Neurologic symptoms including a left VI nerve palsy, facial numbness, diplopia, nystagmus, hyperreflexia, and cognitive impairment rapidly progressed. biopsy (Number ?(Number11infection in her 30s. At the age of 2 years he had mouth sores, which healed slowly. A chorioretinal scar in the remaining eye was thought to be due to congenital toxoplasmosis. At around age 12 years he had recurrent pneumonias and oral candidiasis. At age 19 years a staphylococcal empyema required drainage. Subsequently, a Chlorothiazide chilly agglutinin hemolytic anemia was treated with prednisone, followed by rituximab with resolution. Approximately 2 weeks later on he noticed ideal arm and ideal lower leg weakness, slight aphasia, and dysarthria. MRI showed demyelination in bilateral thalami, midbrain, cerebellar peduncle, and remaining cerebellar hemisphere. Lumbar puncture was positive for JCV by PCR. He had low CD19, CD3, CD4, and CD8 cells. Immunoglobulin levels were low despite alternative. Sequencing of STAT1 recognized the previously identified GOF heterozygous mutation c.1154C T, p.T385M in the DNA binding website [4, 7]. Cerebral spinal fluid (CSF) JC viral weight after 8 weeks of therapy was 27 049 copies/mL and increased to 87 562 copies/mL. MRI showed considerable white matter damage with neuronal death. Neither mirtazapine nor IFN- led to improvement, and he died of aspiration pneumonia. No autopsy was performed. Family members were not screened. Patient 3 was a 32-year-old Hispanic man whose father experienced CMC. He had had recurrent thrush, onychomycosis, warts, and pores and skin ulcers since infancy and developed his 1st pneumonia at age 11 months. At age 14 years he had a pneumonia that resolved with surgery and antibiotics. He had prolonged lymphopenia and at age 24 years developed progressive ataxia with cerebellar atrophy, hepatosplenomegaly, and transient pancytopenia. CD19-, CD3-, and CD4-positive cells were persistently low, but CD8+ cells and immunoglobulins were normal. Bone marrow biopsy showed normal cellularity with slight erythrocytosis. STAT1 sequencing recognized the identified GOF heterozygous mutation c.821G A, p.R274Q in the coiled-coil website . MRI showed a large enhancing lesion in the Chlorothiazide remaining frontal and parietooccipital lobes; in situ hybridization in mind biopsy confirmed JCV. He died within 3 months of analysis. No autopsy was performed. Family members were screened and unaffected. L400Q Prospects to Enhanced IFN-CDriven Response To assess the practical impact of the new mutation explained for patient 1, we examined mutant pSTAT1 Chlorothiazide in comparison with WT STAT1 response. Similar to the previously explained STAT1 GOF mutants, transfection of STAT1 L400Q into the STAT1-deficient U3C cell collection resulted in enhanced pSTAT1 upon activation with IFN- and IFN- for 30 minutes (Number ?(Number22and test. * .05. Abbreviations: GAS, gamma triggered sequence; MFI, mean fluorescence intensity; NS, not stimulated. Review of the Literature Our literature review recognized 26 articles in which instances of syndromic or genetically defined PIDs were associated with PML. All cases, including the individuals reported here, are summarized in Table ?Table1.1. Many of the explained LTBP1 instances (12 of 26) experienced clear clinical features of PID but no molecular analysis, with combined and severe immunodeficiencies becoming more prominent. Table 1. Published Case Reports of Progressive Multifocal Leukoencephalopathy Associated With Main Immunodeficiencies sepsis; pneumococcal pneumonia; malabsorption syndrome; schizophreniaIVIG steroidsAutopsyNoneZu Rhein et al 1978 Severe combined immunodeficiency; no molecular diagnosisM/112n/aNoneAutopsyNoneMisbah et al 1992 Combined immunodeficiency; no molecular diagnosisM/244Warts; bronchiectasis; recurrent otitisNoneCerebellar biopsyNoneRedfearn et al 1993 Hyper IgM syndrome; no molecular diagnosisM/69Recurrent pneumonia; pneumococcal sepsisIVIG since 3 yCSF; mind biopsyCytosine arabinosideKatz et al 1994 Wiskott-Aldrich syndrome; no molecular diagnosisM/1510Candida sepsis; recurrent herpes; pneumonia; liver abscessNoneBrain biopsyIFN- intrathecalMatsushima et al 1997 Wiskott-Aldrich syndrome;a no molecular diagnosisM/36n/aIdiopathic thrombocytopenic purpura; atopic dermatitis; tuberculosisNoneBrain Chlorothiazide biopsySteroids, -globulinJochum et al 1997 Adenosine deaminase deficiency; no molecular diagnosisF/39n/an/an/aBrain biopsyn/aBezrodnik et al 1998 Hyper IgM syndrome; no molecular diagnosisM/536 (alive)PML was first manifestationNoneStereotactic mind biopsyCytosine arabinoside (IV and intrathecal)sepsis)Recurrent ear infections; esophagitis; disseminated histoplasmosisNoneBrain biopsy in situ hybridizationIL-2G Day-Williams et al 2015 DOCK8 (large deletions in chromosome 9p)M/3024.