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Phenotypic heterogeneity of Niemann–Pick disease type C in monozygotic twins

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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.

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Nothing to report.

Ethical standard

The procedures were approved by a local ethical standards committee on human experimentation.

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Authors and Affiliations

  1. Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy

    Alberto Benussi, Antonella Alberici, Enrico Premi, Alessandro Padovani & Barbara Borroni

  2. Neurology Unit, Valle Camonica Hospital, Brescia, Italy

    Valeria Bertasi, Maria Sofia Cotelli & Marinella Turla

  3. University Hospital “Santa Maria della Misericordia”, Udine, Italy

    Andrea Dardis & Stefania Zampieri

  4. Genetic Unit, University of Brescia, Brescia, Italy

    Eleonora Marchina

  5. Nuclear Medicine Unit, University of Brescia, Brescia, Italy

    Barbara Paghera

  6. Institute of Molecular Imaging and Physiology, National Research Council, Milan, Italy

    Francesca Gallivanone & Isabella Castiglioni

Authors
  1. Alberto Benussi
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  2. Antonella Alberici
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  3. Enrico Premi
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  4. Valeria Bertasi
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  5. Maria Sofia Cotelli
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  10. Barbara Paghera
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  11. Francesca Gallivanone
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  14. Barbara Borroni
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Correspondence to Barbara Borroni.

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Benussi, A., Alberici, A., Premi, E. et al. Phenotypic heterogeneity of Niemann–Pick disease type C in monozygotic twins. J Neurol 262, 642–647 (2015). https://doi.org/10.1007/s00415-014-7619-x

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  • DOI: https://doi.org/10.1007/s00415-014-7619-x

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