Fatal JC-virus Granular Cerebellar Neuronopathy associated with Autoimmune Lymphoproliferative Syndrome and Common Variable Immunodeficiency

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Background: JC-virus (JCV) associated granular cerebellar neuronopathy (JCV-GCN), which causes severe ataxia, is a rare complication of severe immunodeficiency and caused by a variant of JCV with a VP1-deletion. JCV-GCN has not yet been reported in patients with autoimmune lymphoproliferative syndrome (ALPS-FAS). We report a 34-year old woman with autoimmune lymphoproliferative syndrome (ALPS-FAS) and common variable immunodeficiency (CVID) who developed JCV-GCN which progressed to fatal progressive multifocal leukoencephalopathy (PML).Methods: Extensive longitudinal virologic, genetic and immunologic characterisation by JCV CSF quantification and sequencing, peripheral blood flowcytometry and exome sequencing. Results: A diagnosis of JCV-GCN was established by findings of severe cerebellar vermis atrophy on MRI and a JCV variant with a VP1-deletion (JCV-VP1) in CSF. During a period of 18 months, at which treatment with high dose immunoglobulin, cidofovir, mirtazapine and high dose fucidic acid were given, cerebellar ataxia was relatively stable. In CSF a mixture of predominantly JCV-VP1 with only low levels of wildtype JCV was found. However, classic PML ensued, with rising JCV- CSF levels and a complete change to JCV-wildtype quasi species without JCV-VP1. Immunological findings were unusual, with disappearance of the original ALPS-FAS phenotype. Trio-exome sequencing identified a heterozygote de novo variant of unknown significance in RAG1. FAS mutations were not detected in the patient or in the parents, suggesting that her previously diagnosed ALPS-FAS-FAS was caused by somatic mosaicism. At the progression to PML, increased expression of T-cell PD-1 was demonstrated, suggesting T-cell exhaustion. Treatment with pembrolizumab, an inhibitor of PD-1, was attempted but followed by rapid and fatal PML progression. Conclusion: JCV-GCN may complicate ALPS and may progress to PML. In JCV-GCN, wild-type and JCV-VP-1 can co-exist in CSF. Quantification and sequencing of JCV in CSF is helpful to characterize and monitor disease and treatment. Progression of disease may be associated with development of T-cell exhaustion, but the benefit PD-1 inhibitor treatment is uncertain.