Neuroimaging in PRUNE1 syndrome: a mini-review of the literature

Abstract

Prune exopolyphosphatase 1 (PRUNE1) is a short-chain phosphatase that is part of the aspartic acid-histidine-histidine (DHH) family of proteins. PRUNE1 is highly expressed in the central nervous system and is crucially involved in neurodevelopment, cytoskeletal rearrangement, cell migration, and proliferation. Recently, biallelic PRUNE1 variants have been identified in patients with neurodevelopmental disorders, hypotonia, microcephaly, variable cerebral anomalies, and other features. PRUNE1 hypomorphic mutations mainly affect the DHH1 domain, leading to an impactful decrease in enzymatic activity with a loss-of-function mechanism. In this review, we explored both the clinical and radiological spectrum related to PRUNE1 pathogenic variants described to date. Specifically, we focused on neuroradiological findings that, together with clinical phenotypes and genetic data, allow us to best characterize affected children with diagnostic and potential prognostic implications.

Keywords: PRUNE1; delayed myelination; enzymatic activity; neurodevelopmental disorder; neurogenesis.

Figure 1

Pathogenic variants in PRUNE1 reported to date. PRUNE1 figure protein with the catalytic domains and the pathogenic variants described so far.

Figure 2

Neuroradiological features of individuals with biallelic PRUNE1 mutations. Sagittal T1-weighted images of a PRUNE1-affected patient performed at 6 months of age (A) and 16 months of age (B) show progressive global brain atrophy, but more specifically evidence of cerebellar and brainstem atrophy, which is out of proportion to the cerebral atrophy. (E,F) Axial T2-weighted images performed at 6 months of age (E) and 16 months of age (F) in the same child, showing progressive diffuse white matter abnormalities along with progressive brain atrophy. (C) Axial inversion recovery and (G) sagittal T1-weighted MRI sequences performed in the patient at 24 months of age show generalized brain volume loss, but with specific evidence of cerebellar atrophy and a diffuse white matter signal abnormality as was seen in her sibling (D,H).