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Niemann-Pick disease type C1

Monday 3 April 2006

Autosomal recessive metabolic disease caused by mutations in the NPC1 gene.

Clinical synopsis

- vertical supranuclear gaze palsy
- pulmonary involvement, severe
- respiratory failure
- hepatomegaly
- neonatal jaundice
-  splenomegaly
- dysphagia
- hypotonia
- developmental delay
- dysarthria
- loss of speech
- mental deterioration
- dementia
- spasticity
- dystonia
- seizures
- cerebellar ataxia
- cataplexy
- neurofibrillary tangles
- behavioral/psychiatric manifestations
- poor school performance
- behavioral problems
- perseverative behavior
- psychosis

HEMATOLOGY

- lipid-laden macrophages (foam cells on bone marrow biopsy)
- ’sea-blue’ histiocytes

PRENATAL MANIFESTATIONS :
- fetal ascites

LABORATORY

- normal or mildly reduced sphingomyelinase activity
- low cholesterol esterification rates
- abnormal cholesterol homeostasis
- foam cells (lipid-laden macrophages) in visceral organs and CNS
- foam cells (lipid-laden macrophages) contain polymorphic cytoplasmic inclusions consisting of lamellar osmiophilic membranes on electron microscopy

MISCELLANEOUS

- highly variable phenotype and age of onset
- neurologic involvement may occur in the absence of visceral involvement
- early death from respiratory failure may occur

Pathogeny

In Niemann-Pick disease type C1 (MIM.257220), the affected gene NPC1 encodes a protein involved in cholesterol trafficking; therefore, in this disorder, cholesterol accumulates in the affected cells.

In the brain, NPC1 is present in astrocytic processes in close apposition to nerve terminals. With defective cholesterol trafficking, terminal axons and dendrites degenerate. NPC is clinically very heterogeneous.

It may present with hydrops fetalis and stillbirth, as neonatal hepatitis, or as a chronic form characterized by progressive neurologic damage. Most common, however, is presentation in childhood, which is marked by ataxia, supranuclear palsy, psychomotor regression, hepatosplenomegaly, and dysarthria.