novo",,"nonsense","F","5","54"
"BPAN","c.405_409del",,"de novo",,"frame shift","F","40","49"
"BPAN","c.411dup",,"unknown",,"frameshift","F","34","127"
"BPAN","c.412insT",,"de novo",,"frameshift","F","39","128"
"BPAN","c.414_419del",,"de novo",,"deletion","F","36","120"
"BPAN","c.437dup",,"unknown",,"splicing defect","F","40","50"
"BPAN","c.439+1G>T",,"de novo",,"splicing defect","F","33","50"
"BPAN","c.439+2T>G",,"de novo",,"splicing defect","F","24","128"
"BPAN","c.447_448del",,"de novo",,"nonsense","F","8","129"
"BPAN","c.447_448del",,"de novo",,"nonsense","F","8","129"
"BPAN","c.476del",,"de novo",,"frameshift","F","43","49"
"BPAN","c.488del",,"de novo",,"frameshift","F","25","130"
"BPAN","c.511C>T",,"de novo",,"nonsense","F","5","54"
"BPAN","c.516G>C",,"de novo",,"frameshift","F","28","50"
"BPAN","c.519+1_519+3del",,"de novo*",,"splicing defect","F","31","131"
"BPAN","c.519+1G>A",,"de novo",,"splicing defect","F","1","132"
"BPAN","c.551del",,"de novo",,"frameshift","F","14","133"
"BPAN","c.587_588del",,"de novo",,"frameshift","F","33","120"
"BPAN","c.587_588del",,"de novo",,"frameshift","F","37","120"
"BPAN","c.597_598del",,"de novo",,"frameshift","F","34","134"
"BPAN","c.597_598del",,"de novo",,"frameshift","M","1","54"
"BPAN","c.606C>G",,"de novo",,"missense","F","37","135"
"BPAN","c.626C>A",,"de novo*",,"frameshift","F","30","136"
"BPAN","c.628T>C",,"de novo",,"missense","F","33","120"
"BPAN","c.637C>T",,"unknown",,"nonsense","F","51","50"
"BPAN","c.654del",,"de novo",,"frameshift","F","13","54"
"BPAN","c.662_663del",,"de novo",,"nonsense","F","33","137"
"BPAN","c.694_703del",,"de novo",,"frameshift","F","44","49"
"BPAN","c.700C>T",,"de novo",,"nonsense","F","39","49"
"BPAN","c.700C>T",,"de novo",,"nonsense","F","40","138"
"BPAN","c.729-2C>G",,"de novo",,"splicing defect","F","22","128"
"BPAN","c.752_754del",,"unknown",,"deletion","F","52","137"
"BPAN","c.830+1G>A",,"unknown",,"nonsense","F","5","60"
"BPAN","c.830+1G>A",,"de novo",,"nonsense","F","6","60"
"BPAN","c.830+1G>A",,"de novo",,"nonsense","F","11","139"
"BPAN","c.830+1G>A",,"de novo",,"nonsense","F","37","49"
"BPAN","c.830+2T>C",,"de novo",,"splicing defect","F","27","46"
"BPAN","c.831-1G>C",,"de novo",,"splicing defect","F","13","54"
"BPAN","c.865C>T",,"unknown",,"nonsense","F","13","140"
"BPAN","c.873C>G",,"de novo",,"nonsense","M","34","58"
"BPAN","c.921del",,"de novo",,"frameshift","F","6","78"
"BPAN","c.969_970insT",,"de novo",,"frameshift","F","30","78, 120"
"BPAN","c.970_971del",,"de novo",,"frameshift","F","4","54, 120"
"BPAN","c.1007_1008del",,"de novo",,"nonsense","F","23","49, 54"
"BPAN","c.1007_1008del",,"de novo",,"frameshift","F","24","49"
"BPAN","c.1007_1008del",,"de novo",,"frameshift","F","33","49, 51"
"BPAN","c.1025_1034del",,"de novo",,"frameshift","M","31","49, 51"
"BPAN","c.1030del",,"de novo",,"frameshift","F","42","49, 137"
"BPAN","c.1033_1034dupAA",,"de novo",,"frameshift","F","33","50, 137"
"BPAN","c.1040_1041del",,"de novo",,"frameshift","F","3","50, 141"
"BPAN","c.1056C>G",,"unknown",,"nonsense","F","9","141, 142"
"BPAN (DEE)","c.614G>A",,"unknown",,"missense","F","3","60, 72"
"BPAN (DEE)","c.831-1G>C",,"de novo",,"splicing defect","F","3","53"
"BPAN (RLS)","c.761_762insAG",,"unknown",,"nonsense","F","16","60"
"BPAN (RLS)","c.830+1G>A",,"de novo",,"nonsense","F","14","63"
"BPAN (RLS)","c.830+2T>C",,"unknown",,"splicing defect","F","42","61"
"BPAN (RLS)","c.868C>T",,"de novo",,"nonsense","F","6","62"
"DEE","c.19C>T",,"de novo",,"nonsense","F","3","143"
"DEE","c.197T>A",,"unknown",,"missense","M","10","74"
"DEE","c.400C>T",,"de novo",,"nonsense","F","6","141"
"DEE","c.401G > C",,"de novo",,"missense","F","2","143"
"DEE","c.454del",,"de novo",,"splicing defect","F","7","72"
"DEE","c.503G > A",,"de novo",,"missense","F","5","143"
"DEE","c.629del",,"de novo",,"frameshift","F","8","72"
"DEE","c.660del",,"de novo",,"frameshift","F","2","72"
"DEE","c.700C>T",,"de novo",,"nonsense","F","2","143"
"DEE","c.700C>T",,"de novo",,"nonsense","F","11","72"
"DEE","c.726C>G",,"de novo",,"nonsense","F","4","72"
"DEE","c.752_754del",,"de novo",,"deletion","M","17","145"
"DEE","c.795delT",,"de novo",,"missense","F","7","146"
"DEE","c.830+1G>A",,"de novo",,"nonsense","M","4","147"
"DEE","c.912del",,"de novo",,"frameshift","F","1","143"
"DEE","c.1007_1008del",,"de novo",,"nonsense","M","2","148"
"DEE","c.1007_1008del",,"de novo",,"nonsense","F","7","72"
"EOEE","chrX:48,809,279-48,829,265del",,"de novo",,"deletion","M","3 mo","56"
"EOEE","c.251del",,"de novo",,"missense","F","8","78"
"EOEE","c.344+1G>A",,"de novo",,"splicing defect","F","2","78"
"EOEE","c.479T>G",,"de novo",,"missense","F","13","78"
"ID","c.19C>T",,"de novo",,"nonsense","F","3","67"
"ID","c.777del",,"de novo",,"frameshift","F","29","71"
"RLS","c.235+1G>T",,"de novo",,"splicing defect","F","22","65"
"RLS","c.319_320del",,"unknown",,"frameshift","F","6","64"
