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Symptomatic manifestations of Niemann-Pick type C disease

The symptoms of Niemann-Pick type C (NP-C) can be grouped into three categories; visceral (systemic), neurologic or psychiatric. The age of onset of visceral symptoms is independent of the onset of neurologic 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 neurologic manifestations in NP-C, with particular emphasis on age at onset of neurologic manifestations (adapted from, Vanier 2010).2

Neurological symptoms1


  • Symptoms more commonly associated with patients aged <4 years are indicated by , symptoms more commonly associated with patients >4 years are indicated by .

    Acquired and progressive spasticity

    Weak indicator of NP-C

    Increased involuntary, velocity-dependent muscle tone

    Ataxia, clumsiness or frequent falls (see how ataxia presents in the film below)

    Moderate indicator of NP-C

    Unsteadiness of gait and poorly coordinated limb movements affecting walking or manipulation, which may start at any age from late childhood to adulthood and is progressive

    Clumsiness and/or falls during childhood may be observed

    Patients may also have experienced difficulties playing sports, and performing gross and fine motor activities

    Delayed developmental milestones

    Ancillary indicator of NP-C

    General term that covers significant and ongoing delays in a child’s development

    Can occur in many areas, including fine and gross motor skills, and language development

    Dysarthria and/or dysphagia (see how dysarthria and dysphagia present in the films below)

    Dysarthria is a moderate indicator of NP-C

    Characterized by poor articulation, slurred speech, and difficulty controlling dynamic vocal characteristics

    Dysphagia is a moderate indicator of NP-C

    May be present early in the disease course

    May manifest as difficulty swallowing liquids, with choking and coughing during feeding, pooling of saliva, and nasal regurgitation.

    However, during disease progression, increasing dysphagia severity can lead to tracheal aspiration, lung infections, and eventually aspirational pneumonia, a leading cause of death for patients with NP-C

    Dystonia

    Moderate indicator of NP-C

    Can cause abnormal dystonic movements and/or postures in the limbs due to excessive involuntary muscle contraction

    Often observed in parallel with ataxia and rarely observed in isolation

    Gelastic cataplexy (see how gelastic cataplexy presents in the film below)

    Very strong indicator of NP-C

    Moderate indicator of NP-C

    Less common than VSGP, but is a characteristic feature of the disease

    Patients may experience sudden loss of muscle tone (without loss of consciousness), typically triggered by an emotional stimulus, for example laughter

    Loss of tone may manifest as sudden falls, sudden head drop or jaw drop

    Outside of patients with NP-C or narcolepsy, gelastic cataplexy is extremely rare

    Hypotonia or central hypotonia (low muscle tone)

    Ancillary indicator of NP-C

    Manifestations are broad, including delayed motor skills, hypermobile or hyperflexible joints, drooling, speech difficulties, poor reflexes, reduced strength, and poor posture

    General hypotonia is a weak indicator of NP-C, but central hypotonia can be one of the first neurologic signs to appear in young children with NP-C

    Myoclonus

    Ancillary indicator of NP-C

    Manifests as brief, involuntary twitching of a muscle or group of muscles

    Patients who have myoclonus often exhibit other signs of neurologic deterioration in parallel

    Seizures (partial or generalized)

    Ancillary indicator of NP-C

    In partial seizures, only a localized area of the brain may be involved and the patient may not lose consciousness

    Generalized seizures involve both hemispheres of the brain

    Vertical supranuclear gaze palsy (VSGP) or vertical supranuclear saccade palsy (VSSP) (see how VSGP presents in the film below)

    Very strong indicator of NP-C

    Weak indicator of NP-C

    Most common neurologic sign of NP-C and is often missed in the initial differential diagnosis (and rarely detected in early infancy)

    VSSP may present first followed by impairment of horizontal saccades and then horizontal gaze

    As the disease progresses, VSGP develops, followed by impairment in 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

    Video-oculography can be used to record eye movements and quantitatively analyze ocular motor function (http://eyeseecam.com/)

    For further guidance on the assessment of ocular motor signs, see Neurocular.com

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 VSGP, the patient is still able to look up but cannot look down

