Abstract
BackgroundNiemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C–C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C.MethodsIn a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered ‘suspected NP-C’ cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible.ResultsIn total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients.ConclusionThis approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis.
Highlights
Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes
We evaluated whether plasma ChT activity and CCL18/pulmonary and activation-regulated chemokine (PARC) concentration might complement clinical assessments for the identification of patients who should undergo further, specific testing for NP-C
In Period 2, which ran from May 2012 to April 2014, ChT activity, CCL18/PARC concentration and NP-C suspicion index (NP-C SI) scores were analyzed in all patients, and NPC1/NPC2 sequencing was performed only in those who had elevated ChT and CCL18/PARC values, and/or an NP-C SI score ≥70
Summary
Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-spe‐ cific, heterogeneous nature of signs/symptoms. The diagnosis of NP-C remains challenging as neurological signs of the disease are extremely varied in terms of severity and age at onset [1, 4]. Patients with very early-onset disease are detected and diagnosed based on pronounced visceral symptoms such as prolonged neonatal jaundice, fetal hydrops and/or ascites [1, 5]. Visceral symptoms can appear long before neurological signs and often go unrecognized, in those with adolescent/adultonset disease [1, 4]
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