Diagnosing Niemann-Pick type C disease

Diagnosing Niemann-Pick type C disease (NP-C) is not straightforward and the highly varied pattern of symptoms means it is often misdiagnosed or goes undetected.¹ Despite this, it is still possible to make a definite diagnosis of NP-C using current techniques. New diagnostic techniques are currently under development that will make it easier to diagnose NP-C in the future.¹

When to suspect NP-C

Symptoms raising suspicion of NP-C:¹

Neonates and infants
	Fetal ascites
	Liver disease, particularly jaundice or pulmonary infiltrates
	Hypotonia without evidence of progression for months
Children (in rare cases these symptoms occur in late childhood and adults)
	Vertical supranuclear gaze palsy (VSGP)
	Progressive ataxia
	Dysarthria
	Dystonia
	Seizures and gelastic cataplexy
	Liver or spleen enlargement, particularly in early childhood
Adolescents and adults
	Psychiatric illness (depression- or schizophrenia-like)

Confirming NP-C

Biochemical testing, histological analyses, genetic testing and imaging techniques are used to confirm NP-C.¹ Biochemical testing is not widely available and can only be performed by a limited number of specialized laboratories.

Biochemical testing
	Fibroblasts cultured from skin biopsy are used to conduct a:
		Cholesterol transport test: cholesterol esterification
		Cholesterol storage test: filipin staining detects lipid accumulation (Figure 1)
Histological analyses
	Foam cells in bone marrow and the spleen
	Seablue histiocytes in bone marrow
	Electron microscopy of skin, rectal neurons, liver or brain can show polymorphous cytoplasmic bodies
Genetic testing
	Not used to make a primary diagnosis, but to:
		Confirm a diagnosis of the variant biochemical phenotype
		Make a prenatal diagnosis
		Identify heterozygotes in probands' families
Imaging
	Magnetic resonance imaging (MRI), computed tomography (CT) or proton magnetic resonance spectroscopy (PET) is used to detect cerebral atrophy

A

B

Figure 1. Fluorescent filipin staining of normal (A) and NP-C fibroblasts (B) showing characteristic perinuclear lysosomal lipid accumulation

References

1. Wraith JE, Imrie J. Understanding Niemann-Pick disease type C and its potential treatment. UK Blackwell Publishing, 2007.