Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C

Purpose: Niemann-Pick disease type C (NP-C) is an autosomal recessive lipid storage disease manifested by an impairment in cellular cholesterol homeos tasis. The clinical phenotype of NP-C is extremely variable, ranging from a n acute neonatal form to an adult late-onset presentation. To facilitate ph enotype-genotype studies, we have analyzed multiple Israeli NP-C families. Methods: The severity of the disease was assessed by the age at onset, hepa tic involvement, neurological deterioration, and cholesterol esterification studies. Screening of the entire NPC1 coding sequence allowed for molecula r characterization and identification of disease causing mutations. Results : A total of nine NP-C index cases with mainly neurovisceral involvement we re characterized. We demonstrated a possible link between the severity of t he clinical phenotype and the cholesterol esterification levels in fibrobla st cultures following 24 hours of in vitro cholesterol loading. In addition , we identified eight novel mutations in the NPC1 gene. Conclusions: Our re sults further support the clinical and allelic heterogeneity of NP-C and po int to possible association between the clinical and the biochemical phenot ype in distinct affected Israeli families.