Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient

Abstract

Variants in the WD repeat 45 (WDR45) gene in human Xp11.23 have recently been identified in patients suffering from neurodegeneration with brain iron accumulation, a genetically and phenotypically heterogeneous condition. WDR45 variants cause a childhood-onset encephalopathy accompanied by neurodegeneration in adulthood and iron accumulation in the basal ganglia. They have been almost exclusively found in females, and male lethality was suggested. Here we describe a male patient suffering from a severe and early neurological phenotype, initially presenting early-onset epileptic spasms in clusters associated with an abnormal interictal electroencephalography showing slow background activity, large amplitude asynchronous spikes and abnormal neurological development. This patient is a carrier of a 19.9-kb microdeletion in Xp11.23 containing three genes, including WDR45. These findings reveal that males with WDR45 deletions are viable, and can present with early-onset epileptic encephalopathy without brain iron accumulation.

Figure 1

Brain MRI performed at 7 months, 19 months and 5 years of age. Axial T2 sequences at different ages failed to detect iron accumulation. SWI sequence (right image) reveals an hyposignal in the basal ganglia at the level of globus pallidus and substantia nigra (white arrows), bilaterally (red nuclei are not shown).

Figure 2

Characterization of the deletion (a). Detection of a 19.9- kb deletion on the X chromosome using array-CGH. The grey box shows the position of the deleted region extending from 48 809 279 to 48 829 265 pb (NCBI36/Hg18). The experiment was performed using dye swap and the results of Cy5 labelling (upper tracks) and Cy3 labelling (lower tracks) are shown for the same patient. (b) Schematic representation of the Xp11.23 region showing the deletion identified in the BPAN patient. The grey bar shows the deleted region. Exons are represented as black, grey or white boxes for WDR45, CCDC120 and PRAF2 genes respectively. Arrows indicate the orientation of the transcription and the position of the translation initiation codon. (c) Quantification of WDR45 genomic DNA targets using qPCR. The control female DNA was arbitrarily set at 1 and each experiment was performed in triplicate. The mean of the three experiments is provided as a number above each condition.