title: Phenotypic heterogeneity of Niemann-Pick disease type C in monozygotic twins.
abstract: We report the case of Niemann-Pick disease type C with extensive phenotypic heterogeneity in two monozygotic twins. One of the twins presented with a history of obsessive-compulsive disorder and slowly progressive inferior limb clumsiness, dysphagia and dysarthria. Neurological examination revealed a broad-based ataxic gait, limb dysmetria, downward vertical gaze palsy, brisk lower limb reflexes and ankle clonus, while neuropsychological assessment revealed global cognitive deficits in multiple domains. Complete neurological and neuropsychological evaluation in the asymptomatic monozygotic twin brother only revealed mild neurological impairment. In the hypothesis of Niemann-Pick disease type C, Filipin test, measurement of plasma oxysterols levels and genetic analysis were carried out in both twins. Filipin staining showed massive intracellular accumulation of non-esterified cholesterol, plasma oxysterols levels were elevated and genetic analysis revealed a homozygous c.2662 C > T (p.P888S) mutation in the NPC1 gene (18q11.2) in both twins. 18F-FDG-PET imaging with single-subject analysis revealed a reduced frontal and temporal glucose metabolism, which correlated with disease progression. This case supports the phenotypic variability of Mendelian inherited disorders in monozygotic twins, likely due to epigenetic differences and post-zygotic mutagenesis.
authors.affiliation: Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Benussi
authors.forename: Antonella
authors.initials: A
authors.lastname: Alberici
authors.forename: Enrico
authors.initials: E
authors.lastname: Premi
authors.forename: Valeria
authors.initials: V
authors.lastname: Bertasi
authors.forename: Maria Sofia
authors.initials: MS
authors.lastname: Cotelli
authors.forename: Marinella
authors.initials: M
authors.lastname: Turla
authors.forename: Andrea
authors.initials: A
authors.lastname: Dardis
authors.forename: Stefania
authors.initials: S
authors.lastname: Zampieri
authors.forename: Eleonora
authors.initials: E
authors.lastname: Marchina
authors.forename: Barbara
authors.initials: B
authors.lastname: Paghera
authors.forename: Francesca
authors.initials: F
authors.lastname: Gallivanone
authors.forename: Isabella
authors.initials: I
authors.lastname: Castiglioni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
mesh_terms: D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000503:physiopathology*; D010375:Pedigree; D010641:Phenotype; D049268:Positron-Emission Tomography; D014430:Twins, Monozygotic; D055815:Young Adult
chemical_list: D019788:Fluorodeoxyglucose F18