WDR45 – Neurodegeneration with Brain Iron Accumulation

WDR45, encoding the WD-repeat protein WIPI4, is required for autophagosome maturation and lysosomal fusion. Heterozygous loss-of-function variants in WDR45 cause β-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation (NBIA) characterized by global developmental delay in early childhood and a second phase of progressive dystonia, parkinsonism, and dementia in adolescence or early adulthood. Brain MRI typically shows iron deposition in the globus pallidus and substantia nigra with characteristic T1 hyperintense halos and T2* hypointensities (PMID:23435086).

BPAN follows an X-linked dominant inheritance pattern, with most WDR45 variants arising de novo. At least 25 unrelated probands harboring heterozygous truncating or splice-site variants have been reported, including both female and rare surviving male cases (PMID:23435086; PMID:25744623). Familial segregation studies identified one additional affected sibling in a kindred with a hemizygous in-frame deletion (PMID:26577041).

The variant spectrum is dominated by premature stop codons, frameshifts, and essential splice-site mutations. A recurrent nonsense change c.865C>T (p.Gln289Ter) has been described in pediatric BPAN patients presenting with Rett-like features and early iron deposition (PMID:25263061). No clear founder alleles have been established.

Functional assays in lymphoblastoid cells and patient fibroblasts demonstrate reduced WDR45 protein levels, accumulation of aberrant early autophagic structures, decreased autophagic flux, and disturbed ferritinophagy leading to iron overload. Markers of ferroptosis are elevated in patient cells, and induced pluripotent stem cell-derived neurons show mitochondrial and lysosomal dysfunction (PMID:23435086; PMID:36076926; PMID:30169597). In vivo, Wdr45 knockout mice exhibit cognitive deficits, ER stress, impaired autophagosome-lysosome fusion, and neuronal loss, recapitulating BPAN pathology (PMID:31204559).

No studies have refuted the WDR45–NBIA association; however, phenotypic variability ranges from classic iron-accumulation syndromes to early-onset epileptic encephalopathy without detectable MRI iron in males. This spectrum underscores the need for early genetic testing even in atypical presentations.

Integration of genetic and experimental evidence establishes WDR45 haploinsufficiency as a definitive cause of NBIA5, mediated by autophagy defects and iron dyshomeostasis. Early recognition via targeted sequencing and characteristic MRI findings enables timely diagnosis, family counseling, and consideration of emerging autophagy-modulating therapies.

Key Take-home: WDR45 loss-of-function is a definitive cause of NBIA; include WDR45 testing in patients with developmental delay and movement disorders with or without iron on MRI.

References

• Nature Genetics • 2013 • De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. PMID:23435086
• Neurobiology of Aging • 2015 • High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism. PMID:25744623
• American Journal of Medical Genetics Part A • 2014 • Early manifestations of BPAN in a pediatric patient. PMID:25263061
• International Journal of Molecular Sciences • 2022 • Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in β-Propeller Protein-Associated Neurodegeneration. PMID:36076926
• Brain • 2018 • Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells. PMID:30169597
• Autophagy • 2020 • WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death. PMID:31204559

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