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WIPI2 is a member of the human WIPI protein family (seven-bladed b-propeller proteins binding phosphatidylinositols, PROPPINs), which play a pivotal role in autophagy and has been implicated in the pathogenesis of several neurological conditions. The homozygous WIPI2 variant c.745G>A; p.(Val249Met) (NM_015610.4) has recently been associated with a neurodevelopmental disorder in a single family. Using exome sequencing and Sanger segregation analysis, here, two novel homozygous WIPI2 variants [c.551T>G; p.(Val184Gly) and c.724C>T; p.(Arg242Trp) (NM_015610.4)] were identified in four individuals of two consanguineous families. Additionally, follow-up clinical data were sought from the previously reported family. Three non-ambulant affected siblings of the first family harbouring the p.(Val184Gly) missense variant presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures and dyskinesia. In contrast, the proband of the second family carrying the p.(Arg242Trp) missense variant, similar to the initially reported WIPI2 cases, presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait. Brain MR imaging in five patients showed prominent white matter involvement with a global reduction in volume, posterior corpus callosum hypoplasia, abnormal dentate nuclei and hypoplasia of the inferior cerebellar vermis. To investigate the functional impact of these novel WIPI2 variants, we overexpressed both in WIPI2-knockout HEK293A cells. In comparison to wildtype, expression of the Val166Gly WIPI2b mutant resulted in a deficient rescue of LC3 lipidation whereas Arg224Trp mutant increased LC3 lipidation, in line with the previously reported Val231Met variant. These findings support a dysregulation of the early steps of the autophagy pathway. Collectively, our findings provide evidence that biallelic WIPI2 variants cause a neurodevelopmental disorder of variable severity and disease course. Our report expands the clinical spectrum and establishes WIPI2-related disorder as a congenital disorders of autophagy.
Objectives: To compare dual-energy CT (DECT) and MRI for assessing presence and extent of traumatic bone marrow edema (BME) and fracture line depiction in acute vertebral fractures. Methods: Eighty-eight consecutive patients who underwent dual-source DECT and 3-T MRI of the spine were retrospectively analyzed. Five radiologists assessed all vertebrae for presence and extent of BME and for identification of acute fracture lines on MRI and, after 12 weeks, on DECT series. Additionally, image quality, image noise, and diagnostic confidence for overall diagnosis of acute vertebral fracture were assessed. Quantitative analysis of CT numbers was performed by a sixth radiologist. Two radiologists analyzed MRI and grayscale DECT series to define the reference standard. Results: For assessing BME presence and extent, DECT showed high sensitivity (89% and 84%, respectively) and specificity (98% in both), and similarly high diagnostic confidence compared to MRI (2.30 vs. 2.32; range 0–3) for the detection of BME (p = .72). For evaluating acute fracture lines, MRI achieved high specificity (95%), moderate sensitivity (76%), and a significantly lower diagnostic confidence compared to DECT (2.42 vs. 2.62, range 0–3) (p < .001). A cutoff value of − 0.43 HU provided a sensitivity of 89% and a specificity of 90% for diagnosing BME, with an overall AUC of 0.96. Conclusions: DECT and MRI provide high diagnostic confidence and image quality for assessing acute vertebral fractures. While DECT achieved high overall diagnostic accuracy in the analysis of BME presence and extent, MRI provided moderate sensitivity and lower confidence for evaluating fracture lines.