"RLS","c.440-2A>G",,"de novo",,"splicing defect","F","5","55"
"West syndrome","c.131-1G>A",,"de novo",,"splicing defect","M","1","85"
"West syndrome","c.248G>A",,"de novo",,"nonsense","M","2","85"
"West syndrome","c.400C>T",,"inherited",,"nonsense","M","7","85"
"unclassified","c.2T>A",,"",,"","","",""
"unclassified","c.19C>T",,"inherited",,"nonsense","M","N.A.","45"
"unclassified","c.52C>T",,"de novo",,"nonsense","F","N.A.","45"
"unclassified","chrX:48934349A>G",,"de novo",,"missense","F","N.A.","45"
"unclassified","c.412G>T",,"de novo",,"nonsense","F","N.A.","45"
"unclassified","c.442_446del",,"inherited",,"nonsense","M","N.A.","45"
"unclassified","c.519+2T>C",,"de novo",,"splicing defect","F","N.A.","45"
"unclassified","c.587-588del",,"de novo",,"frameshift","F","11","149"
"unclassified","c.700C>T",,"de novo",,"nonsense","F","N.A.","45"
"unclassified","c.718dupA",,"de novo",,"nonsense","F","N.A.","45"
"unclassified","c.728+2T>A",,"de novo",,"splicing defect","F","N.A.","45"
"unclassified","c.729-1G>A",,"de novo",,"splicing defect","F","N.A.","45"
"unclassified","c.729-1G>A",,"inherited",,"splicing defect","M","N.A.","45"
"unclassified","c.830+1G>A",,"inherited",,"nonsense","M","N.A.","45"
"unclassified","c.830+1G>A",,"de novo",,"nonsense","F","N.A.","45"
"unclassified","c.944_953del",,"de novo",,"nonsense","F","N.A.","45"
"unclassified","c.1020_1023del",,"de novo",,"frameshift","F","N.A.","45"

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Sex;Ancestry;cDNA;protein;paper
F;German,Irish,English,Austrian;c.1007_1008del;p.Tyr336Cysfs*5;Haack et al 2021
F;German,Sioux,Cherokee;c.38G>C;p.Arg13Pro;Haack et al 2021
F;German,French,Irish;c.-1_5del;p.Met1?;Haack et al 2021
F;African-American;c.293T>C;p.Leu98Pro;Haack et al 2021
F;African-American;c.476del;p.Leu159Argfs*2;Haack et al 2021
F;Hispanic,Puerto-Rican;c.19C>T;p.Arg7*;Haack et al 2021
F;Romanian,French;c.56-1G>A;splicing defect;Haack et al 2021
F;German,Irish,English;c.700C>T;p.Arg234*;Haack et al 2021
F;unknown;c.400C>T;p.Arg134*;Haack et al 2021
M;German,Irish,Scottish;c.228_229del;p.Glu76Aspfs*38;Haack et al 2021
F;Italian,northern-European,Native-American;c.405_409del;p.Lys135Asnfs*2;Haack et al 2021
F;Dutch;c.359dup;p.Lys121Glufs*18;Haack et al 2021
F;Scottish,Irish;c.830+1G>A;splicing defect;Haack et al 2021
M;German;c.19dup;p.Arg7Profs*64;Haack et al 2021
F;Italian;c.235+1G>A;splicing defect;Haack et al 2021
F;unknown;c.1007_1008del;p.Tyr336Cysfs*5;Haack et al 2021
F;unknown;c.694_703del;p.Leu232Alafs*53;Haack et al 2021
F;Pakistani;c.183C>A;p.Asn61Lys;Haack et al 2021
M;English;c.1025_1034delinsACATATTT;p.Gly342Aspfs*12;Haack et al 2021
F;unknown;c.55+1G>C;splicing defect;Haack et al 2021

Subject ID ;Gender ;Age (years) ;Age at deterioration (Years) ;Complementary DNA (NM_007075.3) ;Protein (NP_009006) ;Developmental delay with intellectual disability ;Progressive psychomotor slowing adolescence/ adulthood ;Rett-like features ;Dystonia ;Parkinsonism ;<span class="small-caps">l</span>-DOPA responsive ;Limited expressive language ;Sleep problems ;Epilepsy ;Ocular defects ;T2 hypointense substantia nigra and globus pallidus (high iron) ;T1 hyperintense ‘halo’ midbrain ;Cerebral atrophy ;Cerebellar atrophy ;Other features
60251 ;F ;23 ;– ;c.1007_1008del ;p.Tyr336Cysfs*5 ;+ ;+ ;repetitive midline handwringing ;+ ;+ ;unk ;+ ;REM sleep disorder ;+ ;Astigmatism, myopia ;+ ;+ ;+ ;− ;
63700 ;F ;44 ;26 ;c.38G>C ;p.Arg13Pro ;+ ;+ ;− ;+ ;+ ;+ ;+ ;− ;− ;− ;+ ;+ ;− ; ;
63701 ;F ;30 ;26 ;c.-1_5del ;p.Met1? ;+ ;+ ;+ ;+ ;+ ;+ ;+ ;Excessive movement during sleep ;+ ;High myopia, abnormal pupil shape ;+ ;+ ;+ ;− ;
63702 ;F ;29 ;– ;c.293T>C ;p.Leu98Pro ;+ ;+ ;− ;+ ;− ;na ;+ ;− ;+ ;− ;+ ;+ ;+ ;− ;Posterior ventriculo- megaly
63703 ;F ;43 ;26 ;c.476del ;p.Leu159Argfs*2 ;+ ;+ ;− ;+ ;+ ;unk ;+ ;Sleep-wake cycle disorder ;− ;− ;+ ;+ ;+ ;− ;
63704 ;F ;34 ;25 ;c.19C>T ;p.Arg7* ;+ ;+ ;− ;+ ;+ ;+ ;+ ;− ;− ;Spontaneous retinal detachment ;+ ;+ ;+ ; ;
63705 ;F ;22 ;15 ;c.56-1G>A ;splicing defect ;+ ;+ ;Hand sterotypies ;+ ;+ ;unk ;+ ;− ;+ ;Bilateral partial retinal coloboma ;+ ;+ ;− ;− ;
63706 ;F ;39 ;29 ;c.700C>T ;p.Arg234* ;+ ;+ ;− ;+ ;+ ;+ ;+ ;− ;+ ;− ;+ ;+ ;− ; ;Stroke
63707 ;F ;49 ;37 ;c.400C>T ;p.Arg134* ;+ ;+ ;− ;+ ;+ ;+ ;+ ;Hypersomnolence with choreiform movements at onset of sleep ;+ ;− ;+ ;+ ;+ ;− ;
63709 ;F ;40 ;30 ;c.405_409del ;p.Lys135Asnfs*2 ;+ ;+ ;− ;+ ;+ ;+ ;+ ;− ;− ;Patchy loss of pupillary ruff ;+ ;+ ;+ ;+ ;
63711 ;F ;45 ;31 ;c.359dup ;p.Lys121Glufs*18 ;+ ;+ ;− ;+ ;+ ;unk ;+ ;− ;− ;− ;+ ;+ ;+ ; ;
63712;F ;37 ;26 ;c.830+1G>A ;splicing defect ;+ ;+ ;+ ;+ ;+ ;unk ;+ ;Parasomnia with nocturnal screaming ;− ;− ;+ ;+ ;+ ;+ ;
49841 ;M ;31 ;28 ;c.19dup ;p.Arg7Profs*64 ;+ ;+ ;− ;+ ;+ ;na ;+ ;+ ;+ ;VEP: increased latency ;+ ;− ;+ ;− ;
HS411- 201 ;F ;35 ;30 ;c.235+1G>A ;splicing defect ;+ ;+ ;− ;+ ;+ ;unk ;+ ;− ;− ;− ;+ ;+ ;+ ;+ ;
