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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

Molecular Diagnosis & Therapy volume 21, pages 643–651 (2017)Cite this article

Abstract

Background

Niemann-Pick disease Type C (NP-C) is a rare, autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. Diagnosis of NP-C can be challenging and is frequently delayed. Identifying mutations in individuals with NP-C and their relatives enables genetic counseling and prenatal diagnosis and may support earlier diagnosis. Here we report findings from a prospective cohort study in Turkey, using targeted genetic screening of the families of NP-C probands with homozygous NPC1 or NPC2 mutations.

Methods

Probands were selected from a Turkish National Registration Database. Probands had confirmed diagnosis based on NPC1 or NPC2 mutations, with clear indication for consanguineous, homozygous inheritance. Family members were identified from interviews and pedigree analysis. Genetic analysis was performed on DNA from peripheral blood samples from all subjects.

Results

Four probands and 510 individuals from the four families were included. In these four families, the overall NPC1 or NPC2 heterozygous mutation frequency was 22.7%. A novel mutation was identified in NPC1 (p.T375P; c.1123A>C). A previously described NPC2 mutation (p.E118X; c.352G>T) was also observed in two families from different regions of Turkey. We identified two new patients with NP-C from two families.

Conclusions

This is the largest screening study conducted to date in Turkey in the families of patients with NP-C with homozygous inheritance. We have reported heterozygote frequencies, identified a novel mutation, and detected new patients with NP-C. These findings will aid our understanding of NP-C and may lead to improved recognition and more timely diagnosis.

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Acknowledgements

We are grateful for the collaboration of our patients and their families. Medical writing assistance was provided by Rachel Kendrick and Jennifer Mayes of Fishawack Communications GmbH, and was funded by Actelion Pharmaceuticals Ltd.

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Affiliations

  1. Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Sıhhıye, 06100, Ankara, Turkey

    Meral Topçu & Merih Öztoprak

  2. Department of Medical Genetics, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Dilek Aktas & Mehmet Alikasifoglu

  3. DAMAGEN Genetic Diagnostic Center, Ankara, Turkey

    Dilek Aktas & Mehmet Alikasifoglu

  4. Department of Pediatric Metabolism and Nutrition, Çukurova University Faculty of Medicine, Adana, Turkey

    Neslihan Önenli Mungan

  5. Division of Pediatric Gastroenterology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Aysel Yuce

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  1. Meral Topçu
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Contributions

MT, MÖ, NÖM, and AY were responsible for the clinical examination of patients. DA and MA conceived and designed the molecular biological experiments. DA visited families and collected peripheral blood samples. DA and MA performed NPC1 and NPC2 gene analysis. MT, MÖ, NÖM, AY, MA, and DA co-wrote the manuscript. DA and MT revised the manuscript critically for intellectual content. All authors read and approved the final manuscript for submission.

Corresponding author

Correspondence to Meral Topçu.

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Conflict of interest

This study was supported by Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. MT has received honoraria from Actelion Pharmaceuticals Ltd. All other authors declare that they have no competing interests.

Availability of data and materials

The data supporting the conclusions of this article are included within the article. Any additional genetic data from the subjects are confidential and will not be made available, unless required by law or regulatory authorities for the purpose of verifying information obtained from this study.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all subjects themselves and/or their legal guardians. Prior to commencement of the study, participating physicians obtained approval of the informed consent form from the Research Ethics Board at the Ethics Committee of Hacettepe University and were in compliance with applicable site policies, national privacy regulations, and other state and local laws relating to medical information, as required.

Funding statement

MT has received honoraria from Actelion Pharmaceuticals Ltd. Medical writing assistance was funded by Actelion Pharmaceuticals Ltd.

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Topçu, M., Aktas, D., Öztoprak, M. et al. 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 21, 643–651 (2017). https://doi.org/10.1007/s40291-017-0293-9

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