Reactivation of a dormant infection with the John Cunningham virus (JCV) can lead to the rare neurologic disorders progressive multifocal leukoencephalopathy (PML) and granule cell neuronopathy (GCN), a cerebellar syndrome with progressing cerebellar atrophy. 1 Here, we present a case of infratentorial PML with concomitant GCN in extended interval dosing (EID) of natalizumab associated with a novel mutation at 7th position after the C-terminus of viral capsid protein VP1 in addition to the common noncoding regulatory region (NCRR) mutation. Case report In March 2018, a 65-year-old woman presented with progressive symptoms of holocephalic headache, dizziness, nausea, and psychomotor slowing as well as balance difficulties and left hemibody weakness that started 2 weeks before admission. Her medical history was significant for relapsing-remitting MS initially diagnosed in 2000 with mild residual right-sided weakness. Because of the side effects of previous disease modifying therapy with interferons (flu-like symptoms) and glatiramer acetate (injection site reactions), natalizumab treatment was initiated in August 2010 and discontinued in March 2014 in light of her initial positive anti-JCV serostatus. Owing to the gastrointestinal side effects of subsequent therapy with teriflunomide and dimethyl fumarate (short treatment duration without associated lymphopenia), natalizumab therapy was reinitiated in August 2015 and infusion frequency was changed to EID (initially every 8 weeks, then every 6 weeks) for >2 years before the symptom onset. On admission, mild tetraparesis (4/5) more evident on the left, diffuse 3+ hyperreflexia, positive bilateral Babinski reflexes, and impaired balance with inability to walk were present. Initially observed left-sided hemiataxia evolved into bilateral dysmetria pronounced on the left. MRI of the brain showed abnormal T2/fluid-attenuated inversion recovery hyperintensities in bilateral cerebellar hemispheres with extension into the left middle cerebellar peduncle and the cerebellar atrophy (figure). The patient's most recent anti-JCV antibody indices (Quest Diagnostics, San Juan Capistrano, CA) were 3.32 (July 2016) and 3.42 (October 2017). Her absolute lymphocyte count ranged between 2.18-5.24 × 10 3 /μL. JCV multiplex quantitative PCR analysis performed by the NIH was positive for 1,156 copies/mL in the CSF and 1,070 copies/mL in plasma of the NCRR variant most commonly associated with PML. 2 VP1 mutational analysis of the patient's plasma and CSF (supplementary material 1, links.lww.com/NXG/A250) did not show previously published common mutations at positions L55, K60, S61, D66, S267/S269, or Q271 nor in the C-terminus. However, a novel mutation at 7th position after VP1 C-terminus was detected in the patient's
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