Beta-propeller protein-associated neurodegeneration

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Beta-propeller protein-associated neurodegeneration
Other namesStatic encephalopathy of childhood with neurodegeneration in adulthood, Neurodegeneration with brain iron accumulation 5
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Developmental delay, seizures, mental handicap. In 2nd and 3rd decade patients develop parkinsonism or dystonia.
TreatmentAnticonvulsant, ketogenic diet, and vagus nerve stimulation might be used for seizures, and DBS for dystonia.

Beta-propeller protein-associated neurodegeneration (BPAN) (previously known as Static encephalopathyof childhood with neurodegeneration in adulthood-SENDA) is a rare hereditary X-linked dominant disorder, which is caused by a mutation in the gene WDR45. [1] BPAN belongs to class of disorders called neurodegeneration with brain iron accumulation (NBIA), which causes brain iron elevation and neurodegeneration. [2] Patients with BPAN, develop symptoms, such as early onset developmental delay, seizures, and further neurological decline (such as dystonia, parkinsonism, and dementia, which develops by early adulthood). [3] [4] BPAN is one of the most common NBIA disorder. [5]

Contents

As of 2024, 123 individuals with BPAN have been identified. [6] There are more females than males with this disease, due to nonviability in males with germline mutations (because males have only one X chromosome, where the WDR45 gene is located). [3]

Symptoms

A "halo" in substantia nigra can be seen. MRT T1gewichtet BPAN Diagnostik.jpg
A "halo" in substantia nigra can be seen.
Hypointensity in substantia nigra and globus pallidus can be seen, which means iron accumulation in these parts of the brain. MRT T2gewichtet BPAN Diagnostik.jpg
Hypointensity in substantia nigra and globus pallidus can be seen, which means iron accumulation in these parts of the brain.

Patients with BPAN might experience symptoms such as dysautonomia, abnormal eye movements, atrophy of cerebrum and cerebellum, slow movements, dementia, frontal release signs, developmental delay with Intellectual disability, poor speech, parkinsonism, encephalopathy, rigidity, trouble sleeping, tremor. [7] Patients might occasionally experience aggressive behavior and optic atrophy. [7] Seizures often start as febrile seizures. [8] Various seizure types have been reported in BPAN, such as absence seizures, myoclonic seizures, generalized tonic-clonic seizures, epileptic spasms, atonic seizures. [9] Some patients experienced precocious adrenarche as young as one to two years of age. [10]

On MRI scan of th brain, accamulation of iron in globus pallidus and substantia nigra can be seen, with a "halo" T1 hyperintense signal in the substantia nigra. [9] Patients with WDR45 mutations might also exprience Rett-like syndrome, intellectual disability, West syndrome, early infantile developmental and epileptic encephalopathy, developmental and epileptic encephalopathy. [11]

Diagnosis

Diagnosis can be suspected by clinical findings, such as: [4]

Cause

WDR45 gene is localised on Xp11.23 region (marked with red) Human X chromosome ideogram showing WDR45 location.png
WDR45 gene is localised on Xp11.23 region (marked with red)

BPAN is caused by a mutation in a gene WDR45. [1] Most people with BPAN have a new mutation (which means that mutation is new and none of the parents have it), although there have been cases of person inheriting the pathogenic variant of WDR45 from a asymptomatic parent due to mosaicism. [13]

Pathophysiology

This illustration shows that in WDR45 deficient cells non-TF (transferrin)-bound iron pathway is upregulated (due to abnormal ferritinophagy) and iron accamulates in cell and mitochondria, which causes apoptosis. WT vs WDR45 deletion cells.jpg
This illustration shows that in WDR45 deficient cells non-TF (transferrin)-bound iron pathway is upregulated (due to abnormal ferritinophagy) and iron accamulates in cell and mitochondria, which causes apoptosis.

