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

Pathogenic WDR45 variants cause neurodevelopmental disorders (NDDs) including β-propeller protein-associated neurodegeneration, characterized by developmental delay (DD), ataxia and extrapyramidal signs. Our proband presented at 22 months with DD and now, aged 7, shows intellectual disability, ataxia and movement disorder. MRI is compatible with Leigh syndrome, a mitochondrial disorder (MD) phenotype, without evident brain iron accumulation. A reduction of respiratory chain complex I (cI) and complex II (cII) were found in muscle and fibroblasts, but a primary MD was excluded. Exome sequencing revealed a WDR45 pathogenic variant. Autophagy flux revealed a mildly reduced p62 response in fibroblasts. Our report suggests, for the first time, a possible role of WDR45 in the assembly and enzymatic activity of cI and thus mitochondrial impairment as a potential pathophysiological BPAN mechanism. We recommend considering WDR45 -related NDDs in the differential diagnosis of early-onset neurodevelopmental disorders, especially Leigh-like encephalopathies with cI deficiency,even without brain iron accumulation.