HH56 ;F ;24 ;19 ;c.1007_1008del ;p.Tyr336Cysfs*5 ;+ ;+ ;− ;+ ;+ ;unk ;+ ;− ;+ ;− ;+ ;+ ;+ ;− ;
HH84 ;F ;44 ;unk ;c.694_703del ;p.Leu232Alafs*53 ;+ ;+ ;− ;+ ;+ ;+ ;+ ;− ;− ;− ;+ ;+ ;+ ;− ;Uterine tumour
NBIA10 ;F ;17 ;16 ;c.183C>A ;p.Asn61Lys ;+ ;+ ;− ;+ ;+ ;+ ;+ ;− ;+ ;− ;+ ;+ ;− ;+ ;
HS463 ;M ;31 ;26 ;c.1025_1034del insACATATTT ;p.Gly342Aspfs*12 ;+ ;+ ;− ;+ ;+ ;+ ;+ ;− ;+ ;− ;+ ;+ ;+ ;− ;
HS152 ;F ;43 ;25 ;c.55+1G>C ;splicing defect ;+ ;+ ;+ ;+ ;+ ;+ ;+ ;− ;+ ;− ;+ ;+ ;+ ;− ;
NBIA18 ;F ;27 ;20 ;c.830 + 2T>C ;splicing defect ;+ ;+ ;− ;+ ;+ ;unk ;+ ;− ;− ;− ;unk ;unk ;+ ;− ;Neuro-pathology
NBIA21 ;F ;31 ;29 ;c.1A>G ;start codon abolished ;+ ;+ ;+ ;+ ;− ;na ;+ ;− ;+ ;− ;+ ;+ ;+ ;+ ;
HS415 ;F ;16 ;15 ;c.186delT ;p.Leu63Trp fs*19 ;+ ;+ ;+ ;+ ;+ ;unk ;+ ;− ;+ ;High myopia ;+ ;− ;+ ;+ ;
63708 ;M ;37 ;27 ;c.228_229del ;p.Glu76Aspfs*38 ;+ ;+ ;− ;+ ;+ ;+ ;+ ;− ;− ;− ;+ ;+ ;+ ;− ;Mega cisterna magna, stroke

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#+title: Reunions
* <2022-05-05 jeu.>
Participant :
- Chloé Angelini : interne, a fait sa thèse sur le panel NBIA à Bordeaux
- Bénédicte gérard (Strasbourg) : bio, qui a fait le dia
- Patricia Fergelot (Bordeaux)
- Christelle Durang (Bordeaux)  : ingénieure, travaille sur les levures
- Jean-Paul Lasserre (Bordeaux) : MCU, travaille sur les levures
** Objectif
Impact sur les mitochondrie -> retard de croissance sur les levures
Visiable avec l’équivalent WDR45 mais aussi avec le gène humain WDR45 mais moins partiellement
Proposition de diagnostic pour re-classifier des VOUS
NB: on peut mesure l’autophagie des levures mais aussi la mitophagie (unique aux levures ! )
Acide aminé
Délai : 6 mois mini (recherche)
Pour schéma sur levure : Martin Graef 2018
** Discussion
Patients avec phénotype mild
Pas de dépôts de fer
=> sur ces 2 acides aminés, peut-être phénotype particulier
** Suivi patient NBIA
Centre de référence à Bordeaux en train de monter un projet pour suivre en HdJ des patients NBIA
** Conclusion
 - test sur la levure démarré
 - TODO: contacter les chercheurs qui ont rapporté des variants sur les 2 acides aminés
 - regarder PNDS
 - TODO: envoyer IRM à Chloé
 - lire article de leheri pour phénotyp radio

#+title: Memoire
#+title: WDR45 variant with a milder phenotype
#+options: toc:nil author:nil
#+bibliography: biblio.bib
* Introduction
* BPAN
** NBIA
** Early Phenotype
** Transmission
** MRI
** Therapy/management
* WDR45
** Function
** Other related diseases
* Case report
Here we report two variants in four patients. While two
** Family 1
- familial history: renal agenesis for the paternal grand-father, epilepsy in the maternal cousin of the mother
- 1 healthy sibling, French parents
*** Patient 1
  - pregnancy, birth N
  - age ??
  - neonatal: poor suckling
  - langage lay + fine motor difficulties
  - overlapping of left toes, mild hypertonia of lower limbs, mild dysmorphic features with bilateral epicanthus and hooded eyelids.
  - no epilepsy
  - metabolic, ophtalmologic, hearing N
  - MRI : bilateral and symmetric hypersignal of dentate nucleus in T2, without iron deposition
*** Patient 2 = sister
  - pregnancy, birth N
  - language delay, learning difficulties
  - round face, thick hair, short forehead and a right preaurical fistula.
  - hypermetropia and astigmatism
  - 12 years, no MRI
*** Patient 3 = mother
- learning difficulty at school
- 1 episode of depression
- autonomous in daily life but her level of education is very inferior to that of her two healthy brothers
- brain MRI (for transient visual disturbances) : left cerebellar lesion
*** Genetics testing
- CGH,FMR1, karyotype normal
- NGS : NM_007075.3 c.697C> T p.(Arg233Cys)
- de novo in the mother
- hemizygous in patient 1, heterozygus in the sistier + mother
** Family 2
*** Patient 4
- family : Algerian and French, 3 (2 ?) healthy siblings
- born 38 weeks, weight  -2.5 SD, length -1 SD, OFC
- neonatal : Suckling difficulties,  generalized hypotonia
- motor + speech delay
- No seizure
- at age 4, weigh -2SD, height -1SD,  OFC -3SD
  - no dysmorphic features.
  - axial hypotonia, pyramidal syndrome in the lower limbs, mild peripheral hypertonia and bilateral nystagmus.
- Biological workup normal
- Ophthalmologic , hearing , EEG, cardiac normal,
- MRI : dentate nucleus hyperT2, + abnormal morphology
*** Genetics testing
- CGH,FMR1, karyotype normal
- NGS : hemizygous (NM_007075.3): c.698G>T ;p.(Arg233Leu)
- de novo
* Discussion
** Phenotype
** Phenotype : male and female
** Variants
** Our patients
* Conclusion

Neurogeneration with brain iron accumulation = progressive
extrapyramidal with accumulation of iron in the brain on MRI, usually
basal ganglia.
- 85% have a genetic basis and most of these are due to 4
genes: /PKAN2/,/PLA2G6/, /C19orf12/, /WDR45/.
- In total, 9 genes are reported.
- Classification is based on genes.
- Clincal and MRI may orient to a specific gene (Table 19.2 in [cite:@haylick2018]).
