A novel
            <i>WDR45</i>
            mutation in a patient with β-propeller protein-associated neurodegeneration

Wynn, DonRaphael P.; Pulst, Stefan M.

doi:10.1212/nxg.0000000000000124

Cited by 10 publications

(5 citation statements)

References 6 publications

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“…In contrast to normal individuals, the putaminal pencil lining was observed early during the first decade of life in BPAN patients [20]. A hyperintense halo has also been reported around the substantia nigra using T1-weighted images [30,32,35,36] but this sign seems inconstant [33]. Brain and hippocampal atrophy as well as cortical thinning have been reported in patients with epileptic encephalopathies [34,[36][37][38].…”

Section: Beta-propeller Protein-associated Neurodegenerationmentioning

confidence: 99%

MRI of neurodegeneration with brain iron accumulation

Lehericy

Roze

Goizet

et al. 2020

Current Opinion in Neurology

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Purpose of review The diagnosis of neurodegeneration with brain iron accumulation (NBIA) typically associates various extrapyramidal and pyramidal features, cognitive and psychiatric symptoms with bilateral hypointensities in the globus pallidus on iron-sensitive magnetic resonance images, reflecting the alteration of iron homeostasis in this area. This article details the contribution of MRI in the diagnosis by summarizing and comparing MRI patterns of the various NBIA subtypes. Recent findings MRI almost always shows characteristic changes combining iron accumulation and additional neuroimaging abnormalities. Iron-sensitive MRI shows iron deposition in the basal ganglia, particularly in bilateral globus pallidus and substantia nigra. Other regions may be affected depending on the NBIA subtypes including the cerebellum and dentate nucleus, the midbrain, the striatum, the thalamus, and the cortex. Atrophy of the cerebellum, brainstem, corpus callosum and cortex, and white matter changes may be associated and worsen with disease duration. Iron deposition can be quantified using R2 Ã or quantitative susceptibility mapping. Summary Recent MRI advances allow depicting differences between the various subtypes of NBIA, providing a useful analytical framework for clinicians. Standardization of protocols for image acquisition and analysis may help improving the detection of imaging changes associated with NBIA and the quantification of iron deposition. Keywords dystonia, iron, MRI, neurodegeneration with brain iron accumulation, pyramidal, quantitative susceptibility mapping, R2 Ã mapping, susceptibility-weighted imaging && ,2 && ]. By the time, neurologic features are obvious, brain MRI almost always shows characteristic changes, although these changes may occasionally appear only later over the disease course. Conversely,

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Section: Beta-propeller Protein-associated Neurodegenerationmentioning

confidence: 99%

MRI of neurodegeneration with brain iron accumulation

Lehericy

Roze

Goizet

et al. 2020

Current Opinion in Neurology

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“…A total of 64 patients were included in the analysis, comprising 55 women (85.9%) and nine men (14.1%) (Tables and ) . Mean age at diagnosis was 27.6 ± 14 years (range 1–52), and mean age at deterioration was 27.2 ± 5.7 (range 13–39).…”

Section: Literature Reviewmentioning

confidence: 99%

Beta‐propeller protein‐associated neurodegeneration: a case report and review of the literature

Stige

Gjerde

Houge

et al. 2018

Clinical Case Reports

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Key Clinical MessageBeta‐propeller protein‐associated neurodegeneration (BPAN) is a rare disorder, which is increasingly recognized thanks to next‐generation sequencing. Due to a highly variable phenotype, patients may present to pediatrics, neurology, psychiatry, or internal medicine. It is therefore essential that physicians of different specialties are familiar with this severe and debilitating condition.

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“…To date, most studies on BPAN have focused on case reports and genetic analyses, confirming BPAN as a distinct class of neurodegenerative disease. Recently, de novo mutations in WDR45 (WD repeat domain 45) gene were identified in BPAN patients by exon sequencing [7,13,14]. Further studies on patient-derived lymphoblastoid cells show lower autophagic activity and accumulation of early autophagic structures [13], linking abnormal autophagy to the disease.…”

Section: Introductionmentioning

confidence: 99%

WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death

et al. 2019

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Mutations in the macroautophagy/autophagy gene WDR45 cause β-propeller protein-associated neurodegeneration (BPAN); however the molecular and cellular mechanism of the disease process is largely unknown. Here we generated constitutive wdr45 knockout (KO) mice that displayed cognitive impairments, abnormal synaptic transmission and lesions in several brain regions. Immunohistochemistry analysis showed loss of neurons in prefrontal cortex and basal ganglion in aged mice, and increased apoptosis in prefrontal cortex, recapitulating a hallmark of neurodegeneration. Quantitative proteomic analysis showed accumulation of endoplasmic reticulum (ER) proteins in KO mouse. At the cellular level, accumulation of ER proteins due to WDR45 deficiency resulted in increased ER stress and impaired ER quality control. The unfolded protein response (UPR) was elevated through ERN1/IRE1 or EIF2AK3/PERK pathway, and eventually led to neuronal apoptosis. Suppression of ER stress or activation of autophagy through MTOR inhibition alleviated cell death. Thus, the loss of WDR45 cripples macroautophagy machinery in neurons and leads to impairment in organelle autophagy, which provides a mechanistic understanding of cause of BPAN and a potential therapeutic strategy to treat this genetic disorder.

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A novel WDR45 mutation in a patient with β-propeller protein-associated neurodegeneration

Cited by 10 publications

References 6 publications

MRI of neurodegeneration with brain iron accumulation

MRI of neurodegeneration with brain iron accumulation

Beta‐propeller protein‐associated neurodegeneration: a case report and review of the literature

WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death

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