Ferrera Giulia, Derderian Kevork, Izzo Rossella, Gnutti Barbara, Legati Andrea, Zorzi Giovanna, Lamantea Eleonora, Iuso Arcangela, Ardissone Anna
Child Neurology Unit - Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133, Milan, Italy.
Institute of Human Genetics, Technische Universität München, Munich, Germany.
Eur J Hum Genet. 2025 Mar;33(2):248-251. doi: 10.1038/s41431-024-01745-1. Epub 2024 Nov 22.
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.
致病性WDR45变异会导致神经发育障碍（NDDs），包括β-螺旋桨蛋白相关神经退行性变（BPAN），其特征为发育迟缓（DD）、共济失调和锥体外系症状。我们的患者最初在22个月大时出现发育迟缓，现在7岁，表现为智力残疾、共济失调和僵硬。MRI检查结果提示为 Leigh 综合征，这是一种线粒体疾病（MD）表型，无脑铁沉积。在肌肉和成纤维细胞中发现呼吸链复合体I（cI）和复合体II（cII）的活性降低，且仅在肌肉中cII活性降低；然而，排除了原发性线粒体疾病。外显子组测序发现了一种新发的致病性WDR45变异。自噬通量分析显示p62反应略有降低，自噬进程正常。这是将WDR45与cI组装和活性联系起来的首份报告，表明线粒体功能障碍是BPAN潜在的病理生理机制。我们建议在诊断早发性NDDs时，尤其是伴有cI缺乏的Leigh样脑病，即使无脑铁沉积，也应考虑WDR45相关的NDDs。
