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Novel compound heterozygous mutation in NPC1 gene cause Niemann–Pick disease type C with juvenile onset

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Abstract

Niemann–Pick disease type C (NPC) is a progressive lysosomal storage disorder caused by mutations in the NPC1 (in 95% of cases) or NPC2 (in ~5% of cases) genes, inherited in an autosomal recessive manner. We report the case of a 38-year-old woman with learning disorder from her first year of schooling, and could notice slow progressed cognitive impairment, social withdrawal, apathy, handwriting alterations, deterioration of language skills and dysphagia. Brain magnetic resonance imaging showed severe cerebellar atrophy, hypoplasia of the corpus callosum, asymmetric lateral ventricular enlargement, and severe enlargement of frontal and parietal subarachnoid spaces. Next generation sequencing for NPC genes (NPC1 and NPC2) detected compound heterozygous mutations in NPC1 gene, including c.1553G > A (p.Arg518Gln), paternally inherited, and c.1270C > T (p.Pro424Ser) maternally inherited. The first mutation has been already described in literature and correlated to NPC, while the second mutation is still unknown. Moreover, filipin test and quantification of plasma oxysterols confirmed NPC diagnosis. We can suggest the missense mutation c.1270C > T (p.Pro424Ser) as a new causative mutation of NPC.

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References

  • Bagel J. H., Sikora T. U., Prociuk M., Pesayco J. P., Mizisin A. P., Shelton G. D. et al. 2013 Electrodiagnostic testing and histopathological changes confirm peripheral nervous system myelin abnormalities in the feline model of Niemann-Pick disease type C. J. Neuropathol. Exp. Neurol. 72, 256–262.

    Article  Google Scholar 

  • Benussi A., Cotelli M. S., Padovani A. and Borroni B. 2018 Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC. F1000Res. 7, 194.

  • Esposito M., Dubbioso R., Tozza S., Iodice R., Aiello M., Nicolai E. et al. 2019 In vivo evidence of cortical amyloid deposition in the adult form of Niemann Pick type C. Heliyon 5, e02776.

    Article  Google Scholar 

  • Evans W. R. and Hendriksz C. J. 2017 Niemann-Pick type C disease - the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment. BJPsych. Bull. 41, 109–114.

    Article  Google Scholar 

  • Geberhiwot T., Moro A., Dardis A., Ramaswami U., Sirrs S., Marfa M. P. et al. 2018 Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet. J. Rare Dis. 13, 50.

    Article  Google Scholar 

  • Imrie J., Heptinstall L., Knight S. and Strong K. 2015 Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database. BMC Neurol. 15, 257.

    Article  Google Scholar 

  • Iodice R., Dubbioso R., Topa A., Ruggiero L., Pisciotta C., Esposito M. et al. 2015 Electrophysiological characterization of adult-onset Niemann-Pick type C disease. J. Neurol. Sci. 348, 262–265.

    Article  Google Scholar 

  • Jiang X., Sidhu R., Porter F. D., Yanjanin N. M., Speak A. O., te Vruchte D. T. et al. 2011 A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma. J. Lipid Res. 52, 1435–1445.

    Article  CAS  Google Scholar 

  • Kawazoe T., Yamamoto T., Narita A., Ohno K., Adachi K., Nanba E. et al. 2018 Phenotypic variability of Niemann-Pick disease type C including a case with clinically pure schizophrenia: a case report. BMC Neurol. 18, 117.

    Article  Google Scholar 

  • Koens L. H., Kuiper A., Coenen M. A., Elting J. W., de Vries J. J., Engelen M. et al. 2016 Ataxia, dystonia and myoclonus in adult patients with Niemann-Pick type C. Orphanet J. Rare Dis. 11, 121.

    Article  CAS  Google Scholar 

  • Manganelli F., Dubbioso R., Iodice R., Topa A., Dardis A., Russo C.V. et al. 2014 Central cholinergic dysfunction in the adult form of Niemann Pick disease type C: a further link with Alzheimer’s disease?. J. Neurol. 261, 804–808.

    Article  CAS  Google Scholar 

  • Nadjar Y., Hütter-Moncada A. L., Latour P., Ayrignac X., Kaphan E., Tranchant C. et al. 2018 Adult Niemann-Pick disease type C in France: clinical phenotypes and long-term miglustat treatment effect. Orphanet. J. Rare Dis. 13, 175.

    Article  Google Scholar 

  • Pineda M., Walterfang M. and Patterson MC. 2018 Miglustat in Niemann-Pick disease type C patients: a review. Orphanet J. Rare Dis. 13, 140.

