Beta-Propeller Protein-Associated Neurodegeneration (BPAN) Detected in a Child with Epileptic Spasms

Kaleka, Guneet; McCormick, Michael E.; Krishnan, Anant

doi:10.7759/cureus.5404

Cited by 3 publications

(2 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Epilepsy, a feature most common in the first decade of life in BPAN patients, and dystonia, a feature typical of early adulthood, were instead not displayed by Wdr45 KO mice at any age. Hearing loss, likely confounded by the patients’ marked cognitive decline and therefore reported only in two BPAN cases (Rathore et al 2014 ; Kaleka et al 2019 ), was consistently observed in Wdr45 KO mice both from the progression cohort and phenotyping cohort, as revealed by the clickbox and ABR tests.…”

Section: Discussionmentioning

confidence: 99%

A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse

et al. 2021

View full text Add to dashboard Cite

show abstract

“…A spontaneous anatomical abnormality of the neocortex, focal cortical dysplasia type II (FCDII) is characterized by treatment-resistant epilepsy due to atypical neurons and dyslamination caused by deficient mTOR signaling [ 40 ]. Another severe mTORopathy, beta-propeller protein-associated neurodegeneration (BPAN), is associated with iron accumulation and neurodegeneration, presenting as intellectual disability, psychomotor retardation, febrile seizures, autism, progressive cognitive loss, dementia, dystonia and parkinsonism [ 41 ]. Polyhydramnios, megalencephaly and symptomatic epilepsy (PMSE), or Pretzel syndrome, is a rare brain disorder characterized by macrocephaly, craniofacial dysmorphism, infantile-onset treatment-resistant epilepsy and cognitive decline.…”

Section: Clinical Mtoropathiesmentioning

confidence: 99%

Developing Novel Experimental Models of m-TORopathic Epilepsy and Related Neuropathologies: Translational Insights from Zebrafish

Abreu

Demin

Kotova

et al. 2023

IJMS

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR) is an important molecular regulator of cell growth and proliferation. Brain mTOR activity plays a crucial role in synaptic plasticity, cell development, migration and proliferation, as well as memory storage, protein synthesis, autophagy, ion channel expression and axonal regeneration. Aberrant mTOR signaling causes a diverse group of neurological disorders, termed ‘mTORopathies’. Typically arising from mutations within the mTOR signaling pathway, these disorders are characterized by cortical malformations and other neuromorphological abnormalities that usually co-occur with severe, often treatment-resistant, epilepsy. Here, we discuss recent advances and current challenges in developing experimental models of mTOR-dependent epilepsy and other related mTORopathies, including using zebrafish models for studying these disorders, as well as outline future directions of research in this field.

show abstract

WDR45, one gene associated with multiple neurodevelopmental disorders

Cong

Tijssen

et al. 2021

Autophagy

View full text Add to dashboard Cite

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.

show abstract

Beta-Propeller Protein-Associated Neurodegeneration (BPAN) Detected in a Child with Epileptic Spasms

Cited by 3 publications

References 4 publications

A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse

A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse

Developing Novel Experimental Models of m-TORopathic Epilepsy and Related Neuropathologies: Translational Insights from Zebrafish

WDR45, one gene associated with multiple neurodevelopmental disorders

Contact Info

Product

Resources

About