Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation

Abstract

Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration. We report two sisters who presented with neurodegeneration triggered by infections. The proband, a previously healthy girl, presented at 22.5 months with ataxia and dysarthria following mild gastroenteritis. MRI at onset showed a symmetric signal abnormality of the cerebellar and peritrigonal white matter. Following a progressive course of partial remissions and relapses, she died at 5 years of age. Her older sister had a similar course following varicella infection, she died within 13 months. Both sisters had unremarkable routine laboratory testing, with exception of a transient mild cytopenia in the proband 19 months after presentation. Exome sequencing identified a biallelic perforin1 mutation (PRF1; p.R225W) previously associated with familial hemophagocytic lymphohistiocytosis (FHL). In contrast to FHL, these girls did not have hematopathology or cytokine overproduction. However, 3 years after disease onset, the proband had markedly deficient interleukin-1 beta (IL-1β) production. These observations extend the spectrum of disease associated with perforin mutations to immune-mediated neurodegeneration triggered by infection and possibly due to primary immunodeficiency.

Figure 1

Familial pedigree and photographs of the affected girls. (a) The pedigree shows two loops of consanguinity; however, molecular studies and further family history analysis confirmed additional loops. The affected girls are noted by shaded shapes and the proband by an arrow. (b) Photograph of the elder affected girl. (c) Photograph of the proband.

Figure 2

Brain MRI of patients IV-5 and IV-3, comparing the initial and follow-up studies. Patient IV-5: axial and coronal T2 images (a–d, 22.5 months of age, 2 weeks after onset; e–h, 32.5 months of age, 10 months after onset) show progression of signal abnormality in the cerebellar white matter (fine arrows) with atrophy of the cerebellum and subsequent involvement of the cerebral white matter (thick arrows). Patient IV-3: axial T2 and axial post-contrast T1 images (i–l, 79 months of age, 3 months after onset; m–p, 88 months of age, 12 months after onset) show extensive and progressive signal abnormality involving the cerebellar (thin arrow) and cerebral (thick arrows) white matter, thalami and basal ganglia, with some lesions showing post-contrast enhancement (asterisks).

Figure 3

Inflammasome activation assay. Concentration of IL-1β excreted by PBMCs measured by ELISA. The cells were treated with 10 ng/ml LPS, with or without treatment with ATP. All experiments were performed in triplicate. ‘Controls' represents the mean of seven biological replicates in healthy controls; error bars indicate the standard error of the mean. Proband IL-1β after stimulation with LPS and ATP is significantly decreased in comparison to other healthy controls, and to all five unaffected family members (P<0.05). All heterozygous family members showed no significant difference from controls. Control experiments with media only, or media with ATP, yielded negligible concentration of IL-1β in all samples (data not shown). An asterisk indicates a statistically significant difference between the patient and controls (independent samples t-test, P≤0.05).