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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.
AuthorsAlberto Benussi, Antonella Alberici, Enrico Premi, Valeria Bertasi, Maria Sofia Cotelli, Marinella Turla, Andrea Dardis, Stefania Zampieri, Eleonora Marchina, Barbara Paghera, Francesca Gallivanone, Isabella Castiglioni, Alessandro Padovani, Barbara Borroni
JournalJournal of neurology (J Neurol) Vol. 262 Issue 3 Pg. 642-7 (Mar 2015) ISSN: 1432-1459 [Electronic] Germany
PMID25536905 (Publication Type: Case Reports, Journal Article, Twin Study)
Chemical References
  • Fluorodeoxyglucose F18
Topics
  • Brain (pathology)
  • DNA Mutational Analysis
  • Female
  • Fluorodeoxyglucose F18
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Niemann-Pick Disease, Type C (genetics, physiopathology)
  • Pedigree
  • Phenotype
  • Positron-Emission Tomography
  • Twins, Monozygotic
  • Young Adult

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