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

• DOI: 10.1038/ejhg.2013.20
• Publication Date: 2013-02-27T11:23:08Z
• Authors: Cristina Dias; Allison McDonald; Murat Sincan; Rosemarie Rupps; Thomas Markello; Ramona Salvarinova; Rui F Santos; Kamal Menghrajani; Chidi Ahaghotu; Darren P Sutherland; Edgardo S Fortuno; Tobias R Kollmann; Michelle Demos; Jan M Friedman; David P Speert; William A Gahl; Cornelius F Boerkoel
• Keywords: Male; 0301 basic medicine; Inflammasomes; Interleukin-1beta; 610; interleukin-1 beta; 03 medical and health sciences; Fatal Outcome; 0302 clinical medicine; Recurrence; Humans; Exome; Child; Homeodomain Proteins; Homozygote; familial hemophagocytic lymphohistiocytosis; neurodegeneration; Infant, Newborn; Infant; Sequence Analysis, DNA; Magnetic Resonance Imaging; Pedigree; 3. Good health; Child, Preschool; Mutation; Ataxia; Female; exome sequencing; cerebellar white matter

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.