- PKAN is half of the case and its estimated prevalence is 1/1 000 000 [cite:@gregory2002]
  - female somatic + germline
  - in favor :
    - skewed X inactivation
  Design : in vitro model of neuronal fonction (SH-SY5Y neuroblastoma)
  - modified iron uptake in cells
  - possible link to increased iron uptake in neurons
  - impaired ferritinophagy
  - mitochrondrial iron accumulation + altered mitochrondrial metabolism (possible link to neuronal cell death, neurodegenration)
  data: see[cite:@hayflick2013]
  7 patients: new phenotype
* Footnotes
[fn:1]  c.697C>T (R233*) is sometime reported as c.700C>T when the non-canonical transcript is use
  MRI with arrows :)
** DONE Gregory2009
** DONE Gregory2002
** Treatment
** Biomarker
- 1 case reports with elevated ENO2/NSE[cite:@takano_elevation_2015]
- Soluble transferrin receptor/log ferritin ratio [cite:@belohlavkova_clinical_2020] 5/6 patients
* Other pathologies associated with WDR45
  17 patients (13 females 4 males)
  slowly progressing parkinsoni/dystonia in adulthood + epilepsy + ID + MRI
  https://doi.org/10.1111/ncn3.12427
** DONE Gregory2019
** DONE [cite:@haylick2013] phenotype details of the cohort in [cite:@haack2012]
  ** TODO The protein encoded by WDR45 is characterized as a beta-pro- peller scaffold that serves as a platform to enable specific protein– protein interactions that are important in autophagy.
** DONE [cite:@haack2012] first description of WDR45 in NBIA 19 mutations, 20 subjects.
** TODO [cite:@saitsu2013] nouveau phénotype WDR45 5 patients -> TODO data
** DONE [cite:@Ji_2021] show that WDR45 is required for neural autophagy
** DONE [cite:@Kano_2020] *revue* + 1 patiente
** TODO 1 case report
** TODO https://mediatum.ub.tum.de/1256878
** TODO https://europepmc.org/article/med/31665836
** 3 years old gil https://cpfd.cnki.com.cn/Article/CPFDTOTAL-JSYC201811001060.htm
** 7 females https://www.sciencedirect.com/science/article/abs/pii/S0197458015000548
** 1 male https://movementdisorders.onlinelibrary.wiley.com/doi/abs/10.1002/mdc3.13365
** https://onlinelibrary.wiley.com/doi/10.1111/ene.14679
** https://www.prd-journal.com/article/S1353-8020(18)30496-6/fulltext
** 3 male with west https://www.nature.com/articles/jhg201627
** 1 girl rett-like https://www.sciencedirect.com/science/article/pii/S0890850816300032?casa_token=ehws_TFdQiMAAAAA:zsj3IRGv0EqyuUxRso4zZpNH-p-ygXa5c9QSqb-E8HtcgkxWxZ-SndxH2SdrNxrd0A-EWC8xM2w
**  https://academic.oup.com/brain/article/141/10/3052/5087794?login=true
**  mouse model https://www.tandfonline.com/doi/full/10.1080/15548627.2019.1630224
**  1 girl, rett-like    https://www.nature.com/articles/jhg201418
**  1 male https://www.nature.com/articles/ejhg2015159
**  1 boy https://www.sciencedirect.com/science/article/pii/S1769721217302203?casa_token=t72fvriXW7kAAAAA:SDq-OjjKJAN3lopp-kU4fBypLYAP7sfJjv-PDMpVYRmIS5GGBHUMaywYVB_fHCdk2IlGrOYllak
** DONE [cite:@Umehara_2020] : 1 woman c.233C > A, p. Ser78*
** [cite:@Hattingen_2017]  1 female
** ?? 1 female, epilepsy  : c.830＋2dup
** [cite:@Xixis_2016] 1 case report  ,, epileptic spasm
** https://n.neurology.org/content/92/15_Supplement/P3.8-022.abstract mosais c830+1G>A mosaic
  *O 1 case report https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0041-1739626
** [cite:@Endo_2017] 1 case report, woman
* Other
- Overal with Rett ?
- No biomarker ?
* TODO References
87 papers
Cerebral : only 62% have iron deposit
Pros: huge review, HPO normalization
Cons: Mean age at last follow-up = 13 with survival 100% in the boys
** DONE [#A] @adang2020 review 106 cases 17 new cases (males)  !!
CLOSED: [2022-04-24 Sun 16:23] SCHEDULED: <2022-04-18 Mon>
Males seems more affected
Seizure is a core feature of BPAN, contrary to NBIA but not all patients have them : 80% have seizures ( 84% of males.)
Starts a bit earlier and diagnosed earlier in the male -> more severe ?
  Half do not have iron deposit in the brain
60 CAS Rapportés
** TODO physio @ji2021
** 1 mutation WDR45 for 69 patients NBIA 6 @tscentschier2015
** 1 case report 1 girl @@long2015
Mild
** 7 female patients @carvill2017
6 truncating 1 missense
** 5 young females @chen2019
** 1 case report female @xiong2019
** 1 case report female @ozawa2014
** 1 case report female @morikawa2017
infantile spasms here milder in woman (treatable)
mildl
** 1 case female @hermann2017
Panel négatif initialement -> diag sur qPCR
** wdr45 + plr3a @khalifa2015
** 1 patient female @wynn2017
** 2 twins female @araujo2017
** 1 female 6 years @christoforou2020
** diag at 6 years-old, girl, functional analysis @willoughby2017
A trio was needed
** 1 male, severe @redon201
** [cite:@Noda_2021] brain study in knockout mice
** [cite:@Khoury_2019] 1 case of epileptic encephalopathy
** [cite:@Ak_akaya_2019] 1 patient BPAN mosaicim c.873C>G; p.(Tyr291*)
** [cite:@Liu_2018]  9 month-old c.977-1 C>T) **no iron on MRI**
** [cite:@morisada2016] 1 woman : **21 years = MRI with atrophy only**, 39 years = MIR with classic anomalies !
** [cite:@Sato2020]  1 case, classic BPAN but with lateral parkinsonism
** [cite:@Tang2020] 5 unrelated children with de novo variant **normal MRI**
** male @spiegel2016
** 1 female 38Y in Korea + iron @ryu2015
  Male are more severe
  Most have epilepsy (70 of 81 females and 14 of 15 males)
  Limit: delay to diagnosis of 16 years
** TODO [#A] [cite:@Cong_2021] review 140 variants + 15 unclassified
SCHEDULED: <2022-04-18 Mon>
of WDR45 : 93 patients, 84 women, 9 males with sch
Less variants than Saffari ??
** DONE [cite:@Aring_2021] physiopathology model for WDR45 deficit
** DONE [cite:@Lee_iron_2021] follow-up of Lee2021
same variant
"suggested" that functional and structural changes resulted
in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, c
** [cite:@lee_autophagic_2021] c.977-1G>A effet autophage fibroblaste
** @seibler2018 fonctionnal on WDR45 and PLA2G6 variant
- WDR45 (c.519+1_519+3delGTG; NM_007075.3)
- PLA2G6 (c.91 G>A; NM_003560.2)
** TODO 40 patients, 2 males @Kulikovskaja2018
** TODO 3rd mouse model @biagosch2021
** DONE [#A] review 160 cases, 109 variants @saffari021
  with knock-out
      - in favor : skewed in 10/12 women with WDR45 mutation
- [cite:@zarate_lessons_2015] germline homozygous viable in male but more severe (twin study)
brother hemizygos symptomatic, sister htz symptomatic, mother somatic mosaicim asympt   o
- [cite:@akcakaya_novel_2019] mosaic in male (blood)
- [cite:@adang_phenotypic_2020]: more severe, earlier : 19 males (review 106 cases plus 17 new)
- [cite:@cong_wdr45_2021] majority of germline lethal is male, somatic or germline possible with more sever phenotype
- [cite:@saffari_quantitative_2021] : review, male more severe and earlier
** Mutations :
- missense, truncation
- 23 subjects in [cite:@hayflick2013]
- 5 subjetcs in [cite:@saitsu2013]
** basis, physiopathology in[cite:@aring2021]
- NB: for NBIA, only 2 genes have been associated with iron metabolism (CP ceruloplasmin, CTL ferritin light chain) [cite:@hayflick2018] -> TODO add picture
- WDR45 = one of the 4 human autolog of yeast Atg18 = aurophagy regulator -> deficiency results in autophagic flux (dynamic part of autophagy) ??
