Type A and B forms of
Niemann-Pick disease (
NPD) are
lipid storage disorders caused by deficient activity of the
enzyme acid sphingomyelinase (aSMase) and the resulting accumulation of
sphingomyelin in tissues. In the present study, we investigated two family members who had been diagnosed with Type B
NPD and who had a severe decrease in plasma
high density lipoprotein cholesterol (HDL-C). The proband (a 48-year-old male) had an HDL-C of 0.30 mmol/l (12 mg/dl) and his sister had values of 0.45 mmol/l (17 mg/dl) with severe premature
coronary artery disease (CAD).
Hypertriglyceridemia was found in both cases. aSMase activity measured in skin fibroblasts appeared markedly depressed. The SMPD1 gene, coding for aSMase, was sequenced in affected subjects and all family members. Compound heterozygosity (DeltaR608 and R441X) was identified in both affected patients. Carriers of the DeltaR608 mutation tended to have moderately to severe decreased HDL-C levels, whereas carriers of the R441X mutation, although present only in young subjects (<20 years of age) had normal HDL-C levels. To investigate the cause of the low HDL-C level in these patients, we studied
apoA-I-mediated cellular
cholesterol efflux in fibroblasts. Unlike patients with
Tangier disease,
cholesterol efflux was found to be normal under the experimental conditions used in the present study. On the other hand, we observed a significant increase in the free
cholesterol:esterified
cholesterol ratio in HDL fraction from these patients and a decrease in endogenous
lecithin-cholesterol acyltransferase (LCAT) activity, as determined by the fractional esterification rate. Taken together, these results suggest that (1) compound heterozygosity at the SMPD1 gene causes a severe decrease in aSMase activity and in HDL-C and increases the risk of CAD, (2) this
lipoprotein abnormality is not attributable to defective cellular
cholesterol efflux, (3) abnormal HDL composition might cause a decrease in LCAT activity and a lack of HDL maturation.