Christian J Hendriksz1,2, Mathieu Anheim3, Peter Bauer4,5, Olivier Bonnot6, Anupam Chakrapani7, Jean-Christophe Corvol8, Tom J de Koning9, Anna Degtyareva10, Carlo Dionisi-Vici11, Sarah Doss12, Thomas Duning13, Paola Giunti14, Rosa Iodice15, Tracy Johnston16, Dierdre Kelly17, Hans-Hermann Klünemann18, Stefan Lorenzl19,20, Alessandro Padovani21, Miguel Pocovi22, Matthis Synofzik23,24, Alta Terblanche2, Florian Then Bergh25, Meral Topçu26, Christine Tranchant27, Mark Walterfang28, Christian Velten29, Stefan A Kolb29. 1. a Salford Royal NHS Foundation Trust , Manchester , UK. 2. b University of Pretoria , Pretoria , South Africa. 3. c University of Strasbourg , Hautepierre Hospital , Strasbourg , France. 4. d Institute of Medical Genetics and Applied Genomics, Tübingen University , Tübingen, Germany. 5. e CENTOGENE AG , Rostock , Germany. 6. f CHU and University of Nantes , Nantes , France. 7. g Great Ormond St Hospital for Children , London , UK. 8. h Sorbonne University , UPMC and Hôpital Pitié-Salpêtrière, Department of Nervous System Diseases , Paris , France. 9. i University of Groningen , Groningen , the Netherlands. 10. j Federal State Budget Institution, Research Center for Obstetrics , Gynecology and Perinatology , Moscow , Russia. 11. k Bambino Gesù Children's Hospital , Rome , Italy. 12. l Charite University Medicine Berlin , Department of Neurology , Berlin , Germany. 13. m Münster University Hospital , Münster, Germany. 14. n University College London, Institute of Neurology , London , UK. 15. o University Federico II Naples , Naples , Italy. 16. p Birmingham Women's Hospital , Birmingham , UK. 17. q Birmingham Children's Hospital , Birmingham , UK. 18. r University Clinic for Psychiatry and Psychotherapy, Regensburg University , Regensburg , Germany. 19. s Ludwig Maximillian University , Munich , Germany. 20. t Paracelus Medical University , Salzburg , Austria. 21. u Neurology Unit, Department of Clinical and Experimental Sciences , University of Brescia , Brescia , Italy. 22. v University of Zaragoza , IISA, Zaragoza , Spain. 23. w Department of Neurodegenerative Diseases , Hertie Institute for Clinical Brain Research , Tübingen, Germany. 24. x German Center for Neurodegenerative Diseases (DZNE) , Tübingen, Germany. 25. y University of Leipzig , Department of Neurology , Leipzig , Germany. 26. z Hacettepe University Children's Hospital , Ankara , Turkey. 27. aa CHU Strasburg , Strasburg , France. 28. ab Royal Melbourne Hospital , Melbourne , Australia. 29. ac Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
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.
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.
Entities:
Keywords:
Clinical niche; Diagnosis; Differential diagnosis; Epidemiology; Inborn errors of metabolism (IEM); Niemann-Pick disease type C (NP-C); Screening
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