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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)
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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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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 1018-4813
e-ISSN 1476-5438
Journal European Journal of Human Genetics
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
Grants NBIA Disorders Association
Mariani Foundation
GRUPPO A.N.A. San VitoAl Torre
DOI 10.1038/s41431-024-01745-1
WOS ID 001360910400001
Scopus ID 85210009872
PubMed ID 39578614
Erfassungsdatum 2024-11-27
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