Clinical Manifestation

Signs and Symptoms

In line with the high degree of genetic heterogeneity of NPC, clinical signs and symptoms of the disease are extremely varied, but can be broadly grouped into categories based on presenting symptoms and patients’ age at onset (Table 3).

**Table 3.** Clinical presentation of NPC at different ages of onset (adapted from Patterson et al.¹)
Age of onset	Presentation
Perinatal period: ≤ 3 months	Foetal ascites with persistence after birth Neonatal jaundice (benign, self-limiting or rapidly fatal) Hepatosplenomegaly VSGP usually absent
Early infantile period: 3 months - 2 years	Hypotonia Delayed developmental motor milestones Hepatosplenomegaly VSGP usually absent
Late infantile period: 2 - 6 years	‘Clumsy’, frequent falls (ataxia) Isolated organomegaly VSGP may be present
Juvenile (classical): 6 - 15 years	School failure (impaired intellect and movement) Behavioural problems Ataxia, dysarthria, dystonia Seizures (partial and/or generalised) Gelastic cataplexy VSGP usually present
Adolescent and adult: > 15 years	Dementia Psychosis Progressive neurologic deterioration VSGP may be present

INSERVSGP, vertical supranuclear gaze palsy, increased latency in initiation of vertical saccades with gradual slowing and eventual loss of saccadic velocity.

Neonatal and infantile presentations

The presentation of NPC in early life is non-specifi c and may go unrecognised by inexperienced clinicians. Severely affected babies may have ascites in utero that is detectable using ultrasonography,⁵ with most found to have severe liver disease with hepatosplenomegaly, jaundice, and persistence of ascites after birth.¹ Although enlarged liver or spleen may be present in children presenting with symptomatic liver disease, many NPC cases never exhibit organomegaly. However, the absence of organomegaly does not eliminate a diagnosis of NPC.¹

Extensive pulmonary infiltration with foam cells can occur as a presenting feature in NPC2, and is often fatal early on due to pulmonary failure secondary to impaired diffusion. Some children have early hypotonia and delayed psychomotor development with minimal or absent hepatic or pulmonary dysfunction, and usually do not exhibit vertical supranuclear gaze palsy (VSGP; impaired control of vertical gaze due to degeneration of supranuclear oculomotor pathways in the brainstem) at onset. However, VSGP often occurs eventually in such patients.

Childhood presentation

The classic form of NPC manifests in middle-to-late childhood with apparent clumsiness and gait disturbance that evolves into overt ataxia. Impairment of vertical gaze (up or down) is a frequent initial neurologic finding. Gelastic cataplexy, varying from head nods to complete collapse provoked by humorous stimuli, is characteristic of classic NPC and has been estimated to occur in 20–50% of cases.^1,4,5 Partial and/or generalised seizures also develop in 33–54% of patients,^3,4 and can be difficult to control. Disturbed sleep, possibly related to reduced cerebrospinal fluid hypocretin levels in NPC, suggests effects on hypocretin-secreting cells of the hypothalamus.^7,8

As the disease progresses, most children develop dystonia, typically beginning as action dystonia in one limb, and gradually spreading to involve all of the limbs and axial muscles. Progressive dysphagia and dysarthria also arise, with gradual disruption of speech and swallowing until eventually, oral feeding becomes impossible due to frequent aspiration on food.

Adolescent and adult presentations

Late-onset presentations with partial phenotypes are now being recognised more often.^9,10 Adolescents and adults may present with subtle physical findings associated with various forms of apparent psychiatric illness (e.g., psychosis, depression, schizophreniform pathology).^9,11 Patients may present with neurologic deficits similar to those seen in childhood-onset NPC, but tend to show a much slower rate of progression and are often overshadowed by psychiatric problems.² In particular, the presence of vertical gaze palsy is an important clinical clue and can be useful in diagnosis.⁹ There is frequently a lack of visceral symptoms in adult-onset patients.¹

Overall symptom occurrence

Data from the recent large-scale US survey of NPC1 are possibly the best current source of information on what physicians can expect to encounter in the majority of cases. Common medical and developmental problems reported in this survey are listed in Figure 6.

Figure 6. Common* medical and developmental problems in NPC1 (large-scale survey data from Garver et al.⁴)

Click image for larger version.

*Problems seen in > 10% of respondents.

References:
1. Patterson MC. Niemann–Pick disease Type C. Gene Reviews 2007a (updated 9 July). Accessible at: www.geneclinics.org. Accessed 28^th May 2009.
2. Klünemann HH, Elleder M, Kaminski WE et al. Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Ann Neurol 2002;52:743–9.
3. Vanier MT, Wenger DA, Comly ME et al. Niemann–Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterifi cation. A collaborative study on 70 patients. Clin Genet 1988;33:331–48.
4. Garver WS, Francis GA, Jelinek D et al. The National Niemann–Pick C1 database: report of clinical features and health problems. Amer J Med Genet Part A 2007;143A:1204–11.
5. Manning DJ, Price WI, Pearse RG. Foetal ascites: an unusual presentation of Niemann–Pick disease type C. Arch Dis Child 1990;65:335–6.
6. Philippart M, Engel J, Zimmerman EG. Gelastic cataplexy in Niemann–Pick disease group C and related variants without generalized sphingomyelinase deficiency. Ann Neurol 1983;14:492–3.
7. Kanbayashi T, Abe M, Fujimoto S et al. Hypocretin deficiency in Niemann–Pick type C with cataplexy. Neuropediatrics 2003;34:52–3.
8. Vankova J, Stepanova I, Jech R et al. Sleep disturbances and hypocretin deficiency in Niemann–Pick disease type C. Sleep 2003;26:427–30.
9. Imrie J, Vijayaraghaven S, Whitehouse C et al. Niemann–Pick disease type C in adults. J Inherit Metab Dis 2002;25:491–500.
10. Sévin M, Lesca G, Baumann N et al. The adult form of Niemann–Pick disease type C. Brain 2006;130:120– 33.
11. Josephs KA, Van Gerpen MW, Van Gerpen JA. Adult onset Niemann–Pick disease type C presenting with psychosis. J Neurol Neurosurg Psychiatry 2003;74:528–9.

Niemann-Pick Knowledge Centre
(Type C)