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Ferrera, G.* ; Derderian, K. ; Izzo, R.* ; Gnutti, B. ; Legati, A.* ; Zorzi, G.* ; Lamantea, E.* ; Iuso, A. ; Ardissone, A.*

WDR45-related encephalopathy mimicking Leigh syndrome associated with complex I deficiency: A case report.

Eur. J. Hum. Genet., DOI: 10.1038/s41431-024-01745-1 (2024)
DOI PMC
Free by publisher: Verlagsversion online verfügbar 11/2025
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 1018-4813
e-ISSN 1476-5438
Zeitschrift European Journal of Human Genetics
Verlag Nature Publishing Group
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen NBIA Disorders Association
Mariani Foundation
GRUPPO A.N.A. San VitoAl Torre