Subacute Partially Reversible Leukoencephalopathy Expands the Aicardi-Goutières Syndrome Phenotype

Abstract

Objective: To report a series of atypical presentations of Aicardi-Goutières syndrome.

Methods: Clinical, neuroimaging, and genetic data.

Results: We report a series of six unrelated patients (five males) with a subacute loss of developmental milestones, pyramidal signs, and regression of communication abilities, with onset at ages ranging from 7 to 20 months, reaching a nadir after 4 to 24 weeks. A remarkable improvement of lost abilities occurred in the follow-up, and they remained with residual spasticity and dysarthria but preserved cognitive function. Immunization or febrile illness occurred before disease onset in all patients. CSF was normal in two patients, and in four, borderline or mild lymphocytosis was present. A brain CT scan disclosed a subtle basal ganglia calcification in one of six patients. Brain MRI showed asymmetric signal abnormalities of white matter with centrum semi-ovale involvement in five patients and a diffuse white matter abnormality with contrast enhancement in one. Four patients were diagnosed and treated for acute demyelinating encephalomyelitis (ADEM). Brain imaging was markedly improved with one year or more of follow-up (average of 7 years), but patients remained with residual spasticity and dysarthria without cognitive impairment. Demyelination relapse occurred in a single patient four years after the first event. Whole-exome sequencing (WES) was performed in all patients: four of them disclosed biallelic pathogenic variants in RNASEH2B (three homozygous p.Ala177Thr and one compound heterozygous p.Ala177Thr/p.Gln58*) and in two of them the same homozygous deleterious variants in RNASEH2A (p.Ala249Val).

Conclusions: This report expands the phenotype of AGS to include subacute developmental regression with partial clinical and neuroimaging improvement. Those clinical features might be misdiagnosed as ADEM.

Keywords: Aicardi–Goutières syndrome; acute demyelinating encephalomyelitis; reversible leukoencephalopathy.

Figure 1

Patient 5. Axial (A) and sagittal (B) T2-weighted images show frontotemporal and parietal foci of high signal intensity (arrows) with patchy and asymmetric distribution.

Figure 2

MRI of partially reversible leukoencephalopathy. Patient 3. Initial MRI at the age of 16 months, axial T2-weighted (A) and coronal FLAIR (B) images demonstrate bilateral asymmetric hyperintense areas involving subcortical and periventricular white matter (arrows). Follow-up MRI at the age of 26 months, axial T2-weighted (C), and coronal FLAIR (D) images showing improvement of the abnormal areas.

Figure 3

Patient 2. First MRI at 14 months old, axial FLAIR (A,B) demonstrates the frontoparietal patchy and asymmetric distribution of signal hyperintensity at the cerebral white matter. The second MRI at age 4 (C,D) shows a marked reduction in leukopathy. No atrophy is seen at any time.

Figure 4

MRI showing leukoencephalopathy with contrast enhancement and a relapse-remitting course of the disease. Patient 1. Initial MRI at the age of 20 months. Axial FLAIR image (A) shows bilaterally confluent hyperintensity involving periventricular and subcortical white matter. Axial T2-weighted image (B) demonstrates hyperintensity foci in the pons (arrows). Axial T1-weighted images before (C) and after (D,E) gadolinium administration show scattered foci of contrast enhancement at subcortical and periventricular white matter (arrows in (D)) and pons (arrows in (E)). There is also periventricular ependymal enhancement (arrowheads in (E)). MRI at the age of 28 months, axial FLAIR, and T2 images (F,G) demonstrate a decrease in intensity and extension of the diffuse leukoencephalopathy (F) and of the signal changes in pons (G). In a new MRI at 5 years and 8 months, the axial FLAIR image (H) discloses the confluence of the hyperintense areas in both cerebral hemispheres. Contrast enhancement was seen only in the first MRI.

Figure 5

Patient 4. Axial CT image (A) demonstrates small foci of bilateral basal ganglia calcification (arrows). First MRI images at 17 months, axial T2 (B,C) showing bilateral frontoparietal asymmetric areas of signal hyperintensity. The second MRI at 3 years shows near complete resolution of leukopathy (D,E).