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

Stige, Kjersti Eline; Gjerde, Ivar; Houge, Gunnar; Knappskog, Per M.; Tzoulis, Charalampos

doi:10.1002/ccr3.1358

Cited by 33 publications

(36 citation statements)

References 37 publications

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“…The BPAN-causing variants in WDR45 gene 11,12 are exclusively XLD (Xp11.23) and predominantly de novo. Affected females (86%) display a friendly character and heterogenous clinical features; the morphological phenotypes were described by Stige et al 13 and partially affirmed in our reported case.…”

Section: Discussionsupporting

confidence: 87%

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Childhood Dystonia-Parkinsonism Following Infantile Spasms—Clinical Clue to Diagnosis in Early Beta-Propeller Protein-Associated Neurodegeneration

et al. 2019

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Introduction Beta-propeller protein-associated neurodegeneration (BPAN) is a very rare, X-linked dominant (XLD) inherited member of the neurodegeneration with brain iron accumulation (NBIA) disease family. Case report We present a female case of BPAN with infantile spasms in the first year, Rett-like symptomatology, focal epilepsy, and loss of motor skills in childhood. Menarche occurred at the age of 9, after precocious pubarche and puberty.Dystonia-parkinsonism as extrapyramidal sign at the age of 10 years resulted in radiological and genetic work-up. Results Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) measured 66/120 points in body part-related dystonia symptoms. Cerebrospinal fluid examination showed dopamine depletion.T2 and B0 sequences of the diffusion-weighted magnetic resonance imaging showed susceptibility artifacts with NBIA-typical hypointense globus pallidus (GP) and substantia nigra (SN). Next-generation sequencing revealed a BPAN-causing pathogenic variant in WDR45 (WD repeat-containing protein 45) gene (c.830 + 1G > A, XLD, heterozygous, de novo). Skewed X-inactivation was measured (2:98). Conclusions Autophagy-related X-linked BPAN disease might still be underdiagnosed in female cases of infantile spasms.Skewed X-inactivation will have mainly influenced the uncommon, very early childhood neurodegenerative symptomatology in the present BPAN case. Oral levodopa substitution led to improvement in sleep disorder, hypersalivation, and swallowing.Reduced white matter and hypointense signals in SN and GP on susceptibility sequences in magnetic resonance imaging are characteristic radiological findings of advanced disease in NBIA. No BPAN-typical halo sign in T1-weighted scan at midbrain level was seen at the age of 11 years. NBIA panel is recommended for early diagnosis.

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Section: Discussionsupporting

confidence: 87%

“…On the other hand, 75% suffered from L-Dopa induced dyskinesia. 13 Anticholinergics, baclofen, and trihexyphenidyl are alternative options in NBIA dystonia as well as gabapentin, dronabinol, and deep brain stimulation of GP and SN. 25 No causative therapy exists to date.…”

Section: Discussionmentioning

confidence: 99%

Childhood Dystonia-Parkinsonism Following Infantile Spasms—Clinical Clue to Diagnosis in Early Beta-Propeller Protein-Associated Neurodegeneration

et al. 2019

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“…In central nervous system‐specific Wdr45 knockout mice, the lipidated LC3 levels were increased and the autophagy substrate p62, together with ubiquitin‐positive protein aggregates, accumulated in swollen axons. Cells from patients with beta‐propeller protein‐associated neurodegeneration manifest abnormal accumulations of lipidated LC3, together with increased colocalization of LC3 and mATG9, which is usually absent on mature autophagosomes . The results suggest that WDR45 mutations might compromise autophagosome maturation, potentially by regulating mATG9 localization.…”

Section: Beta‐propeller Protein‐associated Neurodegenerationmentioning

confidence: 94%

“…This review focuses specifically on the role of autophagy in neurological diseases with early‐onset (<20y), which typically manifest in childhood (Table ). Most of these disorders associated with defective autophagy follow autosomal‐recessive inheritance, except beta‐propeller protein‐associated neurodegeneration, which is X‐linked dominant …”

Section: List Of Genes and Diseases Associated With Impaired Autophagmentioning

confidence: 99%

“…Neurodegeneration with brain iron accumulation encompasses a clinically and genetically heterogeneous collection of diseases characterized by iron deposition in the basal ganglia . The manifestations of neurodegeneration with brain iron accumulation include progressive dystonia, Parkinsonism, optic atrophy, and neuropsychiatric abnormalities, with preservation of cognitive function in most cases.…”

Section: Neurodegeneration With Brain Iron Accumulationmentioning

confidence: 99%

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Autophagy in childhood neurological disorders

Zhu¹,

Runwal²,

Obrocki³

et al. 2018

Develop Med Child Neuro

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Autophagy is a tightly modulated lysosomal degradation pathway. Genetic disorders of autophagy during nervous system development may lead to developmental delay, neurodegeneration, and other neurological signs in children. Here we aimed to summarize single gene disorders that perturb various steps of autophagy pathway and their roles in the causation of childhood neurological diseases. Numerous childhood‐onset disorders are caused by mutations that impact the autophagy pathway. These can manifest with a range of features including ataxia, spastic paraplegia, and intellectual disability. Defective proteins causing such diseases can interfere with autophagy flux at different stages of the itinerary. Defective autophagy may be an important contributor to the pathological features of various childhood neurodegenerative diseases and lead to the accumulation of aberrant protein and dysfunctional organelles. Insights into the relevant cell biological processes may help understand pathophysiological mechanisms and inspire autophagy‐restoring therapeutic approaches. What this paper adds Numerous childhood‐onset disorders are caused by mutations that impact the autophagy pathway. Defective autophagy is a feature of some mutations that cause ataxia, spastic paraplegia, and intellectual disability.

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Human WIPI β‐propeller function in autophagy and neurodegeneration

Proikas‐Cezanne,

Haas,

Pastor‐Maldonado

et al. 2023

FEBS Letters

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The four human WIPI β‐propellers, WIPI1 through WIPI4, belong to the ancient PROPPIN family and fulfill scaffold functions in the control of autophagy. In this context, WIPI β‐propellers function as PI3P effectors during autophagosome formation and loss of WIPI function negatively impacts autophagy and contributes to neurodegeneration. Of particular interest are mutations in WDR45, the human gene that encodes WIPI4. Sporadic WDR45 mutations are the cause of a rare human neurodegenerative disease called BPAN, hallmarked by high brain iron accumulation. Here, we discuss the current understanding of the functions of human WIPI β‐propellers and address unanswered questions with a particular focus on the role of WIPI4 in autophagy and BPAN.

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

Cited by 33 publications

References 37 publications

Childhood Dystonia-Parkinsonism Following Infantile Spasms—Clinical Clue to Diagnosis in Early Beta-Propeller Protein-Associated Neurodegeneration

Childhood Dystonia-Parkinsonism Following Infantile Spasms—Clinical Clue to Diagnosis in Early Beta-Propeller Protein-Associated Neurodegeneration

Autophagy in childhood neurological disorders

Human WIPI β‐propeller function in autophagy and neurodegeneration

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