The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease

Abstract

Background: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups (“clinical niches”) have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes.

Methods: Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included.

Findings: Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches.

Conclusions: Several clinical niches have been identified that harbor patients at increased risk of NP-C.

Keywords:

• Niemann-Pick disease type C (NP-C)
• Diagnosis
• Screening
• Clinical niche
• Differential diagnosis
• Epidemiology
• Inborn errors of metabolism (IEM)

Transparency

Declaration of funding

This review was funded by Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.

Declaration of financial/other interests

From Actelion Pharmaceuticals Ltd.: travel expenses AC, AD, AP, CD-V, CJH, CL, HHK, MT, MW, MP, MS, PB, OB, SD, SL; research funding AP, CL, CD-V, CJH, FT-B, J-CC, MW, OB, PB, RI, SD, TD, TdK; consultancy fees AP, CJH, CL, HHK, MT, MW, OB, PB, SL; speaker honoraria CD-V, MP, MS, PB, SD. MA has received speaker honoraria and travel expenses from Abbvie, TEVA, and UCB. J-CC has received speaker honoraria from Abbvie, travel grants from Abbvie, research funding from, Ipsen, and the Michael J Fox Foundation, and consultancy fees from BMS, Zambon, Pfizer, Amarantus, Clevexel, and Abbvie. CD-V has received research grants, investigator fees, speaker honoraria, and travel expenses from Sanofi Genzyme, Orphan Europe, and Nutricia. SD has received research funding from TEVA. CJH is Director of FYMCA Medical Ltd., has received consultancy fees and travel expenses from Alexion, Amicus, Biomarin, Inventiva, Sanofi Genzyme, and Shire, and has undertaken paid research on behalf of Amicus, Biomarin, Sanofi Genzyme and Shire. SL has received consultancy fees and travel expenses from TEVA, Boehringer, Gruenenthal, and UCB6e. AP has received research funding, consultancy fees and travel expenses from Eli-Lilly, GE Health, and Lundbeck. CT has received speaker honoraria and travel expenses from Abbvie, Zambon, TEVA, and UCB. CV and SK are employees of Actelion Pharmaceuticals Ltd. TJ, PG and AT have no conflicts to declare.

Acknowledgments

Matthew Reilly PhD at InTouch Medical Ltd provided medical writing support in the preparation of this manuscript, paid for by Actelion Pharmaceuticals Ltd.