In cell-line model of BPAN, researchers found that, WDR45 deficiency impairs ferritinophagy (a process where ferritin is targeted and degraded, conseuqently iron is released in lysosomes). [14] [15] Due to impairment of ferritinophagy, non-TF (transferrin)-bound iron pathway predominates iron transporting, which causes accumulation of iron in cell and mitochondria. [14] Due to accumulation of iron in mitchondria, its function is impaired, by impairing mitochondrial respiration, also iron goes Fenton reaction and generates reactive oxygen species, which is harmful to cells and can initiate apoptosis (a form of programmd cell death) and neurodegeneration. [14] Also, accumulation of lipofuscin (an indicator of oxidized lipid aggregates) can be seen. [16] WDR45 deficiency promotes abnormal localisation of ATG2A to endoplasmic reticulum-mitochondria contact sites, which enhances transmission of phosphatidylserine (to mitochondria), and consequently phosphatidylethanolamine is synthesised, phosphatidylethanolamine is highly sensetive to peroxidation, due to that composition, cell is driven to lipid damage by iron and cause ferroptosis. [16]

WDR45 participates in disassembly of stress granule, by competing with G3BP1, which in turn releases caprin-1 protein, and in BPAN this function is lost, which might provide a link between neurodevelopmental and neurodegenerative phenotype. [17]

Treatment

Deep brain stimulation can be used for dystonia in older patients with BPAN Typical deep brain stimulation setup.jpg
Deep brain stimulation can be used for dystonia in older patients with BPAN

This disease doesn't have a cure, but management of symptoms are possible. [13] [18] ASM s are generally used to control seizures, ketogenic diet, and vagus nerve stimulation can also be used to control seizures. [13] deep brain stimulation can be used for dystonia in older patients with BPAN. [13]

Iron chelating therapy had been tried, although it didn’t show any results, and one patient experienced worsening of Parkinsonism, which caused withdrawal of the medication. [19]

Research

In 2024, researchers successfuly skipped an abnormal pseudoexon in patient with BPAN, using ASO s, which could prevent or attenuate onset of extrapyramidal (such as parkinsonism) symptoms in patient. [20]

In 2025, researchers found that biotin(vitamin B7) might increase WDR45 transcription on inactive X chromosome in BPAN female patient's fibroblasts, through histone biotinylation. [21] In the same yeear (2025) researchers successfuly reversed BPAN phenotype in mouse using AAV-mediated gene transfer. [22]

History

BPAN was described first time by Gregory and colleagues in 2009, where patients experienced developmental delays at first, then patients developed parkinsonism in their 20s-30s, in addition some patients responded well to levedopa. [23] In 2012 Haack and colleagues found the causing gene and propesed the name for that disorder "Beta-propeller protein-associated neurodegeneration" before that it was called "Static encephalopathy of childhood with neurodegeneration in adulthood". [3] [1]

