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About Niemann-Pick type C disease

Niemann-Pick type C (NP-C) is an inherited neurovisceral disease caused by mutations in one of two genes (NPC1 and NPC2). It is characterized by a unique defect in cellular lipid trafficking that leads to toxic accumulation of lysosomal lipids.1,2

NP-C is commonly misdiagnosed and often remains undetected due to its heterogeneous clinical presentation, lack of clinical awareness of the disease and the need for complex biochemical testing.3 As a result, the journey to diagnosis can be long and frustrating for patients and their families.4

Timing and presentation of NP-C symptoms vary widely amongst patients and include a range of systemic and neurologic signs that are not specific to the disease. Typical, early symptoms of NP-C, presenting in early infancy, include prolonged cholestatic jaundice, hepatosplenomegalyhypotonia and delay in motor milestones.2,5–8

Vertical supranuclear gaze palsy (VSGP), and vertical supranuclear saccade palsy (VSSP), are the most common neurologic signs of NP-C but are rarely detected in early infancy. VSSP may be present before visceral, neurologic, or psychiatric manifestations occur and is sometimes the only symptom of NP‑C in adults. Therefore voluntary saccades should be tested by asking the patient to voluntarily look up and down.2,5–8 As NP-C progresses, VSGP emerges and is commonly followed by impairment of horizontal saccades and then horizontal gaze. For further guidance on the assessment of ocular motor signs, see Neurocular.com.

In the late infantile and juvenile periods a number of other highly variable and progressive neurologic symptoms can present, for example, progressive cerebellar signs, ataxiadystoniadysphagiadysarthriagelastic cataplexy, and seizures. These may be accompanied by learning difficulties and behavioral problems.2,5–8

Recent analysis suggests that symptoms may also occur in clusters according to the age of the presenting patient.8 VSGP, ataxia, and dysphagia become more common with increasing age, with high prevalence in patients diagnosed with NP-C at >10 years of age.8 Progressive cognitive decline and motor symptoms, such as dystonia and progressive and acquired spasticity, usually appear in adolescence or early adulthood. These signs can be accompanied by psychiatric symptoms, such as early-onset psychosis, paranoid delusions, hallucinations or delusional ideation.2,5–8 All of these symptoms increase in both severity and impact on quality of life as NP-C progresses.  

Rates of disease progression and life expectancy vary widely; however, the majority of patients die between 10 and 25 years of age.3 The early onset of neurologic symptoms i.e. in early childhood leads to faster deterioration and earlier death than for those affected in adolescence or adulthood as shown in Figure 1.2 Progressive neurologic manifestations in NP-C have a profound effect on quality of life of both patients and their carers/family. Early identification of NP-C and therefore early treatment with symptomatic and disease-specific therapies can dramatically improve quality of life for all those affected.2,9

 

Figure 1: Age at onset of neurological manifestations versus lifespan in French NP-C patients (Vanier et al, 2010)3

References

  1. Wraith JE, Imrie J. Understanding Niemann-Pick disease type C and its potential treatment. UK Blackwell Publishing, 2007.
  2. 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.
  3. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.
  4. Klünemann HH, 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.
  5. 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.
  6. 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.
  7. Imrie 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.
  8. 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
  9. 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.