Diagnostic value of plasma lysosphingolipids levels in a Niemann–Pick disease type C patient with transient neonatal cholestasis
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Abstract
Objectives
Niemann–Pick disease type C (NPC) is a lysosomal storage disease due to impaired intracellular lipid trafficking caused by biallelic pathogenic variants in NPC1 or NPC2 genes. NPC is classified according to the age of onset of neurological manifestations. Cholestatic liver disease can be transient or lead to liver failure. Accompanying neurological findings can be observed at any age. In this report, an infant with a homozygous pathogenic variant in NPC1 gene whose diagnosis was eventually confirmed by specific biomarkers is described.
Case presentation
A sixteen-day-old male was admitted to hospital with prolonged jaundice. He had mild hepatosplenomegaly, conjugated hyperbilirubinemia, elevated liver transaminases, and mild hypoalbuminemia. Cholestasis resolved spontaneously and patient was readmitted due to progressive hepatosplenomegaly without any neurologic findings when he was 8 months old. Molecular investigations detected homozygous c.1123A > C (p.Thr375Pro) pathogenic variant in NPC1 gene. NPC-specific lysosomal biomarkers such as Lysosphingomyelin and Lysosphingomyelin-509 were elevated, confirming the diagnosis.
Conclusions
The clinical features of NPC are highly heterogeneous, from disease severity or age of onset to disease progression. Patients presenting with transient neonatal cholestasis and should be regularly followed for neurodevelopmental status and visceromegaly. In the case of variants of unknown significance in NPC1 gene, lysosomal biomarkers play an important role when genetic analyses are inconclusive.
Acknowledgments
None.
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Research funding: None declared.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: The local Institutional Review Board deemed the study exempt from review.
References
1. Vanier, MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16. https://doi.org/10.1186/1750-1172-5-16.Search in Google Scholar PubMed PubMed Central
2. Vanier, MT, Gissen, P, Bauer, P, Coll, MJ, Burlina, A, Hendriksz, CJ, et al.. Diagnostic tests for Niemann-Pick disease type C (NP-C): a critical review. Mol Genet Metab 2016;118:244–54. https://doi.org/10.1016/j.ymgme.2016.06.004.Search in Google Scholar PubMed
3. Geberhiwot, T, Moro, A, Dardis, A, Ramaswami, U, Sirrs, S, Marfa, MP, et al.. International Niemann-Pick Disease Registry (INPDR). Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet J Rare Dis 2018;13:50. https://doi.org/10.1186/s13023-018-0785-7.Search in Google Scholar PubMed PubMed Central
4. Patterson, MC, Mengel, E, Wijburg, FA, Muller, A, Schwierin, B, Drevon, H, et al.. Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet J Rare Dis 2013;8:12. https://doi.org/10.1186/1750-1172-8-12.Search in Google Scholar PubMed PubMed Central
5. Wraith, JE, Guon, N, Rohrbach, M, Hwu, WL, Korenke, GC, Bembi, B, et al.. Natural history of Niemann-Pick disease type C in a multicentre observational retrospective cohort study. Mol Genet Metab 2009;98:250–4. https://doi.org/10.1016/j.ymgme.2009.06.009.Search in Google Scholar PubMed
6. Seker Yilmaz, B, Baruteau, J, Rahim, AA, Gissen, P. Clinical and molecular features of early infantile Niemann Pick type C disease. Int J Mol Sci 2020;21:5059. https://doi.org/10.3390/ijms21145059.Search in Google Scholar PubMed PubMed Central
7. Berry-Kravis, E. Niemann-Pick disease, type C: diagnosis, management and disease-targeted therapies in development. Semin Pediatr Neurol 2021;37:100879. https://doi.org/10.1016/j.spen.2021.100879.Search in Google Scholar PubMed
8. Sheth, J, Joseph, JJ, Shah, K, Muranjan, M, Mistri, M, Sheth, F. Pulmonary manifestations in Niemann-Pick type C disease with mutations in NPC2 gene: case report and review of literature. BMC Med Genet 2017;18:5. https://doi.org/10.1186/s12881-017-0367-x.Search in Google Scholar PubMed PubMed Central
