title: Niemann-Pick disease type C1 predominantly involving the frontotemporal region, with cortical and brainstem Lewy bodies: an autopsy case.
abstract: Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lipid storage disorder. Two disease-causing genes (NPC1 and NPC2) have been identified. NPC is characterized by neuronal and glial lipid storage and NFTs. Here, we report a man with juvenile-onset progressive neurological deficits, including pyramidal signs, ataxia, bulbar palsy, vertical supranuclear ophthalmoplegia, and psychiatric symptoms; death occurred at age 37 before definitive clinical diagnosis. Post mortem gross examination revealed a unique distribution of brain atrophy, predominantly in the frontal and temporal lobes. Microscopically, lipid storage in neurons and widely distributed NFTs were observed. Lipid storage cells appeared in systemic organs and filipin staining indicated intracellular cholesterol accumulation in hepatic macrophages. Electron microscopy revealed accumulation of lipids and characteristic oligolamellar inclusions. These findings suggested an NPC diagnosis. Neuronal loss and gliosis were frequently accompanied by NFTs and occurred in the frontal and temporal cortices, hippocampus, amygdala, basal forebrain, basal ganglia, thalamus, substantia nigra and brain stem nuclei. Lewy bodies (LBs) were observed in most, but not all, regions where NFTs were evident. In contrast, neuronal lipid storage occurred in more widespread areas, including the parietal and occipital cortices where neurodegeneration with either NFTs or LBs was minimal. Molecular genetic analysis demonstrated that the patient had compound heterozygous mutations in the cysteine-rich loop (A1017T and Y1088C) of the NPC1 gene. To our knowledge there has been no previous report of the A1017T mutation. The pathological features of this patient support the notion that NPC has an aspect of α-synucleinopathy, and long-term survivors of NPC may develop a frontotemporal-predominant distribution of brain atrophy.
authors.affiliation: Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Chiba
authors.forename: Hiraku
authors.initials: H
authors.lastname: Komori
authors.forename: Shiro
authors.initials: S
authors.lastname: Takei
authors.forename: Sanae
authors.initials: S
authors.lastname: Hasegawa-Ishii
authors.forename: Noriko
authors.initials: N
authors.lastname: Kawamura
authors.forename: Kaori
authors.initials: K
authors.lastname: Adachi
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.forename: Masanori
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Enokido
authors.forename: Zen
authors.initials: Z
authors.lastname: Kouchi
authors.forename: Futoshi
authors.initials: F
authors.lastname: Yoshida
authors.forename: Atsuyoshi
authors.initials: A
authors.lastname: Shimada
mesh_terms: D000328:Adult; D001933:Brain Stem / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D002540:Cerebral Cortex / Q000473:pathology; D005625:Frontal Lobe / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016631:Lewy Bodies / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D013702:Temporal Lobe / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein
keywords: Lewy body; NPC1 gene; Niemann-Pick disease type C; frontotemporal atrophy; neurofibrillary tangle