Niemann-Pick disease type C1
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.