1 - Department of Neuroradiology, Centro Hospitalar Universitário do Porto, Portugal
2 - Department of Neuroradiology, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central, Portugal
- XVII Congresso da SPNR. 25 e 26 de Novembro de 2022, Lisboa
Introduction: Defects affecting ion and water homoeostasis may lead to different forms of CNS disease. The chlorine channel 2 (ClCN2) spans the cell membrane, being fundamental in transepithelial transport, homeostasis, and cell excitability. GlialCAM, a subunit of ClNC2, and membrane protein MLC1, both contribute for stabilizing this channel, forming a complex for astrocytic regulatory volume decrease after cell swelling. However, ClCN2 mutations fundamentally differ from GlialCAM and MLC2, and our aim is to review their distinct clinical-imaging findings through three genetically proven pediatric patients.
Results: An 18-month-old premature boy had abnormal routine cranial-US. MRI showed diffuse white matter (WM) involvement, predominantly in the internal capsules, cerebral peduncles, and middle cerebellar peduncles, with associated diffusion restriction. Clinically he only presentes slight ataxia. Genetics confirmed ClCN2 mutation. A 12-month-old boy with increased head circumference undergoes MRI showing extensive diffuse supratentorial WM involvement, with increased diffusibility. He remained asymptomatic and imaging findings regressed in follow-up MRIs. GlialCAM mutation was genetically proven. An 11-month-old boy with difficult-to-control epilepsy. MRI showed extensive WM involvement, with increased diffusibility and temporal subcortical cysts. Genetics confirmed MLC1 mutation. Clinically, there is significant developmental delay, epilepsy, and skeletal deformations.
Discussion: Our findings are in line with the literature: the first two mutations have a benign clinical course, unlike MLC1 mutation, typically leading to worse clinical outcomes. MRI findings are also distinctive: ClCN2-related disease preferentially affects WM structures that are (relatively) spared by MLC1/GlialCAM-related diseases, namely the corpus callosum, internal capsules, brainstem, and cerebellum. Another intriguing question concerns the size of the myelin vacuoles: while in MLC1/GlialCAM-related diseases, ADC-values of the affected WM are highly increased reflecting large vacuoles/ increased extracellular spaces, ClCN2 mutation leads to low ADC-values due to small intramyelinic vacuoles/oedema. Although the exact mechanisms around ClCN2-GlialCAM-MLC1-pathway are unclear, each genetic mutation leads to distinct clinical-imaging phenotypes.
Keywords: CLCN-2mutation;GLIALCAMmutation;MLC1mutation; MRI phenotypes