9. Wheeler, S, Sillence, DJ. Niemann-Pick type C disease: cellular pathology and pharmacotherapy. J Neurochem 2020;153:674–92. https://doi.org/10.1111/jnc.14895.Search in Google Scholar PubMed
10. McKay Bounford, K, Gissen, P. Genetic and laboratory diagnostic approach in Niemann Pick disease type C. J Neurol 2014;261(Suppl 2):S569–75. https://doi.org/10.1007/s00415-014-7386-8.Search in Google Scholar PubMed PubMed Central
11. Giese, AK, Mascher, H, Grittner, U, Eichler, S, Kramp, G, Lukas, J, et al.. A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease. Orphanet J Rare Dis 2015;10:78. https://doi.org/10.1186/s13023-015-0274-1.Search in Google Scholar PubMed PubMed Central
12. Deodato, F, Boenzi, S, Taurisano, R, Semeraro, M, Sacchetti, E, Carrozzo, R, et al.. The impact of biomarkers analysis in the diagnosis of Niemann-Pick C disease and acid sphingomyelinase deficiency. Clin Chim Acta 2018;486:387–94. https://doi.org/10.1016/j.cca.2018.08.039.Search in Google Scholar PubMed
13. Maekawa, M, Jinnoh, I, Matsumoto, Y, Narita, A, Mashima, R, Takahashi, H, et al.. Structural determination of Lysosphingomyelin-509 and discovery of novel class lipids from patients with Niemann-Pick disease type C. Int J Mol Sci 2019;20:5018. https://doi.org/10.3390/ijms20205018.Search in Google Scholar PubMed PubMed Central
14. Maekawa, M, Iwahori, A, Mano, N. Biomarker analysis of Niemann-Pick disease type C using chromatography and mass spectrometry. J Pharm Biomed Anal 2020;30:113622. https://doi.org/10.1016/j.jpba.2020.113622.Search in Google Scholar PubMed
15. Konuş, OL, Ozdemir, A, Akkaya, A, Erbaş, G, Celik, H, Işik, S. Normal liver, spleen, and kidney dimensions in neonates, infants, and children: evaluation with sonography. AJR Am J Roentgenol 1998;171:1693–8. https://doi.org/10.2214/ajr.171.6.9843315.Search in Google Scholar PubMed
16. Grace, ME, Balwani, M, Nazarenko, I, Prakash-Cheng, A, Desnick, RJ. Type 1 Gaucher disease: null and hypomorphic novel chitotriosidase mutations-implications for diagnosis and therapeutic monitoring. Hum Mutat 2007;28:866–73. https://doi.org/10.1002/humu.20524.Search in Google Scholar PubMed
17. Topçu, M, Aktas, D, Öztoprak, M, Mungan, NÖ, Yuce, A, Alikasifoglu, M. Prospective Turkish Cohort Study to investigate the frequency of Niemann-Pick disease type C mutations in consanguineous families with at least one homozygous family member. Mol Diagn Ther 2017;21:643–51. https://doi.org/10.1007/s40291-017-0293-9.Search in Google Scholar PubMed
18. De Castro-Orós, I, Irún, P, Cebolla, JJ, Rodriguez-Sureda, V, Mallén, M, Pueyo, MJ, et al., Spanish NP-C Group. Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study. J Transl Med 2017;15:43. https://doi.org/10.1186/s12967-017-1146-3.Search in Google Scholar PubMed PubMed Central
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Articles in the same Issue
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- Review Article
- Impact of Obesity on Bone Metabolism in Children
- Mini Review
- Late sequelae of drug reaction with eosinophilia and systemic symptoms (DRESS) cause thyroid dysfunction and thyroiditis: review of literature
- Original Articles
- Moderating effect of bone maturation on the relationship between body fat and insulin resistance
- Prevalence of nephropathy in Indian children and youth with type 1 diabetes mellitus
- Initial neutrophil/lymphocyte and lymphocyte/monocyte ratios can predict future insulin need in newly diagnosed type 1 diabetes mellitus
- Subcutaneous adipose tissue is a positive predictor for bone mineral density in prepubertal children with Prader–Willi syndrome independent of lean mass
- The attitudes, experiences, and self-competencies of pediatric endocrinology fellows and attending physicians regarding diabetes technology: the Turkey experience
