Abstract
Pathogenic WDR45 variants cause neurodevelopmental disorders (NDDs) including β-propeller protein-associated neurodegeneration (BPAN), characterized by developmental delay (DD), ataxia and extrapyramidal signs. Our patient, initially presenting at 22 months with DD, now, aged 7, shows intellectual disability, ataxia and rigidity. MRI findings were suggestive of Leigh syndrome, a mitochondrial disorder (MD) phenotype, with no brain iron accumulation. Reduced activity of respiratory chain complex I (cI) and complex II (cII) was identified in muscle and fibroblasts, and a cII reduction in muscle only; however, a primary MD was excluded. Exome sequencing revealed a de novo pathogenic WDR45 variant. Autophagic flux analysis showed a mildly reduced p62 response, with normal autophagy progression. This is the first report linking WDR45 to cI assembly and activity, indicating mitochondrial dysfunction as a potential pathophysiological BPAN mechanism. We recommend considering WDR45-related NDDs when diagnosing early-onset NDDs, particularly Leigh-like encephalopathies with cI deficiency, even without brain iron accumulation.
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All data generated/analyzed during this study are available from the corresponding author on reasonable request.
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Funding
The clinical studies were carried out thanks to funding from GRUPPO A.N.A. San Vito Al Torre. Biochemical and molecular studies were carried out at the Center for the Study of Mitochondrial Pediatric Diseases funded by the Mariani Foundation. Iuso was funded by the NBIA Disorders Association for the investigation of autophagy and complex I assembly in BPAN cells.
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G Ferrera, K Derderian, R Izzo, B Gnutti, A Legati, G Zorzi, E Lamantea, A Iuso, A Ardissone. Data curation: G Ferrera, A Iuso, A Ardissone Formal analysis: K Derderian, R Izzo, B Gnutti, A Legati, E Lamantea. Investigation: G Ferrera, A Iuso, A Ardissone. Methodology: G Ferrera, A Ardissone. Project administration: G Ferrera, A Ardissone. Supervision: A Iuso A Ardissone. Validation: A Iuso, E Lamantea. Visualization: A Iuso A Ardissone. Roles/Writing - original draft: G Ferrera, A Iuso, A Ardissone. Writing - review & editing: G Ferrera, G Zorzi, A Iuso, A Ardissone.
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The boy’s parents provided informed consent for MRI acquisition, muscle and skin biopsy and genetic analysis and consented to the use of anonymized personal data for scientific purposes according to the ethical standards of the 1964 Declaration of Helsinki.
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Ferrera, G., Derderian, K., Izzo, R. et al. WDR45-related encephalopathy mimicking Leigh syndrome associated with complex I deficiency: a case report. Eur J Hum Genet 33, 248–251 (2025). https://doi.org/10.1038/s41431-024-01745-1
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DOI: https://doi.org/10.1038/s41431-024-01745-1
