The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes

Abstract

Niemann-Pick type C1 disease (NPC1) is an autosomal recessive lipid storage disorder characterized by clinical manifestations involving primarily the liver and brain ( 1 ). The onset of signs or symptoms can occur at any age and have a variable phenotype. The classic clinical phenotype is also variable and includes mid-to-late childhood onset of gait disturbance followed by progressive neurodegeneration with vertical gaze palsy, seizures, and dementia, resulting in death during the second or third decade ( 2-4 ). The clinical phenotype of NPC1 disease has been categorized according to the age of onset of symptoms ( 5, 6 ), including an early-onset, rapidly progressive form associated with hepatic dysfunction and psychomotor delay during infancy, the classic form, and a late-onset type characterized by a slowly progressive intellectual impairment in adolescence or adulthood.The gene responsible for NPC1 disease, NPC1 , was localized to chromosome 18 using linkage analysis and subsequently identifi ed using positional mapping and Abstract Niemann-Pick type C1 disease (NPC1) is an autosomal recessive lysosomal storage disorder characterized by neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration. The present study provides the lipid profi les, mutations, and corresponding associations with the biochemical phenotype obtained from NPC1 patients who participated in the National NPC1 Disease Database. Lipid profi les were obtained from 34 patients (39%) in the survey and demonstrated signifi cantly reduced plasma LDL cholesterol (LDL-C) and increased plasma triglycerides in the majority of patients. Reduced plasma HDL cholesterol (HDL-C) was the most consistent lipoprotein abnormality found in male and female NPC1 patients across age groups and occurred independent of changes in plasma triglycerides. A subset of 19 patients for whom the biochemical severity of known NPC1 mutations could be correlated with their lipid profi le showed a strong inverse correlation between plasma HDL-C and severity of the biochemical phenotype. Gene mutations were available for 52 patients (59%) in the survey, including 52 different mutations and fi ve novel mutations (Y628C, P887L, I923V, A1151T, and 3741_ 3744delACTC). Together, these fi ndings provide novel information regarding the plasma lipoprotein changes and mutations in NPC1 disease, and suggest plasma HDL-C represents a potential biomarker of NPC1 disease severity. -Garver, W.

Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage

“…Compared with the age-and sex-matched unaffected reference population ( 16 ), NPC patients of our cohort were overrepresented in the lower 5th percentile group with regard to HDL-c, LDL-c, and free cholesterol, as well as above the 95th percentile with regard to triacylglycerides (TGs). This corroborates previous fi ndings that NPC patients have a higher probability for low HDL-c, LDL-c, and blood cholesterol levels, whereas TG levels tend to be increased ( 30 ). No evident differences between biochemically "variant" and "classic" NPC patients were found for LDL-c, cholesterol, and TG.…”

“…Although this may not be due to shortcomings of routine genomic sequencing in identifying deep intronic NPC1 mutations ( 5 ), one previous study reported a high coincidence of the "variant" cellular phenotype with no apparent defects in the NPC1 gene ( 39 ). Therefore, it is tempting to speculate that variants in additional, yet-unidentifi ed genes have an impact on the NPC cellular phenotype, and modifi ers of lysosomal cholesterol levels have been demonstrated in cell and animal models (e.g., 14,30,40 ).…”

Altered vitamin E status in Niemann-Pick type C disease

“…Total cholesterol levels in plasma samples from NPC patients were <200 mg/dl; i.e., within the normal range for adults as defi ned by the American Heart Association ( 80 ). These values are similar to those reported previously for NPC1 patients ( 81 ). Importantly, plasma levels of ␣ -tocopherol and the most prevalent vitamin E form in the US diet, ␥ -tocopherol, were within the clinically normal range (12-50 M) ( 82 ).…”

Differential Association of Niemann-Pick C1 Gene Polymorphisms with Maternal Prepregnancy Overweight and Gestational Diabetes

“…Subsequent studies performed to determine the transferability of NPC1 obesity risk alleles have also discovered alleles associated with decreased fasting insulin levels and increased risk for type 2 diabetes independent of body weight in other populations [10][11][12] . These findings were noteworthy since NPC1 mutations were originally known to be responsible for a rare and fatal autosomal-recessive lipid-storage disorder called NPC1 disease [13,14] . With respect to this disease, the NPC1 derived and minor allele for 3182T>C encoding the Ile1061Thr residue predisposes to most diagnosed cases of NPC1 disease in the United States, particularly among Hispanic patients living in the Northern Rio Grande Valley region of New Mexico and Colorado [14] .…”

“…These findings were noteworthy since NPC1 mutations were originally known to be responsible for a rare and fatal autosomal-recessive lipid-storage disorder called NPC1 disease [13,14] . With respect to this disease, the NPC1 derived and minor allele for 3182T>C encoding the Ile1061Thr residue predisposes to most diagnosed cases of NPC1 disease in the United States, particularly among Hispanic patients living in the Northern Rio Grande Valley region of New Mexico and Colorado [14] . Population studies suggest that this NPC1 mutation may have resulted from a founder effect originating from Spanish descendants that migrated and settled in this region [15,16] .…”