WDR45 – Beta-Propeller Protein-Associated Neurodegeneration (BPAN)

Beta-propeller protein-associated neurodegeneration (BPAN), also termed neurodegeneration with brain iron accumulation 5, is an X-linked dominant disorder caused by heterozygous mutations in the autophagy gene WDR45. Affected individuals present with global developmental delay in childhood, evolving into dystonia, parkinsonism and dementia in adolescence or early adulthood, accompanied by iron accumulation in the globus pallidus and substantia nigra on MRI.

Genetic studies have identified multiple de novo loss-of-function variants in WDR45 across unrelated probands. Initial exome sequencing in two individuals and subsequent screening in three additional subjects revealed five distinct de novo heterozygous mutations, including nonsense, frameshift and splice-site changes ([PMID:23435086]). Additional case reports have described novel variants such as c.322del (p.Ser108ValfsTer12) ([PMID:25044655]) and c.488delC (p.Pro163ArgfsTer34) ([PMID:25301227]), demonstrating a spectrum of truncating alleles that impair protein function.

Segregation analysis shows that these variants arise predominantly de novo, with negative parental testing in most families and rare instances of parental mosaicism. One sib-pair study reported an inherited in-frame deletion segregating with disease in a male and his higher-functioning sister, with the mother mosaic for the alteration, underscoring variable expressivity and mosaic transmission ([PMID:26577041]).

Functional assays in patient-derived lymphoblastoid cells and fibroblasts reveal impaired autophagic flux, accumulation of aberrant autophagic structures, and increased intracellular iron and oxidative stress. Autophagy marker analyses demonstrate reduced LC3-II induction upon bafilomycin A1 treatment, while ultrastructural studies show diminished autophagosomes and lysosomal dysfunction ([PMID:30169597]). More recent work highlights disrupted ferritinophagy and ferroptosis pathways in mutant cells, linking WDR45 deficiency to iron dyshomeostasis and neuronal vulnerability.

The mechanism of pathogenicity is consistent with haploinsufficiency: loss-of-function WDR45 variants compromise autophagy-mediated organelle turnover, leading to iron deposition and subsequent neurodegeneration. Concordant findings across cellular and imaging studies support a direct link between defective autophagy and the BPAN phenotype.

Early recognition of BPAN is facilitated by characteristic MRI findings and prompt genetic testing for WDR45 mutations. Genetic diagnosis enables reproductive counseling and consideration of emerging therapies aimed at restoring autophagy or chelating iron. Key Take-home: WDR45 loss-of-function variants cause BPAN via haploinsufficiency of autophagy function, with clear diagnostic markers on neuroimaging and molecular testing.

References

• Nature Genetics • 2013 • De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood PMID:23435086
• Brain • 2018 • Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells PMID:30169597

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