- Adiposity measures in screening for metabolic syndrome among Chinese children and adolescents
- Increased anxiety symptoms in pediatric type 1 diabetes during the acute phase of COVID-19 lockdown
- Pediatric adrenal insufficiency: thirty years experience at a Portuguese hospital
- Spectrum of PAH gene mutations and genotype–phenotype correlation in patients with phenylalanine hydroxylase deficiency from Turkey
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- Familial early-onset obesity in Turkish children: variants and polymorphisms in the melanocortin-4 receptor (MC4R) gene
- An update of the mutation spectrum of phenylalanine hydroxylase (PAH) gene in the population of Turkey
- Primary hypertriglyceridemia induced pancreatitis in a cohort of Pakistani children
- Investigation of the relationship between serum sclerostin and dickkopf-1 protein levels with bone turnover in children and adolescents with type-1 diabetes mellitus
- Case Reports
- Diagnostic value of plasma lysosphingolipids levels in a Niemann–Pick disease type C patient with transient neonatal cholestasis
- A 7-year-old boy with central diabetes insipidus presenting with thickened pituitary stalk and anti-rabphilin-3A antibody positivity
- Homozygous missense variant of PTH (c.166C>T, p.(Arg56Cys)) as the cause of familial isolated hypoparathyroidism in a three-year-old child
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Articles in the same Issue
- Frontmatter
- Review Article
- Impact of Obesity on Bone Metabolism in Children
- Mini Review
- Late sequelae of drug reaction with eosinophilia and systemic symptoms (DRESS) cause thyroid dysfunction and thyroiditis: review of literature
- Original Articles
- Moderating effect of bone maturation on the relationship between body fat and insulin resistance
- Prevalence of nephropathy in Indian children and youth with type 1 diabetes mellitus
- Initial neutrophil/lymphocyte and lymphocyte/monocyte ratios can predict future insulin need in newly diagnosed type 1 diabetes mellitus
- Subcutaneous adipose tissue is a positive predictor for bone mineral density in prepubertal children with Prader–Willi syndrome independent of lean mass
- The attitudes, experiences, and self-competencies of pediatric endocrinology fellows and attending physicians regarding diabetes technology: the Turkey experience
- Adiposity measures in screening for metabolic syndrome among Chinese children and adolescents
- Increased anxiety symptoms in pediatric type 1 diabetes during the acute phase of COVID-19 lockdown
- Pediatric adrenal insufficiency: thirty years experience at a Portuguese hospital
- Spectrum of PAH gene mutations and genotype–phenotype correlation in patients with phenylalanine hydroxylase deficiency from Turkey
- Serum spexin levels are not associated with size at birth but are associated with metabolic syndrome components in prepubertal children born at term
- Familial early-onset obesity in Turkish children: variants and polymorphisms in the melanocortin-4 receptor (MC4R) gene
- An update of the mutation spectrum of phenylalanine hydroxylase (PAH) gene in the population of Turkey
- Primary hypertriglyceridemia induced pancreatitis in a cohort of Pakistani children
- Investigation of the relationship between serum sclerostin and dickkopf-1 protein levels with bone turnover in children and adolescents with type-1 diabetes mellitus
- Case Reports
- Diagnostic value of plasma lysosphingolipids levels in a Niemann–Pick disease type C patient with transient neonatal cholestasis
- A 7-year-old boy with central diabetes insipidus presenting with thickened pituitary stalk and anti-rabphilin-3A antibody positivity
- Homozygous missense variant of PTH (c.166C>T, p.(Arg56Cys)) as the cause of familial isolated hypoparathyroidism in a three-year-old child
- Long-term follow-up of transient neonatal diabetes mellitus due to a novel homozygous c.7734C>T (p.R228C) mutation in ZFP57 gene: relapse at prepubertal age
