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New variants in Spanish Niemann–Pick type c disease patients


Niemann–Pick type C (NPC) disease is a rare inherited disease, with progressive neurodegeneration as the main symptom. It is a lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes, leading to a lysosomal cholesterol trafficking impairment. Disease indicators are the clinical suspicion and biomarker levels. However, a genetic study is mandatory for the diagnosis, which is complicated due to the different variants with unknown significance. The aim of this work was to identify the variants responsible for NPC in our pediatric population. Twenty-two samples from non-related infants believed to have NPC disease were analyzed during the last 3 years. Surrogate biomarkers of the disease were evaluated whenever possible. Sanger sequencing for both genes is reported for all samples. Complementary genetic studies were performed when necessary. NPC disease was confirmed in 31.8% of subjects due to homozygous or compound heterozygous genetic variants in NPC1. The following four novel variants were identified: a gross deletion variant composed of the gene promoter and the first exon, NM_000271.3:c.385delT, NM_000271.3:c.1553+1342_1655-291del, and NM_000271.3:c.1757delA. None had functional activity and all resulted in important structural changes in the protein.

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Acid sphingomyelinase deficiency


Chemokine (C–C motif) ligand 18/pulmonary and activation-regulated chemokine




Human gene mutation database




Lysosomal storage disease


Multiplex ligation-dependent probe amplification


National Center for Biotechnology Information


Niemann–Pick type C


Open reading frame


Protein data bank


Sterol-sensing domain


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The authors thank all the patients and physicians that provide us the samples.


There is no funding source.

Author information

LLF, Ph.D. designed, performed, and interpreted the Sanger sequencing studies, drafted the initial manuscript, and reviewed and revised the manuscript. JJC, Ph.D. performed part of the biomarker studies, performed and interpreted MLPA studies, and reviewed and revised the manuscript. LAE, M.D., Ph.D., SS, M.D., and AV, M.D., performed the clinical study and reviewed and revised the manuscript. CL coordinated and prepared sample matrices and reviewed and revised the manuscript. PI, Ph.D. performed the biomarker studies and critically reviewed the manuscript for important intellectual content. PG, Ph.D. performed clinical studies, confirmed and accepted the final reports, and reviewed and revised the manuscript. All authors approved of the final manuscript as submitted and agree to be accountable for all aspects of the work.

Correspondence to Laura López de Frutos.

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The authors declare that they have no conflict of interest.

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The study was conducted in accordance with the principles stated in the Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects, Helsinki, Finland, 1964, and as amended in Fortaleza, Brazil, 2013. The study design was approved by the institutional board of the FEETEG foundation.

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López de Frutos, L., Cebolla, J.J., Aldámiz-Echevarría, L. et al. New variants in Spanish Niemann–Pick type c disease patients. Mol Biol Rep (2020).

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  • New variants
  • Niemann–pick type C
  • NPC1
  • Pathogenic variants