- Model [cite:@aring2021] :
    - 2 DNA traces of differents peaks on 1 male (2 amplicons on exon 2)
  - severity based on when and where the mutation occurs in embryogenesis (like in Rett's syndrome)
  - Subset : disordered sleep, ocular defects and Rett-like hand stereotypies (Table 1).
*** MRI
- 13 MRI from 11 patients seen
  - T2 hypointense : substantia nigra and globus pallidus
  - all 13 : substantia nigra : more hypointense
  - 6/10 global pallidus hypointensity variable
  - T1: **halo** in substantia nigra and cerebral pedoncule (center = dark, hyperintensite haloi)
    -> unique to BPAN ?
  - 19/23 : generalized cerebral atrophy
  - 6/23 cerebellar atrophy
*** Neuropatho : 1 patient
- gross: mild cerebellar atrophy, thinned cerebral peduncles, dark/grey brown in substantia nigra
- microscopic (globus pallidus, substantia nigra)
  - iron
  - numerous large axonal spheroids, siderophages, reactive astrocytes
  - severe neuronal loss
  - putamen, thalamus, granular cell layer also affected
  -  tau-positive neurofibrillary tangles in hippocampus, neocortex, putamen, hypothalamus
** X-linked ?
- Most are female, de novo
- [cite:@haack2012] hypothesis: somatic mosaicism in male, germline likely not viable in male
d iron deposit in substantia nigra and globus pallidus (reports not seens)
  - Various seizure types
  - EEG changes
- The prominent parkinsonism observed in BPAN justifies the designation of WDR45 as a PARK family gene
  - L-dopa is very efficent but only for a short period of time. Side effects led to interruption in a few years
  - deterioration of cognition concomitant with onset of the movement disorder, with progressive loss of limited expressive language skills advancing to severe dementia in end stages.
- life expectancy :
  - 18 living (16 to 44 years)
  - 5 female died during 30-50 years
    - 1 ; severe parkinsonism and dysphagia at 48 years of age (11 years after neurological deterioration)
    - 2 aspiration pneumonia
    - 2 unknown causes
- all : neurological deterioration in adolescence/early adulthood: dystonia, parkinsonism, and new cognitive decline.
  - mean age 25.3 years (range 15–37 years).
  - parkinsonism = prominent bradykinesia, rigidity and freezing of gait; however, tremor was noted in only two subjects.
  - Dystonia common in adolescence
- comorbid features in childhood : seizures, spasticity, disordered sleep and stereotypies that further define the BPAN phenotype.
- suspicion : 7 patients in [cite:@gregory2009]
- confirmed + molecular basis in [cite:@haack2012] [cite:@hayflick2013]
* Beta-propeller protein associated neurodegeneration
** Phenotype [cite:@hayflick2013]
*** Clinical
- All (23): global developmental delay in infancy/early childhood + ID as adult
- Most children : made slow developmental gains over time. Developmental quotients ranged from 30–50, with severely limited expressive language in childood.
- Most : clumsy children (broad-based or ataxic gait) but generally healthy.
- 6: spasticity.
- 13: epilepsy in childhood requiring treatment
BPAN = X-linked, WDR45 and distinc phenotype. No X-linked phenotype !
- non-progresive until adulthood, then parkinsonism, dystonia, dementia
* Why publish another case ?
- few males published
- most published cases are severe
- comfort the idea that males are more affected
- same aminoacid but different missense
- variant not yet reported no but there was a confusion [fn:1]
- few inherited cases
* NBIA

26173968
32387008
30115852
30612247
23647500
28361255
25870938
32655987
28561066
32811771
30220557
28554332
30553463
29075622
29171013
31293896
23757263
29981852
31536831
31487502
30713886
28821231
24142851
26715604
29112993
28932395
27159028
25533962
28878728
30440138
31737037
28628100
24896178
31737037
23447832
28211668
23176820
24209435
25356899
28643035
23687123
29325618
26795593
29082105
33092153
26790960
30204590
31505688
23674487
24790802
28261264
25363768
29695595
25363768
30842224
31238825
31632858
33251766
23390121
26096995
27521716
31466010
22892189
32335071
20301334
28191890
31791873
29600274
26208877
29983692
33109474
24847269
25849321
31665836
29860786
30539914
26240209
31139143
32963168
28135719
24781210
31525124
28551038
27349085
27349079
27030146
25744623
24621584
25263061
31721365
25044655
26123052
29682453
24610255
28371320
26633542
30455156
30746416
30746416
26022463
23435086
27171548
30341275
32307390
25817843
30169597
32264724
32079455
27681470
25131622
29322350
30843302
29720203
29445477
26481852
28711740
26725113
33037762
28542792
30369941
27535217
25592411
24384561
29286531
30713893
25301227
24368176
31204559
31404774
31512412
29681108
27957548
10.4172/1747-0862.1000381
31332960
26609730
27435640
26859818
26577041
26000824
28820312
31618753
27652284
32253874
32253879

#+bibliography: biblio.bib
- Why this paper ?
** NBIA
** MRI
- may be normal in early childhood
- hypointensen signal in substantia nigra, globus pallidus
- FIGURE: hypoT2, halo T1 from [cite:@hayflick_beta-propeller_2013-1]
- pathognomonic : hyperintense halo in T1 in substantia nigra and cerebral peduncles
** Therapy/management
- no marker but 1 case report with ENO2[cite:@takano_elevation_2016]
* WDR45
** Other related diseases
(the number of cases reported in given in [cite:@cong_wdr45_2021] )
** Family 1
*** Patient 1
  - pregnancy, birth N
  - age ??
  - neonatal: poor suckling
  - langage lay + fine motor difficulties
  - overlapping of left toes, mild hypertonia of lower limbs, mild dysmorphic features with bilateral epicanthus and hooded eyelids.
  - no epilepsy
  - metabolic, ophtalmologic, hearing N
  - MRI : bilateral and symmetric hypersignal of dentate nucleus in T2, without iron deposition
*** Patient 2 = sister
  - pregnancy, birth N
  - language delay, learning difficulties
  - round face, thick hair, short forehead and a right preaurical fistula.
