Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype).
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5/16 skin#
The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Clinical examination should include comprehensive neurological and ophthalmological evaluations. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. Cataplexy, seizures and dystonia are other common features. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. The most characteristic sign is vertical supranuclear gaze palsy. The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form).
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The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120,000 live births.