title: Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2.
abstract: This is the first description of slowly progressive Niemann-Pick disease type C (NPC) without the typical lysosomal storage in bone marrow and viscera in two descendants of a group of 17th century French-Canadians. The index patient was a married 43-year-old woman with onset of dementia in her thirties, later followed by the development of ataxia and athetoid movements. Her autopsy disclosed frontal lobe atrophy, neurolysosomal storage with oligolamellar inclusion and tau-positive neurofibrillary tangles. Of the 119 family members screened, only a married 42-year-old sister displayed symptoms of a dementia. Both women displayed vertical supranuclear ophthalmoplegia; expressive aphasia; concrete, stimulus-bound, perseverative behavior; and impaired conceptualization and planning. Cultured fibroblasts showed decreased cholesterol esterification and positive filipin staining, but no mutation was detected in coding or promoter regions of the NPC1 gene using conformation sensitive gel electrophoresis and sequencing. Sequencing showed a homozygous gene mutation that is predicted to result in an amino acid substitution, V39M, in the cholesterol binding protein HE1 (NPC2). Adult-onset NPC2 with lysosomal storage virtually restricted to neurons represents a novel phenotypic and genotypic variant with diffuse cognitive impairment and focal frontal involvement described for the first time.
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Regensburg School of Medicine, Universitatsstrasse 84, 93053 Regensburg, Germany. hans.kluenemann@bkr-regensburg.de
authors.forename: Hans H
authors.initials: HH
authors.lastname: Klünemann
authors.forename: Milan
authors.initials: M
authors.lastname: Elleder
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Kaminski
authors.forename: Karen
authors.initials: K
authors.lastname: Snow
authors.forename: Janis M
authors.initials: JM
authors.lastname: Peyser
authors.forename: John F
authors.initials: JF
authors.lastname: O'Brien
authors.forename: David
authors.initials: D
authors.lastname: Munoz
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
authors.forename: Helmfried E
authors.initials: HE
authors.lastname: Klein
authors.forename: William W
authors.initials: WW
authors.lastname: Pendlebury
mesh_terms: D000328:Adult; D001284:Atrophy / Q000235:genetics; D002352:Carrier Proteins; D005260:Female; D005625:Frontal Lobe / Q000473:pathology*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009542:Niemann-Pick Diseases / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; C104585:NPC2 protein, human; D033921:Vesicular Transport Proteins