The Spectrum of Niemann-Pick Type C Disease in Greece

Abstract

Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2 genes. We present the clinical, biochemical, and molecular findings in 14 cases diagnosed in Greece during the last 28 years. Age at diagnosis ranged from 2.5 months to 48 years. Systemic manifestations were present in 7/14 patients. All developed neurological manifestations (age of onset 5 months to 42 years). Six patients are still alive (age: 5–50 years). Classical filipin staining pattern was observed in all but four patients (3 NPC1, 1 NPC2). The rate of LDL-induced cholesteryl ester formation was severely reduced in 4/7 and significantly reduced in 3/7 patients studied. Increased chitotriosidase activity was observed in 9/12 patients. Mutation analysis in 11 unrelated patients identified 12 different mutations in the NPC1 gene: eight previously described p.E1089K (c.3265G>A), p.F284Lfs*26 (c.852delT), p.A1132P(c.3394G>C), del promoter region and exons 1-10, p.R1186H (c.3557G>A), p.P1007A (c.3019C>G), p.Q92R(c.275A>G),p.S940L (c.2819C>T), and four novel ones: (p.N701K fs*13 (c.2102-2103insA), p.K1057R (c.3170A>G), IVS23+3insT(c.3591+3insT), p.C1119*(c.3357T>C); and the previously described IVS2+5G>A(c.190+5G>A) mutation in the NPC2 gene. All patients were of Greek origin. Assuming a birth rate of 100,000/year, a rough incidence estimate for NPC disease in Greece would be 0.5/100,000 births.

Athina Xaidara was deceased at the time of publication.

Appendices

Take Home Message

In 13 NPC1 and 1 NPC2 patients we identified 13 different mutations (4 novel) and ten genotypes; classical filipin staining was observed in eight patients.

Contribution of Individual Authors

Mavridou I.: Fibroblast cultures; filipin staining; mutation analysis by PCR; writing of the paper

Dimitriou E.: Assay of chitotriosidase activity

Vanier MT: Filipin staining; LDL-induced cholesteryl ester formation test; writing of the paper

Vilageliu L., Grinberg D.: Mutation analysis by DNA sequencing, writing of the paper

Latour P: Mutation analysis by DNA sequencing

Xaidara A, Lycopoulou L, Bostantjopoulou S, Zafeiriou D: Attending physicians

Michelakakis H: Coordinated the study; writing of the paper

Guarantor: Helen Michelakakis PhD

Conflict of Interest

MT Vanier has received honoraria and travel reimbursements from Actelion Phamaceuticals Ltd. as a member of advisory committees and speaking engagements, as well as honoraria from Shire for participating in a DSM Board. D. Zafeiriou has received research and travel grants, as well as honoraria for lecturing and participating at Advisory Boards from Genzyme-Sanofi, Shire, Actelion and Biomarin. H. Michelakakis has received honoraria and travel reimbursements from Genzyme-Sanofi, Actelion, research grant from Actelion. E. Dimitriou has received travel reimbursements from Genzyme-Sanofi and Shire. I. Mavridou has received travel reimbursement from Genzyme-Sanofi, Actelion, and Shire.

The study was approved by the Ethics Committee of the Institute of Child Health.

Vilageliu L. and Grinberg D. received funding from the Spanish Ministry of Science and Innovation (SAF2011-25431, SAF2014-56562-R) and from the Catalan Government (2014SGR932).