  • With advanced VSGP, the patient can no longer look up or down


  •  

Psychiatric symptoms1


  • Symptoms commonly observed in patients aged <4 years are indicated by •, symptoms commonly observed in patients >4 years are indicated by •

    Disruptive or aggressive behavior in adolescence or childhood

    Ancillary indicator of NP-C

    Pre-senile cognitive decline or dementia (in adult patients)

    Strong indicator of NP-C (in combination with other key signs)

    Affects all patients with NP-C as they age

    Initially presents as learning difficulties and behavioral disturbances or impaired performance in school or the workplace

    In infants, delayed developmental milestones may be observed

    Cognitive impairments, including those in logical thinking, attention, working memory, word retrieval difficulties, interpersonal ‘distance’ and executive function, may be observed

    Mental regression

    Psychotic symptoms (hallucinations, delusions and/or thought disorder)

    Moderate indicator of NP-C (strong indicator when in combination with other key signs of NP‑C)

    Common in patients who are diagnosed in adolescence or early adulthood

    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-C

    Patients may experience significant psychiatric symptoms despite receiving treatment

Visceral symptoms1–7


Symptoms observed in patients aged <4 years are indicated by , symptoms observed in patients >4 years are indicated by

Hydrops fetalis

Ancillary indicator of NP-C

Hydrops fetalis is the accumulation of fluid in two or more compartments in a fetus1

Isolated unexplained splenomegaly (historical and/or current) with or without hepatomegaly

Strong indicator of NP-C

The most common indicator of NP-C in early-onset NP-C and may occur with or without hepatomegaly

Organoomegaly can be particularly difficult to recognize in older-onset patients; organs can be palpable but usually require an abdominal ultrasound examination to detect enlargement

Hepatomegaly (historical or current)

Strong indicator of NP-C

Ancillary indicator of NP-C

A very common and highly suggestive feature in NP-C, but rarely occurs without splenomegaly

Prolonged, unexplained neonatal jaundice or cholestasis

Strong indicator of NP-C

Moderate indicator of NP-C

History of prolonged, unexplained neonatal jaundice or cholestasis frequently occurs in patients with early- or late-infantile forms of NP-C

Fetal edema or ascites

Weak indicator of NP-C

Patients with severe NP-C typical in the pre- or perinatal period may have fetal hydrops or ascites

Sibling with fetal ascites

Ancillary indicator of NP-C

Rare, abnormal accumulation of fluid in the fetal peritoneal fluid1

Direct bilirubinemia

Weak indicator of NP-C

Increased conjugated direct bilirubin levels

Pulmonary infiltration with foam cells

Strong indicator of NP-C

Usually only affects those patients with early-onset disease or severe NPC2 mutations, and it is often fatal

Family history1–7

 

 

Symptoms observed in patients aged <4 years are indicated by , symptoms observed in patients >4 years are indicated by

Cousin with NP-C

Strong indicator of NP-C

A confirmed NP-C diagnosis in cousins should raise suspicion of NP-C

Parent or sibling with NP-C

Very strong indicator of NP-C

A confirmed NP-C diagnosis in an immediate family member is a key discriminatory sign of NP-C

Provides sufficient justification to refer a patient for confirmatory testing

Symptoms classified by age of onset1–7

 

Previously, clinical NP-C phenotypes were broadly grouped based on age at onset of neurologic symptoms:2,8

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)

This categorization of symptoms was used to evaluate the disease course and response to treatment as well as assisting in clinical management and genetic counseling. More recently, analysis of clinical signs and symptoms suggests that ‘<4 years’ and ‘>4 years’ age categories may be more appropriate.4–6

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;106:330–44.
  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;78:1560–7.
  4. Wraith JE, Sedel F, Pineda M, et al. Niemann-Pick type C Suspicion Index tool: analyses by age and association of manifestations. J Inherit Metab Dis 2014;37:93–101.
  5. 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.
  6. 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.
  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. Bonnot O, Klünemann HH, Sedel F, et al. Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systemic review. Orphanet J Rare Dis 2014;9:65.
  9. Wraith E, Baumgartner M, Bembi B et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab 2009;98:152–65. 
  10. 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.
  11. 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.