Severe demyelination in a patient with a late infantile form of Niemann‐Pick disease type C

Abstract

Niemann-Pick disease type C (NPC) is a cholesterol storage disease caused by defective cellular cholesterol transportation. The onset and progression of NPC are variable, and autopsy findings have mainly been reported for the adult and juvenile forms of this disease. Here we report the clinical and pathological findings from a 9-year-old female patient with the late infantile form of NPC due to NPC1 gene mutation. She had notable splenomegaly at 4 months of age. She lost the ability to speak at 18 months of age. She learned to walk, but often fell and could no longer walk after 30 months. At 3 years of age, she was diagnosed with NPC. Sequence analysis of the NPC1 gene revealed compound heterozygous mutation of T2108C (F703S) and C2348G (S813X) (both novel). Thereafter, the patient suffered repeated respiratory infections and died of respiratory failure at 9 years of age. Pathological findings included cerebral atrophy (particularly of white matter), severe demyelination, and the loss of neurons from the cerebrum and from the nuclei of the brain stem. Remnant neuronal cells and microglia in the cerebrum, cerebellum, and brain stem had become swollen and foamy. Neurons of the hippocampal CA1 and Purkinje cells were relatively spared, and senile plaques and axonal spheroids were not present. Foamy cells were also observed in other organs, especially the spleen and bone marrow. The F703S mutation in this patient was localized in a sterol-sensing domain (SSD). Severe neurological phenotypes have been previously reported in patients with missense mutations in an SSD. It is considered that the combination of a nonsense mutation and missense mutation in an SSD was responsible for the severe neurological phenotype of our present patient. While pathological findings of adult/juvenile forms of NPC have included swollen neurons and glia, neuronal cell loss, and NFTs, demyelination may be a predominant finding in the infantile form of NPC.

Mass spectrometry imaging of lipids: untargeted consensus spectra reveal spatial distributions in Niemann-Pick disease type C1

“…6A). This observation is consistent with reduced myelin in NPC1 (58,59). Owing to the spatial resolution limits of our instrument, we are unable to localize intra-lysosomal storage in the Npc1 mutant animals.…”

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

“…Impaired removal of myelin debris by microglia can heavily compromise re-myelination upon injury (Cantuti-Castelvetri et al, 2018, Gabande-Rodriguez et al, 2018. Hypomyelination phenotype described in NPC mouse models and human patients has been mainly associated to a cell autonomous impairment of oligodendrocytes (Kodachi, Matsumoto et al, 2017, Qiao et al, 2018, Takikita et al, 2004, Weintraub et al, 1987, Weintraub et al, 1985, Yu & Lieberman, 2013. Our data reveal that at pre-symptomatic stage, when myelination process just started (Foran & Peterson, 1992), Npc1 -/microglia already show increased myelin uptake.…”

Modeling Niemann-Pick disease type C1 in zebrafish: a robust platform for in vivo screening of candidate therapeutic compounds

“…Specifically, the Purkinje neurons in the cerebellum of adult npc1 mutants were more diffuse than the Purkinje neurons in control fish, which were found in a compact layer surrounding the granular layer. Axonal spheroids and cerebellar Purkinje cell loss are neuropathological findings described in NPC1 patients and mammalian models ( Kodachi et al, 2017 ; Loftus et al, 1997 ; Maue et al, 2012 ; Miyawaki et al, 1982 ; Munana et al, 1994 ). Although some npc1 mutants can survive to adulthood, they did not reproduce.…”