{Reference Type}: Case Reports
{Title}: Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature.
{Author}: Zerbe CS;Marciano BE;Katial RK;Santos CB;Adamo N;Hsu AP;Hanks ME;Darnell DN;Quezado MM;Frein C;Barnhart LA;Anderson VL;Uzel G;Freeman AF;Lisco A;Nath A;Major EO;Sampaio EP;Holland SM;
{Journal}: Clin Infect Dis
{Volume}: 62
{Issue}: 8
{Year}: Apr 2016 15
{Factor}: 20.999
{DOI}: 10.1093/cid/civ1220
{Abstract}: <B>BACKGROUND: </B>Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs).<BR><B>METHODS: </B>STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed.<BR><B>RESULTS: </B>We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only.<BR><B>CONCLUSIONS: </B>The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.