title: Differences in Niemann-Pick disease Type C symptomatology observed in patients of different ages.
abstract: Niemann-Pick disease Type C (NP-C) is a genetic lipid storage disorder characterised by progressive neurovisceral symptomatology. Typically, disease progression is more pronounced in patients with early onset of neurological symptoms. Heterogeneous clinical presentation may hinder disease recognition and lead to delays in diagnosis. Here we describe the prevalence of signs and symptoms observed in patients with NP-C and analyse the relationship between these symptoms in different age groups.
  
  
  
  The combined patient cohort used in the analyses comprised NP-C cases (n=164) and controls (n=135) aged 0 to 60years from two previously published cohorts; a cohort of all ages from which patients ≤4years of age were excluded and a cohort with early-onset NP-C and age-matched controls. The analysis of relationships between different signs and symptoms was performed for both NP-C cases and controls in two sub-groups, ≤4 and >4years of age, using cluster analyses. The threshold of 4years of age was selected to reflect the minimum age cut-off for satisfactory discriminatory power of the original NP-C SI. To assess the prevalence of individual signs and symptoms at age of diagnosis, patients were categorised by age into 5-year sub-groups, and prevalence values estimated for each sign and symptom of NP-C.
  
  
  
  Two main clusters of symptoms were clearly defined for NP-C cases in each age sub-group, whereas clusters were not as clearly defined for controls. For NP-C cases ≤4years of age, one cluster comprised exclusively visceral symptoms; the second cluster combined all other signs and symptoms in this age group. For NP-C cases >4years of age, each cluster contained a mixture of visceral, neurological and psychiatric items. Prevalence estimations showed that visceral symptoms (e.g. isolated unexplained splenomegaly) were most common in NP-C cases ≤4years of age. Neurological symptoms were generally more common in NP-C cases >4years of age than in younger patients, with the exception of hypotonia and delayed developmental milestones.
  
  
  
  These analyses provide a comprehensive overview of symptomatology observed in a large combined cohort of patients with NP-C and controls across a wide range of ages. The results largely reflect observations from clinical practice and support the importance of multi-disciplinary approaches for identification of patients with NP-C, taking into account age-specific manifestations and their possible correlations.
authors.affiliation: ZKJM MC University Mainz, Mainz, Germany. Electronic address: mengel@kinder.klinik.uni-mainz.de.
authors.forename: Eugen
authors.initials: E
authors.lastname: Mengel
authors.affiliation: Fundació, Hospital Sant Joan de Déu, Centre for Biomedical Research on Rare Diseases, CIBERER, Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Salford Royal NHS Foundation Trust, Manchester, UK; University of Pretoria, Steve Biko Academic Unit, Department of Paediatrics and Child Health, Pretoria, South Africa.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Hendriksz
authors.affiliation: Department of Neuropsychiatry, Royal Melbourne Hospital and Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Walterfang
authors.affiliation: Syntax for Science SL, Basel, Switzerland.
authors.forename: Juan V
authors.initials: JV
authors.lastname: Torres
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Kolb
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D001523:Mental Disorders / Q000453:epidemiology*; D008875:Middle Aged; D009422:Nervous System Diseases / Q000453:epidemiology*; D052556:Niemann-Pick Disease, Type C / Q000150:complications / Q000473:pathology*; D015995:Prevalence; D013163:Splenomegaly / Q000453:epidemiology*; D014781:Viscera / Q000473:pathology*; D055815:Young Adult
keywords: Clinical features; Cluster; Diagnosis; NP-C; Niemann-Pick disease Type C; Prevalence; Symptoms