    Article  Google Scholar 

  • Pineda M., Juríčková K., Karimzadeh P., Kolnikova M., Malinova V., Insua J. L. et al. 2019 Disease characteristics, prognosis and miglustat treatment effects on disease progression in patients with Niemann-Pick disease Type C: an international, multicenter, retrospective chart review. Orphanet. J. Rare Dis. 14, 32.

    Article  Google Scholar 

  • Polese-Bonatto M., Bock H., Farias A. C. S., Mergener R., Matte M. C., Gil M. S. et al. 2019 Niemann-Pick Disease Type C: mutation spectrum and novel sequence variations in the human NPC1 Gene. Mol. Neurobiol. 56, 6426–6435.

    Article  CAS  Google Scholar 

  • Rego T., Farrand S., Goh A. M. Y., Eratne D., Kelso W., Mangelsdorf S. et al. 2019 Psychiatric and cognitive symptoms associated with Niemann-Pick type C disease: Neurobiol. Manage. CNS Drugs 33, 125–142.

    Article  Google Scholar 

  • Sobrido M. J., Bauer P., de Koning T., Klopstock T., Nadjar Y., Patterson M. C. et al. 2019 Recommendations for patient screening in ultra-rare inherited metabolic diseases: what have we learned from Niemann-Pick disease type C? Orphanet. J. Rare Dis. 14, 20.

    Article  Google Scholar 

  • Sun A. 2018 Lysosomal storage disease overview. Ann. Transl. Med. 6, 476.

    Article  CAS  Google Scholar 

  • Takamura A., Sakai N., Shinpoo M., Noguchi A., Takahashi T., Matsuda S. et al. 2013 The useful preliminary diagnosis of Niemann-Pick disease type C by filipin test in blood smear. Mol. Genet. Metab. 110, 401–404.

    Article  CAS  Google Scholar 

  • Winstone A. M., Stellitano L. A. and Verity C. M. 2017 Niemann-Pick type C as a cause of progressive intellectual and neurological deterioration in childhood. Dev. Med. Child Neurol. 59, 965–972.

    Article  Google Scholar 

  • Vanier M. T. 2010 Niemann-Pick disease type C. Orphanet. J. Rare Dis. 5, 16.

    Article  Google Scholar 

  • Zhang H., Wang Y., Lin N., Yang R., Qiu W., Han L. et al. 2014 Diagnosis of Niemann-Pick disease type C with 7-ketocholesterol screening followed by NPC1/NPC2 gene mutation confirmation in Chinese patients. Orphanet. J. Rare Dis. 9, 82.

    Article  CAS  Google Scholar 

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Acknowledgments

Special acknowledgements for this paper are due to Mrs Eleonora Di Fatta for her valuable assistance in the translation and preparation of the text, Dr Andrea Dardis for performing oxysterols assay and Filipin test, and the Lab technicians Angelo Gloria, Valeria Chiavetta and Rosanna Galati for their precious help in performing the analysis. This work has been partially supported by the Italian Ministry of Health – Ricerca Corrente 2017 funds.

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Authors and Affiliations

  1. Oasi Research Institute – IRCCS, 94018, Troina, Italy

    Maria Cristina Costanzo, Antonio Gennaro Nicotera, Mirella Vinci, Aurelio Vitello, Francesco Calì & Sebastiano Antonino Musumeci

  2. Child Neuropsychiatry Unit, Department of Human Pathology of the Adult and Developmental Age, University of Messina, 98125, Messina, Italy

    Antonio Gennaro Nicotera

  3. Regional Referral Centre for Inborn Errors Metabolism, Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Catania, 95123, Catania, Italy

    Agata Fiumara

Authors
  1. Maria Cristina Costanzo
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  2. Antonio Gennaro Nicotera
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  3. Mirella Vinci
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  4. Aurelio Vitello
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  5. Agata Fiumara
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  6. Francesco Calì
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  7. Sebastiano Antonino Musumeci
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Correspondence to Antonio Gennaro Nicotera.

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Corresponding editor: H. A. Ranganath

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Costanzo, M.C., Nicotera, A.G., Vinci, M. et al. Novel compound heterozygous mutation in NPC1 gene cause Niemann–Pick disease type C with juvenile onset. J Genet 99, 30 (2020). https://doi.org/10.1007/s12041-020-01198-7

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  • DOI: https://doi.org/10.1007/s12041-020-01198-7

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