}
@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},