References

  1. 1 2 3 "Entry- #300894 - NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5; NBIA5- OMIM- (OMIM.ORG)". www.omim.org. Retrieved 2026-01-07.
  2. ↑ Khalilian, Sheyda; Fathi, Mohadeseh; Ghahghaei-Nezamabadi, Akram; Miryounesi, Mohammad; Ghafouri-Fard, Soudeh (2024-12-04). "Neurodegeneration with brain iron accumulation 5: report of three cases" . Neurogenetics. 26 (1): 14. doi:10.1007/s10048-024-00783-7. ISSN   1364-6753. PMID   39627470.
  3. 1 2 3 Haack, Tobias B.; Hogarth, Penelope; Kruer, Michael C.; Gregory, Allison; Wieland, Thomas; Schwarzmayr, Thomas; Graf, Elisabeth; Sanford, Lynn; Meyer, Esther; Kara, Eleanna; Cuno, Stephan M.; Harik, Sami I.; Dandu, Vasuki H.; Nardocci, Nardo; Zorzi, Giovanna (2012-12-07). "Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA". American Journal of Human Genetics. 91 (6): 1144–1149. doi:10.1016/j.ajhg.2012.10.019. ISSN   1537-6605. PMC   3516593 . PMID   23176820.
  4. 1 2 Gregory, Allison; Kurian, Manju A.; Haack, Tobias; Hayflick, Susan J.; Hogarth, Penelope (1993), Adam, Margaret P.; Bick, Sarah; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "Beta-Propeller Protein-Associated Neurodegeneration", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   28211668 , retrieved 2026-01-07
  5. ↑ Mollereau, Bertrand; Hayflick, Susan J.; Escalante, Ricardo; Mauthe, Mario; Papandreou, Apostolos; Iuso, Arcangela; Celle, Marion; Aniorte, Sahra; Issa, Abdul Raouf; Lasserre, Jean Paul; Lesca, Gaetan; Thobois, Stéphane; Burger, Pauline; Walter, Ludivine (2023-08-11). "A burning question from the first international BPAN symposium: is restoration of autophagy a promising therapeutic strategy for BPAN?". Autophagy. 19 (12): 3234–3239. doi:10.1080/15548627.2023.2247314. ISSN   1554-8635. PMC   10621268 . PMID   37565733.
  6. ↑ Goedhart, Caitlin; Basalom, Shuaa; Skinner, Stephanie; Brost, Caroline (2024-03-08). "P318: Ironing out the BPAN phenotypic spectrum: A report of three new BPAN cases and review of the literature". Genetics in Medicine Open. 2 101212. doi: 10.1016/j.gimo.2024.101212 . ISSN   2949-7744.
  7. 1 2 "Orphanet: Clinical signs and symptoms". www.orpha.net. Retrieved 2026-01-07.
  8. ↑ Nishioka, Kenya; Oyama, Genko; Yoshino, Hiroyo; Li, Yuanzhe; Matsushima, Takashi; Takeuchi, Chisen; Mochizuki, Yoko; Mori-Yoshimura, Madoka; Murata, Miho; Yamasita, Chikara; Nakamura, Norimichi; Konishi, Yohei; Ohi, Kazuki; Ichikawa, Keiji; Terada, Tatsuhiro (2015-05-01). "High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism" . Neurobiology of Aging. 36 (5): 2004.e9–2004.e15. doi:10.1016/j.neurobiolaging.2015.01.020. ISSN   0197-4580. PMID   25744623.
  9. 1 2 Hayflick, Susan J.; Kruer, Michael C.; Gregory, Allison; Haack, Tobias B.; Kurian, Manju A.; Houlden, Henry H.; Anderson, James; Boddaert, Nathalie; Sanford, Lynn; Harik, Sami I.; Dandu, Vasuki H.; Nardocci, Nardo; Zorzi, Giovanna; Dunaway, Todd; Tarnopolsky, Mark (2013-05-17). "β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation". Brain: A Journal of Neurology. 136 (Pt 6): 1708–1717. doi:10.1093/brain/awt095. ISSN   1460-2156. PMC   3673459 . PMID   23687123.
  10. ↑ Wilson, Jenny L; Gregory, Allison; Kurian, Manju A; Bushlin, Ittai; Mochel, Fanny; Emrick, Lisa; Adang, Laura; Groups, Beta-propeller protein-associated neurodegeneration Guideline Contributions; Hogarth, Penelope; Hayflick, Susan J (2021). "Consensus clinical management guideline for beta-propeller protein-associated neurodegeneration". Developmental Medicine & Child Neurology. 63 (12): 1402–1409. doi:10.1111/dmcn.14980. ISSN   1469-8749. PMID   34347296.
  11. ↑ Cong, Yingying; So, Vincent; Tijssen, Marina A. J.; Verbeek, Dineke S.; Reggiori, Fulvio; Mauthe, Mario (2021-12-02). "WDR45 , one gene associated with multiple neurodevelopmental disorders". Autophagy. 17 (12): 3908–3923. doi:10.1080/15548627.2021.1899669. ISSN   1554-8627. PMC   8726670 . PMID   33843443.
  12. ↑ "HYPOMYELINATION definition and meaning | Collins English Dictionary". www.collinsdictionary.com. 2026-01-05. Retrieved 2026-01-07.
  13. 1 2 3 4 Philadelphia, The Children's Hospital of. "WDR45-Related Disorders and BPAN | Children's Hospital of Philadelphia". www.chop.edu. Retrieved 2026-01-07.