  - hypermetropia and astigmatism
  - 12 years, no MRI
*** Patient 3 = mother
- learning difficulty at school
- 1 episode of depression
- autonomous in daily life but her level of education is very inferior to that of her two healthy brothers
- brain MRI (for transient visual disturbances) : left cerebellar lesion
*** Genetics testing
- CGH,FMR1, karyotype normal
- de novo in the mother
- hemizygous in patient 1, heterozygus in the sistier + mother
- NGS : NM_007075.3 c.697C> T p.(Arg233Cys)
- familial history: renal agenesis for the paternal grand-father, epilepsy in the maternal cousin of the mother
- 1 healthy sibling, French parents
** Family 2
- [cite:@adang_phenotypic_2020] with a 19 male cohort
  - more profound development delay
  - more seizure in male but not earlier and more refractory epilepsy
  - earlier in male
** Variants
- decipher : score for the gene
- /in silico/ score for our variant (varsome)
- predited consequence : no significative difference
- FIGURE: all reported variants
* Scripts :noexport:
#+begin_src python :results output
# Missing variants ?? We should have 123+17 but 2 are missing...
import pandas as pd
d = pd.read_csv("data_cong.csv")
print(d.diagnosis.value_counts(normalize=True).mul(100))
# print(d.disease.value_counts)
#+end_src
#+RESULTS:
#+begin_example
BPAN             62.589928
DEE              12.230216
unclassified     12.230216
BPAN (RLS)        2.877698
EOEE              2.877698
RLS               2.158273
West syndrome     2.158273
BPAN (DEE)        1.438849
ID                1.438849
Name: diagnosis, dtype: float64
#+end_example
** Download all paper
#+begin_src sh
pip install metapub
#+end_src
#+begin_src python :results output
from metapub import PubMedFetcher
from metapub import FindIt
with open("papers_pmid.txt") as f:
    with open("papers_doi.txt", "w") as fo:
        for pmid in [l.rstrip() for l in f.readlines()]:
            article = PubMedFetcher().article_by_pmid(pmid)
            if article.doi is not None:
                fo.write(article.doi + "\n")
#+end_src
#+RESULTS:
#+begin_src sh
cat papers_doi.txt | xargs -I {} PyPaperBot --dwn-dir . --doi "{}"
#+end_src
** Stats sur Cong
** Our patients
- phenotype
  - milder phenotype in female (family 1)
  - all patients have neurodevelopmental delay
  - no typical MRI iron deposit : too early ?
  - no seizures but not all reported case have them
  - no movement disorder : male are too young
  - neurologic symptoms in one patient, correspond to a subset of the phenotype (hypotonia)
- 2 very close missense variant, with different symptoms
  - C-terminal section ??
* Conclusion
  - BPAN is a recent diagnostic
  - the phenotype has been well studied with now over 160 cases
  - mostly severe phenotype
  - here we report both a de novo and an inherited new variants
  - with a milder phenotype
  - and 2 very cloose missense variants
- biphasic evolution for femail
- [cite:@saffari_quantitative_2021] seizures are more severe for male :
  - more motor seizure , especially infantile spasmes
  - more childhood onset epilpectic encphalopathies
  - more progressive encephalopathy
- more behavioural anomalies in mal
- but :
  - seizure not more frequent in male
  - onset is not earlier for males (at least statistically)
  - stereotypies only in female
  - movement disorder more pronounced in female
*** Patient 4
- family : Algerian and French, 3 (2 ?) healthy siblings
- born 38 weeks, weight  -2.5 SD, length -1 SD, OFC
- neonatal : Suckling difficulties,  generalized hypotonia
- motor + speech delay
- No seizure 
- at age 4, weigh -2SD, height -1SD,  OFC -3SD
  - no dysmorphic features.
  - axial hypotonia, pyramidal syndrome in the lower limbs, mild peripheral hypertonia and bilateral nystagmus.
- Biological workup normal
- Ophthalmologic , hearing , EEG, cardiac normal,
- MRI : dentate nucleus hyperT2, + abnormal morphology
*** Genetics testing
- CGH,FMR1, karyotype normal
- NGS : hemizygous (NM_007075.3): c.698G>T ;p.(Arg233Leu)
- de novo
- 3 recent reviews  [cite:@cong_wdr45_2021], [cite:@saffari_quantitative_2021], [cite:@adang_phenotypic_2020] with a 19 male cohort
** Phenotype
- non-neurological:
  - urinary incontinence
  - dysphagia
  - precocious puberty
- survival :[cite:@saffari_quantitative_2021]
** Phenotype : male and female
  - facial dysmorphy
- confirm the mostly neurological phenotype : developmental delay, abnormal cNS morpho, seizures
  - DI severe-profound, usually with speech disorder on the expressive or no speech
- Chronology
  1. developpemental delay/seizures in the first two years of life
  2. brain iron accumulation much later (median age = 11)
  3. Movement disorders, developemental regression, mental deterioration
* Discussion
* Case report
- BPAN 66.4%
- Rett-like syndrome 2.1%
- intellectual disability 1.4%
- developmental and epileptic encephalopathy 12.1%
- early-onset epileptic encephalopathy (EOEE) 2.9%
- West syndrome 2.1%
** Function (see [cite:@cong_wdr45_2021] )
- protein structure : N-terminal beta-propeller (definition)
- endoplasmic reticulum homeostasis
- mitochondrial alteration (morphology and function)
- iron homeostasis
- autophagy (update by [cite:@ji_upbeta-propeller_2021] )
- estimation 35-40% (Stige 2018)
- Review in [cite:@hayflick_neurodegeneration_2018]
- unclear why only globus pallidus and substantia nigra are targeted
- clinics and MRI are heterogenous : table 19.2 in[cite:@hayflick_neurodegeneration_2018]
** Early Phenotype
- described by [cite:@hayflick_beta-propeller_2013-1] : 23 patients
- initial diagnosis may be : atypical rett or epilepctic encephalopathy
- all = global developemental delay. Most had some gains over time.
  - IQ = 30-50 with expressive language severely limited
- most = broad/ataxic gait
- 13/23 epilepsy + treatement, with various types
- adolescence/early adulthood : dystonia, parkinsonism, cognitive decline (mean 25.3 years)
  - parkinsonism without tremor
  - L-dopa is effective but only for a short time
- additional features : disordered sleep (6/23), ocular defects (7/23), atypical Rett-like syndrome (7/23), bowel and bladder incontinence (most)
** Transmission
- most = de novo [cite:@hayflick_neurodegeneration_2018]
- some familial cases recorded
- male : not rare
  - expand the phenotype for male
  - 2 families with the same variant
* BPAN
- NBIA = group of pathologies sharing the degeneration of globus pallidus and substantia nigra  due to iron accumulation
  - suspected on clinical feature + MRI
  - phenotype and genetics are heretogenous
  - more than 85% have a genetic etiology
  - classified by gene (so there may have overlapping phenotype)
- BPAN = a subset
  - first reported in 2012
  - distinct phetotypes : non progressive until adulthood ->> parkinsonism, dystonia and dementia
* Introduction
#+title: WDR45 variant with a milder phenotype
#+options: toc:nil author:nil

Asgarov Fatima^{1}, Cecilia Altuzarra^{2}, Daniel Amsallem^{2} ,
Bénédicte Gérard^{3}, Patricia Fergelot^{4}, Alain Verloes^{5}, Juliette
Piard ^{1, 6}.
Compléter les affiliations
1- Centre de Génétique Humaine, Université de Franche-Comté, CHU,
Besançon, France
2- Service de Neuropédiatrie, CHU, Besançon, France
3-
4-
5-
6- Unité de recherche en neurosciences intégratives et cognitives EA481,
Université de Franche-Comté, Besançon, France
Corresponding author
Dr. Juliette Piard, Centre de Génétique Humaine, Centre Hospitalier et
Universitaire
2, place Saint-Jacques, 25000 Besançon, France
E-mail: [[mailto:jpiard@chu-besancon.fr][_jpiard@chu-besancon.fr_]]
Abstract
* Introduction
  :PROPERTIES:
  :CUSTOM_ID: introduction
  :END:
Neurodegeneration with brain iron accumulation (NBIA) is a group of
inherited neurologic disorders characterized by abnormal accumulation of
iron in the basal ganglia. (Gregory and Hayflick, 2013).
