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Symptomatic manifestations of Niemann-Pick type C disease

The symptoms of Niemann-Pick type C disease (NP-C) can be grouped into three categories; visceral (systemic), neurological or psychiatric categories. The age of onset of visceral symptoms is independent of the onset of neurological disease, which occurs along a continuous spectrum with considerable overlap between the age categories (see Figure 1).1,2

Patients that present with a number of symptoms across all three categories should be considered for referral to a specialist center.

Figure 1: Visceral and neurological manifestations in NP-C, with particular emphasis on age at onset of neurological manifestations (Vanier 2010)2

Visceral symptoms1


  • Isolated unexplained splenomegaly (historical and/or current) with or without hepatomegaly
    • Strong indicator of NP-C3
    • Present with variable intensity in almost 50% of patients with NP-C2
    • Hepatosplenomegaly can be particularly difficult to recognize in adults and usually requires an abdominal ultrasound

  • Prolonged, unexplained neonatal jaundice or cholestasis
    • Strong indicator of NP-C3
    • Appears in the first days or weeks of life and is usually associated with progressive hepatosplenomegaly1
    • Jaundice usually resolves spontaneously by 2 to 4 months of age2

  • Liver disease in early life
    • Patients with severe NP-C typical in the pre- or peri-natal period may have fetal hydrops, ascites, neonatal cholestasis, hepatosplenomegaly and/or liver failure1

  • Pulmonary infiltration with foam cells
    • Usually only affects those patients with early onset disease or severe NPC2 mutations and it is often fatal1

 

Neurological symptoms1


  • Vertical supranuclear gaze palsy (VSGP) (see how VSGP presents in the film below)
    • Very strong indicator of NP-C3
    • Most common neurological sign of NP-C
    • Ocular-motor abnormalities are one of the earliest neurological signs of NP-C and are seen in around 80% of patients (although detected in nearly all patients when properly examined)
    • Initial sign is usually impaired voluntary saccadic eye movements (SEM) in the late-infantile period
    • A rigorous neurological examination of VSGP should include testing of smooth pursuits, saccades and vergence (movement of the two eyes in opposite directions)
    • In all patients, saccadic, pursuit and vergence movements should be examined in both vertical and horizontal planes
    • Vertical SEM impairment is affected first, followed by horizontal SEM impairment
    • VSGP may be missed if voluntary saccades are not assessed
      Click on the film to view how to test for VSGP or see assessment 2. within red box below:
 

1. To assess the smooth pursuit, patients should be tested for their ability to follow an object
2. To assess the vertical voluntary saccades the physicians will ask the patient to spontaneously move their gaze up and
    down without following an object (ask to look between two points fixed by the upper part of their head and at chest level)


  • With mild vertical SEM impairment, the patient is still able to look up but cannot look down

  • With advanced vertical SEM impairment, the patient can no longer look up or down

  • Gelastic cataplexy (see how gelastic cataplexy presents in the film below)
    • Very strong indicator of NP-C3
    • Less common than VSGP, but is a characteristic feature of the disease
    • Patients may experience sudden loss of muscle tone (without loss of consciousness), which is typically triggered by an emotional stimulus, for example laughter
    • Loss of tone may involve the legs, neck or jaw. Therefore, cataplexy may manifest as sudden falls, sudden head drop or jaw drop, triggered by laughing

  • Ataxia, clumsiness or frequent falls (see how ataxia presents in the film below)
    • Moderate indicator of NP-C3
    • Poorly coordinated movements affecting walking or manipulation, which may start at any age from late childhood to adulthood and is progressive

  • Dysarthria (see how dysarthria presents in the film below)
    • Moderate indicator of NP-C3
    • Characterized by poor articulation and slurred speech

  • Dysphagia (see how dysphagia presents in the film below)
    • Moderate indicator of NP-C3
    • May be present early in the disease course
    • May manifest initially as difficulty swallowing liquids. However, during disease progression, increasing dysphagia severity can lead to aspiration and malnutrition

  • Dystonia
    • Moderate indicator of NP-C3
    • Can cause abnormal dystonic postures in hands, feet or face

  • Acquired and progressive spasticity
    • Weak indicator of NP-C3
    • Altered muscle tone performance

  • Delayed developmental milestones
    • General term that covers significant and ongoing delays in a child’s development

  • Epileptic seizures
    • Most frequent in late-infantile or juvenile-onset NP-C patients
    • May experience different types of seizures, for example, partial/focal, generalized, absence, myoclonic or tonic-clonic, of variable frequency and intensity1

  • Central hypotonia (low muscle tone)

  • Myoclonus (brief, involuntary twitching of a muscle or a group of muscles)

  • Progressive hearing loss

The films presenting NP-C neurological symptoms have been developed and produced by: Dr Nicholas Smith, Pediatric Neurologist-Neurometabolic Diseases, Department of Medicine, University of Cambridge and Mrs Jackie Imrie, Clinical Nurse Specialist in Niemann-Pick disease, Royal Manchester Children's hospital, with the assistance of Professor JE Wraith, St. Mary's Hospital, Manchester and the generous support of the featured patients and their families.

 

Psychiatric symptoms1


  • Pre-senile cognitive decline and/or dementia
    • Strong indicator of NP-C3 (but not highly specific)
    • Affects all patients with NP-C
    • Initially presents as learning difficulties and behavioral disturbances in school or the workplace
    • In infants, delayed developmental milestones may be observed

  • Psychotic symptoms (hallucinations, delusions and/or thought disorder)
    • Moderate indicator of NP-C3
    • Common in patients who are diagnosed with later-onset disease
    • Symptoms include delusions, auditory hallucinations and disorganized thought and behavior and so can often be misdiagnosed as schizophrenia or other forms of psychosis
    • Visual hallucinations, cognitive impairment and resistance to treatment with neuroleptics and mood stabilizers can indicate the presence of organic psychosis

  • Treatment-resistant psychiatric symptoms
    • Weak indicator of NP-C3

  • Other psychiatric disorders
    • Weak indicator of NP-C3
    • Including aggression, paranoia, depression, bipolar disorder and obsessive-compulsive disorders

 

Symptoms classified by age of onset


Clinical NP-C phenotypes can be broadly grouped based on age at onset of neurological symptoms:

  • pre-perinatal onset (≤ 3 months)
  • early infantile onset (age 3 months ≤ 2 years)
  • late infantile onset (2 years to < 6 years)
  • juvenile onset (6 – 15 years)
  • adolescent/adult onset (> 15 years).4

Clinical signs and symptoms characteristic of NP-C by age at onset are summarized in Figure 2. This categorization of symptoms is useful in evaluating the disease course and response to treatment as well as assisting in clinical management and genetic counseling.

Figure 2: Characteristic clinical signs and symptoms of NP-C by age at onset (Wraith et al, 2009) 4

 

References

  1. 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(3):330-344.
  2. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.
  3. 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(20):1560-7.
  4. Wraith E, Baumgartner M, Bembi B et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab 2009;98:152–165.