WDR45 mutations may cause a MECP2 mutation-negative Rett syndrome phenotype

Mutations in the autophagy-relatedWD domain repeat 45 (WDR45) gene cause beta-propeller protein-associated neurodegeneration (BPAN), a distinct form of neurodegeneration with brain iron accumulation (NBIA). Clinical and imaging features comprise childhood-onset global developmental delay with further regression in early adulthood, progressive dystonia, parkinsonism, stereotypies, and iron deposition in the basal ganglia. Female and the few existing male patients show similar phenotypes, probably because of somatic mosaicism in males and skewed X-chromosome inactivation (XCI) in females, as WDR45 is located on Xp11.23. To date, about 60 cases have been reported, many of whom had a different initial clinical diagnosis. Hyperkinetic movements and stereotypies overlap with Rett syndrome features, another X-linked disorder most commonly caused byMECP2mutations. Indeed, for 7% of the reported cases of BPAN, the initial diagnosis was Rett syndrome, prompting us to perform the first mutational screen of the WDR45 gene in a large cohort of MECP2 mutation-negative Rett syndrome patients.