NBIA includes the diagnoses of pantothenate kinase-associated
neurodegeneration (PKAN), phospholipase-associated neurodegeneration
(PLAN), fatty acid hydroxylase-associated neurodegeneration (FAHN),
mitochondrial protein-associated neurodegeneration (MPAN), Kufor Rakeb
syndrome, aceruloplasminemia, neuroferritinopathy, and beta-propeller
protein-associated neurodegeneration (BPAN).
BPAN is an X-linked condition due to pathogenic variants in /WDR45/
which encodes the WD repeat domain phosphoinositide-interacting protein
4 (WIPI4) (Kaleka et al.). WDR45 protein functions as a beta-propeller
scaffold and plays a putative role in autophagy through its interaction
with phospholipids and autophagy-related proteins. Loss of WDR45
function has been linked to defects in autophagic flux in patient and
animal cells. However, the role of WDR45 in iron homeostasis remains
elusive (Seibler et al., 2018).
Main clinical signs of BPAN are seizures, developmental delay,
intellectual disability with absent to limited expressive language and
behavioral disturbances with Rett syndrome-like features (Gregory and
Hayflick, 2013).*Seizures* are common during childhood, often starting
as febrile seizures then multiform [cite:@nishioka2015]. During
adolescence and early adulthood seizures tend to become less prominent,
while cognitive decline, progressive parkinsonism and dystonia emerge as
characteristic findings.
A clear female predominance has been described in patients with BPAN and
lethality for males with germline hemizygous variants was initially
suggested The description of few male cases was attributed to somatic
mosaicism. However, observations of affected male patients recently
described with germline variants inherited from their asymptomatic or
pauci-symptomatic mother were challenging this hypothesis.
Here, we report two unrelated male patients with missense variants in
/WDR45/ and a moderate phenotype. While two siblings (brother and
sister) and their mother shared the first variant, the second variant
occurred /de novo/.
* Material and methods
  :PROPERTIES:
  :CUSTOM_ID: material-and-methods
  :END:
* Participants
  :PROPERTIES:
  :CUSTOM_ID: participants
  :END:
* Written informed consent was obtained from all participants.
  :PROPERTIES:
  :CUSTOM_ID: written-informed-consent-was-obtained-from-all-participants.
  :END:
* Methods
  :PROPERTIES:
  :CUSTOM_ID: methods
  :END:
* NGS (Family 1)
  :PROPERTIES:
  :CUSTOM_ID: ngs-family-1
  :END:
* NGS (family 2)
  :PROPERTIES:
  :CUSTOM_ID: ngs-family-2
  :END:
* Sanger sequencing
  :PROPERTIES:
  :CUSTOM_ID: sanger-sequencing
  :END:
* Functional study (?)
  :PROPERTIES:
  :CUSTOM_ID: functional-study
  :END:
* Results
  :PROPERTIES:
  :CUSTOM_ID: results
  :END:
* Clinical features
  :PROPERTIES:
  :CUSTOM_ID: clinical-features
  :END:
*_Family 1_*
*Patient 1* was the first child of non-consanguineous parents of French
origin (figure 1). The pregnancy was uncomplicated. He was born at 36
weeks of gestation with a birth weight of 3010 g ( +1,5 SD), a birth
length of 48 cm (+0,5 SD) and a birth occipito-frontal-circumference of
34 cm (-1 SD). In the neonatal period, he had poor suckling and two
episodes of neonatal bronchiolitis requiring hospitalization. The
initial motor development was satisfactory. Autonomous walking was
acquired at 17 months. A language delay and fine motor difficulties were
noted at kindergarten. At the age of nine, the language was still very
poor. He said a dozen of words without association. Toilet training was
not acquired at night. He was oriented in a specialized school at the
age of 6. He can't read or write. Fine motor skills remain difficult
(image 1(A)). Clinical examination showed an overlapping of left toes, a
mild hypertonia of lower limbs, and mild dysmorphic features with
bilateral epicanthus and hooded eyelids. He had no epilepsy. The
metabolic screening did not show any abnormalities. Ophthalmologic
examination and hearing test were all normal. A brain MRI at age 7
showed bilateral and symmetric hypersignal of dentate nucleus in T2 with
no signs of iron deposition (figure 2).
*Patient 2* is the sister of P1. She was born at 38 weeks of gestation
with a birth weight of 2760 g (+1 SD), a birth length of 50 cm (-0.5 SD)
and a birth occipito-frontal-circumference of 32.5 cm (-1.5 SD). She
walked at 14 months. She presented a language delay and learning
difficulties. She is monitored in speech therapy. Toilet training of
night was acquired at the age of 9. Clinical examination showed a round
face, thick hair, short forehead and a right preaurical fistula. She has
corrective glasses for hyperopia and astigmatism (image 1(B)).
*Patient 3* is the mother of patient 1 and 2. She presented learning
difficulty at school and an episode of depression. She is completely
autonomous in daily life but her level of education is very inferior to
that of her two healthy brothers. A brain MRI realized after transient
visual disturbances indicated a left cerebellar lesion without expansive
character.
*** _Family 2_
    :PROPERTIES:
    :CUSTOM_ID: family-2
    :END:
*Patient 4* was the second child of healthy non-consanguineous parents
of Algerian and French origins. He had three healthy siblings.He was
born at 38 weeks of gestation with a birth weight of 3110 g ( -2.5 SD),
a birth length of 50,5 cm (-1 SD) and a birth
occipito-frontal-circumference of 34 cm (-1 SD). Suckling difficulties
and generalized hypotonia were noted in the neonatal period. .
Psychomotor milestones were delayed : head control was obtained at 4-5
months, sitting at 10 months and standing with support at 18 months of
age. At age 4, he was not ambulatory and had no speech. A gluten-free
diet was set up for gluten intolerance No seizure was reported. When
examined at age 4, he weighed 13.6 kg (-2SD), was 79 cm tall (-1SD) and
had an OFC of 47.5 cm (-3SD). There were no dysmorphic features.
Neurological examination showed axial hypotonia, pyramidal syndrome in
the lower limbs, mild peripheral hypertonia and bilateral nystagmus.
Biological workup included normal blood parameters, hepatic enzymes,
renal and metabolic screening. Ophthalmologic examination, hearing test,
EEG, and cardiac ultrasound were all normal. A brain MRI, performed at
age four, showed delayed myelination, ventricular and pericerebral
spaces enlargement, bilateral hypersignal of dentate nucleus in T2 and
bilateral hypersignal of subcortical white matter in the temporal
regions. Brain MRI repeated at age 6 showed additional cerebellar
atrophy, symmetrical T1 hyposignal and T2 hypersignal of dentate
nucleus. There were no signs of iron deposition.
* Genetics studies
  :PROPERTIES:
  :CUSTOM_ID: genetics-studies
  :END:
*_Family 1_*
Karyotype, array-CGH and fragile X study didn't show any abnormalities.
High-throughput sequencing study identified the hemizygous c.697C> T ;
p.(Arg233Cys) variant in /WDR45./Extensive family segregation study
showed that the variant was present at the heterozygous state in his
mother and his sister and was absent in his maternal uncles and maternal
grand-parents. ( Figure 1). Thus, the variant occurred /de novo/ in his
mother.
