title: 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.
  
  
  RESULTS
  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.
authors.affiliation: a Salford Royal NHS Foundation Trust , Manchester , UK.|b University of Pretoria , Pretoria , South Africa.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Hendriksz
authors.affiliation: c University of Strasbourg , Hautepierre Hospital , Strasbourg , France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.affiliation: d Institute of Medical Genetics and Applied Genomics, Tübingen University , Tübingen, Germany.|e CENTOGENE AG , Rostock , Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.affiliation: f CHU and University of Nantes , Nantes , France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonnot
authors.affiliation: g Great Ormond St Hospital for Children , London , UK.
authors.forename: Anupam
authors.initials: A
authors.lastname: Chakrapani
authors.affiliation: h Sorbonne University , UPMC and Hôpital Pitié-Salpêtrière, Department of Nervous System Diseases , Paris , France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.affiliation: i University of Groningen , Groningen , the Netherlands.
authors.forename: Tom J
authors.initials: TJ
authors.lastname: de Koning
authors.affiliation: j Federal State Budget Institution, Research Center for Obstetrics , Gynecology and Perinatology , Moscow , Russia.
authors.forename: Anna
authors.initials: A
authors.lastname: Degtyareva
authors.affiliation: k Bambino Gesù Children's Hospital , Rome , Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.affiliation: l Charite University Medicine Berlin , Department of Neurology , Berlin , Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Doss
authors.affiliation: m Münster University Hospital , Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Duning
authors.affiliation: n University College London, Institute of Neurology , London , UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.affiliation: o University Federico II Naples , Naples , Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Iodice
authors.affiliation: p Birmingham Women's Hospital , Birmingham , UK.
authors.forename: Tracy
authors.initials: T
authors.lastname: Johnston
authors.affiliation: q Birmingham Children's Hospital , Birmingham , UK.
authors.forename: Dierdre
authors.initials: D
authors.lastname: Kelly
authors.affiliation: r University Clinic for Psychiatry and Psychotherapy, Regensburg University , Regensburg , Germany.
authors.forename: Hans-Hermann
authors.initials: HH
authors.lastname: Klünemann
authors.affiliation: s Ludwig Maximillian University , Munich , Germany.|t Paracelus Medical University , Salzburg , Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorenzl
authors.affiliation: u Neurology Unit, Department of Clinical and Experimental Sciences , University of Brescia , Brescia , Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.affiliation: v University of Zaragoza , IISA, Zaragoza , Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Pocovi
authors.affiliation: w Department of Neurodegenerative Diseases , Hertie Institute for Clinical Brain Research , Tübingen, Germany.|x German Center for Neurodegenerative Diseases (DZNE) , Tübingen, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: b University of Pretoria , Pretoria , South Africa.
authors.forename: Alta
authors.initials: A
authors.lastname: Terblanche
authors.affiliation: y University of Leipzig , Department of Neurology , Leipzig , Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Then Bergh
authors.affiliation: z Hacettepe University Children's Hospital , Ankara , Turkey.
authors.forename: Meral
authors.initials: M
authors.lastname: Topçu
authors.affiliation: aa CHU Strasburg , Strasburg , France.
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.affiliation: ab Royal Melbourne Hospital , Melbourne , Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Walterfang
authors.affiliation: ac Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Velten
authors.affiliation: ac Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Kolb
mesh_terms: D006801:Humans; D052556:Niemann-Pick Disease, Type C / Q000453:epidemiology*; D015995:Prevalence; D035583:Rare Diseases / Q000453:epidemiology*
keywords: Clinical niche; Diagnosis; Differential diagnosis; Epidemiology; Inborn errors of metabolism (IEM); Niemann-Pick disease type C (NP-C); Screening