title: 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.
authors: 1] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada [2] Genetics and Health Cluster, Child and Family Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada.
authors: Cristina
authors: C
authors: Dias
authors: Allison
authors: A
authors: McDonald
authors: Murat
authors: M
authors: Sincan
authors: Rosemarie
authors: R
authors: Rupps
authors: Thomas
authors: T
authors: Markello
authors: Ramona
authors: R
authors: Salvarinova
authors: Rui F
authors: RF
authors: Santos
authors: Kamal
authors: K
authors: Menghrajani
authors: Chidi
authors: C
authors: Ahaghotu
authors: Darren P
authors: DP
authors: Sutherland
authors: Edgardo S
authors: ES
authors: Fortuno
authors: Tobias R
authors: TR
authors: Kollmann
authors: Michelle
authors: M
authors: Demos
authors: Jan M
authors: JM
authors: Friedman
authors: David P
authors: DP
authors: Speert
authors: William A
authors: WA
authors: Gahl
authors: Cornelius F
authors: CF
authors: Boerkoel
mesh_terms: D001259:Ataxia / Q000235:genetics* / Q000821:virology*; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012008:Recurrence; D017422:Sequence Analysis, DNA
chemical_list: D018398:Homeodomain Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C082157:PRRX1 protein, human