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Symptoms of Niemann-Pick type C disease

Niemann-Pick type C (NP-C) is characterized by a number of highly variable clinical symptoms that can be categorized as visceral (systemic), neurologic or psychiatric.1–3 The most common symptoms are shown in Table 1. One of the strongest indicators of NP-C is when a patient presents with symptoms in more than one of these categories.1,4–7 Therefore, linking these symptoms together can facilitate fast and differential diagnosis of NP-C.

Table 1: Symptoms of NP-C1–3,6,8–11. Symptoms more commonly associated with patients aged <4 years are indicated by •, symptoms more commonly associated with patients >4 years are indicated by •.

Visceral symptoms Neurological symptoms Psychiatric symptoms Family history
Hepatomegaly (historic or current) Vertical supranuclear gaze palsy (VSGP) or vertical supranuclear saccade palsy Early-onset psychosis Parent or sibling with NP-C
Splenomegaly (historic or current, with or without hepatomegaly)  Ataxia, clumsiness or frequent falls Prominent visual hallucinations Cousin with NP-C•
Prolonged unexplained neonatal jaundice Dysphagia Treatment-resistant psychiatric symptoms•  
Pulmonary infiltrates with foam cells Dysarthria Pre-senile cognitive decline and/or dementia  
Fetal hydrops Dystonia Disruptive or aggressive behavior in adolescence or adulthood  
Fetal edema or ascites Gelastic cataplexy Cognitive dysfunction or impairment  
Neonatal cholestasis Acquired and progressive spasticity• Mental regression  
Fetal edema Hypotonia    
Sibling with fetal ascites Delayed developmental milestones•    
Direct bilirubinemia Seizures (partial or generalized)•    
  Myoclonus    
  Deafness    
  Central hypotonia    
 

NP-C is commonly undetected or misdiagnosed due to its heterogeneous clinical presentation characterized by a wide range of symptoms that individually are not specific to the disease.

Interviews with patients and carers as well as healthcare professionals as part of the NP-C Patient and Healthcare Professional Survey confirmed that, in general, an early diagnosis of NP-C depends on individual symptoms, which occur sequentially, being linked together and then linked to the possibility of NP-C.12

Vertical supranuclear gaze palsy (VSGP) and vertical supranuclear saccade palsy (VSSP), are the most common neurologic signs of NP-C but are often missed in the initial differential diagnosis (and rarely detected in early infancy). Initially, VSSP may present followed by impairment of horizontal saccades and then horizontal gaze. When examining a patient it is important to test their ability to follow an object but also to test the voluntary saccades by asking the patient to spontaneously move their gaze up and down between two objects. For further guidance on the assessment of ocular motor signs, see Neurocular.com.

For more information about the symptoms of NP-C, please visit symptomatic manifestations of Niemann-Pick type C and the NP-C Suspicion Index.

Resources

A series of Signs & Symptoms cards are available, which summarize the typical symptoms that might alert neurologists, pediatricians, metabolic disease specialists and psychiatrists to the possibility of NP-C and prompt further investigation and referral.

The NP-C Quick Guides  also provide information regarding patient symptomatology and key signs which are suggestive of NP-C.

The NP-C Suspicion Index (SI) has been developed by international experts to help identify patients suspected of having NP-C, with a view to establishing better and earlier diagnosis.4,12 The NP-C SI is suitable for patients of all ages, with an NP-C SI0–4 years and an NP-C SI>4 years available for patients up to 4 years of age and older than 4 years of age, respectively. To find out more about this tool, please visit NPC-SI.com

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References

  1. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.
  2. Mengel E, Klünemann HH, Lourenço CM, et al. Niemann-Pick disease type C symptomatology: an expert-based clinical description. Orphanet J Rare Dis 2013;8:166.
  3. Mengel E, Pineda M, Hendriksz CJ, et al. Difference in Niemann-Pick disease Type C symptomatology observed in patients of different ages. Mol Genet Metab 2017;120:180–9.
  4. Hendriksz C, Pineda M, Fahey M et al. The Niemann-Pick disease Type C Suspicion Index: development of a new tool to aid diagnosis. J Rare Dis Diagn Ther 2015;1:11.
  5. Synofzik M, Harmuth F, Stampfer M, et al. NPC1 is enriched in unexplained early onset ataxia: a targeted high-throughput screening. J Neurol 2015;262:2557–63. 
  6. Wijburg FA, Sedel F, Pineda M, et al. Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C. Neurology 2012;78:1560–7.
  7. Pineda M, Mengel E, Jahnova H, et al. A Suspicion Index to aid screening of early-onset Niemann-Pick disease Type C (NP-C). BMC Pediatr 2016;16:107.
  8. Patterson MC, Hendriksz CJ, Walterfang M, et al., on behalf of the NP-C Guidelines Working Group. Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update. Mol Genet Metab 2012;106:330–44.
  9. Patterson MC, Mengel E, Wijburg FA, et al. Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet J Rare Dis 2013;8:12.
  10. 1Imrie J, Heptinstall L, Knight S, Strong K. Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-years update form the UK clinical database. BMC Neurol 2015;15:257.
  11. Marquardt T, Clayton P, Gissen P, et al, on behalf of the NP-C Diagnostics Working Group. New consensus recommendations for the detection and diagnosis of Niemann-Pick disease type C. J Inherit Metab Dis 2016;39:35.
  12. Klünemann H, Wraith E, Wijburg F. Niemann-Pick Type C Disease – Report on Results from the Niemann-Pick Type C Patient and Healthcare Professional Survey. Eur Neurol Rev 2011;6:12–5.