*_Family 2_*
Karyotype, array-CGH and fragile X study didn't show any abnormalities.
NGS study revealed the presence of the hemizygous (NM_007075.3):
c.698G>T ;p.(Arg233Leu) variation in /WDR45/. Parental study indicated
that the variant occurred /de novo/.
* Neuropsychological assessment
  :PROPERTIES:
  :CUSTOM_ID: neuropsychological-assessment
  :END:
*Patient 1.* Listening and understanding skills revolve around
understanding multi-part directions. It can make sentences with a
subject and a verb, but the sentence structuring ends there. The lexical
stock articulated and understood by all is limited. He is able to copy
some simple words. He can write his first name from memory. He shows
emerging skills in his socialization. The total psyco_motor results
indicate that he is limited in his cognitive abilities, with an overall
score that places him in the zone of average impairment.
*Patient 2.* A slight intellectual disability was indeed found during
the initial assessment (M. Campello, November 2018, CHU) while a
multiple learning disability was highlighted on the last assessment.
** Discussion
   :PROPERTIES:
   :CUSTOM_ID: discussion
   :END:
Since the causative gene was first identified in 2012, more than 80
caseshave been published in the literature. The majority of individuals
described to date are severely delayed with prominent expressive speech
impairment, epileptic encephalopathy, autism, and/or a Rett-like
syndrome. However, the phenotype of BPAN is expanding recognize with
milder cases emerging, thus expanding the phenotypic spectrum of this
condition.
Among reported cases, 20 male patients were described. Four of these
patients were mosaic, however they did not show less severe phenotype
compared to others.
Generally, female patients present less severe symptoms compared to
males. Among described cases, 93% of female cases present delayed
development, 53% of them have epilepsy and 57% have parkinsonism.
However all male patients present intellectual deficiency and 70% of
them have epileptic symptoms. Moreover all of these symptoms appears in
early ages in male cases compared to females.
Most of described mutations of WDR45 are /de novo/ mutations. 2
inherited male cases were been reported. In 2016 Zarate and al.,
detected a new in-frame deletion in the WDR45 gene (c.161_163delTGG, p.
(Val54del)) which was in hemizygous, heterozygous and mosaic states in
the brother, sister and mother, respectively. The variant was not found
in the father of the patients. The patient was a 20 year old male with a
history of global developmental delay and epilepsy. He had never been
able to walk independently and relies on the wheelchair. He was
completely dependent on the activities of daily living. He had several
contractures with limited range of motion. At age 20, her brain magnetic
resonance imaging (MRI) revealed severe diffuse brain atrophy and
findings suggesting iron deposition in the globus pallidus and
substantia nigra. His 14-year-old sister presented static
encephalopathy. Developmental problems appeared during the first year of
life. She only knows a few colors and can count to 20. She is able to
dress and undress, use utensils, and speak in short sentences. An MRI of
the brain revealed a deposit of iron in the basal ganglia. The mother of
patients was in good health.
Nakashima et al. have been reported a family with c.400C> T mutation.
First patient which was a 7-year-old boy and was the first child of
outbred parents. Psychomotor delay was identified by the lack of visual
fixation and ocular follow-up early in the postnatal period. At the age
of 5 months, a retinitis pigmentosa-like eye fundus was noted and
convulsions with spasms began. At 7 months, he presented with cluster
epileptic spasms. Brain MRI showed delayed myelination and generalized
cerebral and cerebellar atrophy at 8 months of age.At 4 years and 5
months, T2-weighted brain MRI did not detect apparent iron deposition,
but l Sensitivity-weighted imaging (SWI) involved iron deposition
(hypointensity) in the globus pallidus and the substantia nigra. At
present, the patient is bedridden and unable to control his head. A
profound intellectual disability has been recognized and he is unable to
pronounce meaningful words. His dizygotic twin sister had developmental
delay and intellectual disability. At 9 and 10 months and 2 years, she
had had complex febrile convulsions. At age 3, his EEG showed frequent
focal spikes or polyspike, but brain MRI at 2 years was normal. She
presented with mild hypotonia and no spasticity. Its development
milestones have been delayed. She could hold out at 2 years and 3 months
of age. She is unable to pronounce meaningful words. The mother of
patients was mosaic for mutation. She was in good health. 3 months of
age.
The principal anatomical indication of BPAN is the accumulation of iron
in in the basal ganglia which could be detected using radiography.
Iron-sensitive sequences, such as SWI, GRE, and T2*, should be used as a
first-line diagnostic investigation to identify the characteristic
changes in BPAN. By the time clear neurologic features are present, the
brain MRI almost always shows characteristic changes, although iron may
be visible only later in the disease course (Gregory and Hayflick,
2013). MRI in early childhood is nearly always reported normal, although
generalized cerebellar and cerebral atrophy and corpus callosum thinning
have been already described. As the disease progresses, T2w, but mainly
T2* and susceptibility‐weighted imaging sequences, reveal hypointensity
as a sign of early‐stage iron deposition. Iron accumulates mainly in the
SN and, to a lesser extent, in the GP. Prominent SN hypointensity is
often evident as a thin, dark central band surrounded by a peripheral
hyperintense halo (halo sign) on axial T1w images (Russo et al., 2019).
Neuropathologic findings include axonal spheroids in the CNS and, in
some types, in peripheral nerves. In both of indentified cases in this
study, bilateral and symmetric hypersignal of dentate nucleus in T2 was
observed in childhood without any signs of iron deposition which
correlated with recent data of the literature.
BPAN is an X-linked condition, the existence of milder female cases is
conceivable by way of possible X-inactivation. However, the existence of
these mildly affected individuals could also potentially be reflective
of mutations that have less of a detrimental effect on protein function.
The phenotype of BPAN is expanding and it is important to recognize that
a spectrum of severity with milder cases is emerging. There are three
cases were reported which clearly describe patients with milder BPAN
phenotypes: first, a 17-year-old female who attends a basic stream in
high school, is verbal but has issues with sentence structure, grammar
and articulation, and with no motor delays or seizures, variation
c.251A>G (p.Asp84Gly) (Long et al., 2015).; the second, a 36-year-old
female with an IQ of 45, who graduated from high school with assistance
and has intelligible speech, and had epilepsy that remitted at menarche
c.64DelT  (p.Cys22Alafs*16) (Fonderico et al., 2017).; third, 6-year-old
girl presented with mild motor delay and moderate speech delay, who was
reported to have had normal development up to 2 and a half years old.
The patient has difficulties in both receptive and expressive language
but can currently say upwards of 500 words and can speak in sentences.
Sequencing of the /WDR45/ gene revealed that the patient is heterozygous
for a /de novo/ variant c.299T>C (p.Phe100Ser) (Chard et al., 2019).
These observations suggest that the severity of the phenotype is
dependent on the location and type of mutation which could modify the
protein function more or less. However in general, a milder phenotype is
observed in females with point mutations compared to deletions, in males
any type of mutation results in a severe phenotype. Here, we reported
that a same mutation in male results more severe phenotype than female
by demonstrating the example of the family two where the mother of the
patient 1 was with normal phenotype without any symptoms. Finally, we
could conclude that the both mutations which were resulted with the
change of the same amino acid (233Arg) in the protein were pathogen in
male patients.
** References
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