Objective: Clinical, neuroimaging, genetic and biochemical characterization of a patient with a PSP-like phenotype carrying a splicing mutation in NPC2.

Background: Niemann-Pick type C disease (NPC) is an autosomal recessive, lysosomal storage disorder resulting from mutations in either the NPC1 or NPC2 genes. The heterogeneous clinical presentation of late-onset NPC overlaps with diverse neuropsychiatric and movement disorders, hampering its diagnosis. It is debated whether heterozygous NPC mutations can cause atypical forms of the disease or confer susceptibility to dementia, parkinsonism and other movement disorders.

Methods: Clinical history, neurological and general examination, family history, brain MRI, FDG-PET scan, neuropsychological assessment. Screening of mutations in NPC1 and NPC2 was performed through targeted next generation sequencing. Filipin staining was carried out on cultured fibroblasts.

Results: A 65-year-old woman presented with behavioral changes and progressive gait disorder starting in the sixth decade. She had an akinetic-rigid syndrome with hoarse voice, left arm dystonia, retrocollis, dysphagia and vertical supranuclear gaze palsy. Neurocognitive exam revealed frontal executive dysfunction. MRI showed cortical and brainstem atrophy, enlarged ventricles, thinned corpus callosum and scattered white matter hyperintensities. On FDG-PET there was severely decreased metabolism in perisylvian regions associated with the cortical atrophy, and relative hypometabolism in the anterior frontal cortex. A splicing variant in NPC2, c.441+1G>A, was detected in heterozygous state. This variant is rare in the general population (<1%) and has been reported before in patients with a suspicion of NPC. Plasma chitotridosidase and beta-glucosidase levels were normal. Staining with the cholesterol binding reagent filipin showed an intermediate pattern of intracellular cholesterol trafficking. Treatment with miglustat was initiated.

Conclusions: NPC is a treatable neurometabolic disease that must be considered in the differential diagnosis of adult onset movement disorders. Although the pathogenic role of the c.441+1G>A variant has not been fully demonstrated, it affects alternative splicing of NPC2 in vitro. Heterozygous NPC mutations may contribute to late-onset neurodegenerative manifestations of the FTD-Parkinsonism spectrum. Further investigation of NPC1/NPC2 mutations and abnormalities of lipid metabolism is needed in FTD-P and PSP.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-heterozygous-splicing-variant-in-npc2-in-a-patient-with-psp/