Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia

Abstract

Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T₂-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.

Keywords: ClC-2 chloride channels; MRI; ataxia; leucoencephalopathies.

Graphical abstract

Figure 1

MRI findings in patients with CLCN2-related leucoencephalopathy and ataxia. Brain MR from patient 3 (A–L). Axial T2-weighted images (A, D, G, J) demonstrate symmetric bilateral hyperintensity involving the cerebral and cerebellar white matter, posterior limb of internal capsules, midbrain cerebral peduncles, central tegmental tracts (arrowheads in G) and middle cerebellar peduncles. The corresponding DWI (B, E, H, K) and ADC maps (C, F, I, L) suggest restricted diffusion, manifest as DWI hyperintensity and ADC map hypointensity, bilaterally in the subcortical cerebral white matter (arrows in C), posterior limb of internal capsules (arrows in F), midbrain cerebral peduncles (arrows in I) and middle cerebellar peduncles (arrows in L). Brain MR from patient 1 (M–R). Axial T2-weighted images (M, N, P, Q) show symmetric bilateral mild hyperintensity involving the cerebral white matter, which is more prominent in the subcortical region of the right parietal lobe (arrow in M); there is also hyperintensity in the posterior limb of internal capsules, midbrain cerebral peduncles, central tegmental tracts (arrowhead in N) and middle cerebellar peduncles. Also notice the compromise of the splenium of the corpus callosum (arrow in Q). The corresponding ADC maps (O, R) demonstrate hyperintensity in the posterior limb of internal capsules and middle cerebellar peduncles (arrows in O), which represents facilitation (not restriction) of the movement of water molecules. There is some restriction in the splenium of the corpus callosum, shown as hypointensity in the ADC map (arrowhead in R).

Figure 2

Brain MR from patient 10 (A–F), demonstrating putaminal involvement. Axial T2-weighted images (A, B) demonstrate hyperintense foci in the ventral and dorsal portions of both putamina (arrows). Axial FLAIR image (C) discloses the same hyperintensity (arrows). These foci present facilitated diffusion, characterized by hyperintensity in the corresponding ADC map (D, arrows). Axial T1 (E) and post-contrast T1 (F) demonstrate these foci as hypointense, without enhancement (arrows).

Figure 3

Schematics of the ClC-2 chloride channel showing protein domains and reported variants.