  14. 1 2 3 Aring, Luisa; Choi, Eun-Kyung; Kopera, Huira; Lanigan, Thomas; Iwase, Shigeki; Klionsky, Daniel J.; Seo, Young Ah (2021-12-08). "A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation". Journal of Neurochemistry. 160 (3): 356–375. doi:10.1111/jnc.15548. ISSN   0022-3042. PMC   8811950 . PMID   34837396.
  15. ↑ Jiewen, Wang; Nayiyuan, Wu; Mingjing, Peng; Linda, Oyang; Xianjie, Jiang; Qiu, Peng; Yujuan, Zhou; Zuping, He; Qianjin, Liao (2023-12-18). "Ferritinophagy: research advance and clinical significance in cancers". Cell Death Discovery. 9 (1) 463. doi:10.1038/s41420-023-01753-y. ISSN   2058-7716. PMC   10728094 . PMID   38110359.
  16. 1 2 Wiśniewska, Karolina; Szota, Maria; Żabińska, Magdalena; Szulc, Aneta; Grabowski, Łukasz; Węgrzyn, Grzegorz; Pierzynowska, Karolina (2025-11-24). "Iron Dysregulation in Neurodegeneration with Brain Iron Accumulation (NBIA): Links between Mutations Occurring in BPAN, PKAN, MPAN and PLAN Types and Iron Metabolism". Molecular Neurobiology. 63 (1): 152. doi:10.1007/s12035-025-05479-z. ISSN   1559-1182. PMC   12641038 . PMID   41276763.
  17. ↑ Li, Yin; Fang, Jie; Ding, Yuqi; Zhang, Xilong; Liu, Ying; Qiu, Wanting; Xu, He; Kang, Yunzhe; Chen, Jiayu; Gao, Yanyan; Zhao, Yan G.; Yang, Peiguo; Wang, Bo; Tian, Wenmin; Chen, Yang (2025-06-05). "β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1". Nature Communications. 16 (1): 5227. Bibcode:2025NatCo..16.5227L. doi:10.1038/s41467-025-60583-x. ISSN   2041-1723. PMC   12141619 . PMID   40473629.
  18. ↑ Meyerink, Brandon L.; Karia, Krishna S.; Rechtzigel, Mitchell J.; Patthi, Prithvi R.; Edwards, Ariana C.; Howard, Jessica M.; Aaseng, Elizabeth R.; Aftab, Shamiq; Weimer, Jill M.; Pilaz, Louis-Jan (2025-02-28). "Mutation in Wdr45 leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model". Frontiers in Neuroscience. 19 1545004. doi: 10.3389/fnins.2025.1545004 . ISSN   1662-453X. PMC   11907653 . PMID   40092065.
  19. ↑ Lim, Shen-Yang; Tan, Ai Huey; Ahmad-Annuar, Azlina; Schneider, Susanne A.; Bee, Ping Chong; Lim, Jia Lun; Ramli, Norlisah; Idris, Mohamad Imran (2018-05-30). "A Patient with Beta-Propeller Protein-Associated Neurodegeneration: Treatment with Iron Chelation Therapy". Journal of Movement Disorders. 11 (2): 89–92. doi:10.14802/jmd.17082. ISSN   2005-940X. PMC   5990906 . PMID   29860786.
  20. ↑ Yamada, Mamiko; Maeta, Kazuhiro; Suzuki, Hisato; Kurosawa, Ryo; Takenouchi, Toshiki; Awaya, Tomonari; Ajiro, Masahiko; Takeuchi, Atsuko; Nishio, Hisahide; Hagiwara, Masatoshi; Miya, Fuyuki; Matsuo, Masafumi; Kosaki, Kenjiro (2024-03-18). "Successful skipping of abnormal pseudoexon by antisense oligonucleotides in vitro for a patient with beta-propeller protein-associated neurodegeneration". Scientific Reports. 14 (1): 6506. Bibcode:2024NatSR..14.6506Y. doi:10.1038/s41598-024-56704-z. ISSN   2045-2322. PMC   10948761 . PMID   38499569.
  21. ↑ Reche-López, Diana; Romero-González, Ana; Álvarez-Córdoba, Mónica; Suárez-Carrillo, Alejandra; Cilleros-Holgado, Paula; Piñero-Pérez, Rocío; Gómez-Fernández, David; Romero-Domínguez, José Manuel; López-Cabrera, Alejandra; González-Granero, Susana; García-Verdugo, José Manuel; Sánchez-Alcázar, José A. (2025-02-04). "Biotin Induces Inactive Chromosome X Reactivation and Corrects Physiopathological Alterations in Beta-Propeller-Protein-Associated Neurodegeneration". International Journal of Molecular Sciences. 26 (3): 1315. doi: 10.3390/ijms26031315 . ISSN   1422-0067. PMC   11818482 . PMID   39941083.
  22. ↑ Carisi, Maria Carla; Shamber, Claire; Bishop, Martha; Sangster, Madison; Chandrachud, Uma; Meyerink, Brandon; Pilaz, Louis Jean; Grishchuk, Yulia (2025-03-01). "AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration" . Human Gene Therapy. 36 (5–6): 637–652. doi:10.1089/hum.2024.224. ISSN   1043-0342. PMID   39978419.
  23. ↑ Gregory, A.; Polster, B. J.; Hayflick, S. J. (2008-11-03). "Clinical and genetic delineation of neurodegeneration with brain iron accumulation". Journal of Medical Genetics. 46 (2): 73–80. doi:10.1136/jmg.2008.061929. ISSN   1468-6244. PMC   2675558 . PMID   18981035.
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