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Niemann-Pick type C (NPC) is a neurodegenerative lysosomal storage disorder caused by defects in the lysosomal proteins NPC1 or NPC2. NPC cells are characterized by reduced lysosomal calcium levels and impaired sphingosine transport from lysosomes. Natural killer (NK) cells kill virally infected/transformed cells via degranulation of lysosome-related organelles. Their trafficking from lymphoid tissues into the circulation is dependent on sphingosine-1-phosphate (S1P) gradients, sensed by S1P receptor 5 (S1P5). We hypothesized that NK-cell function and trafficking could be affected in NPC disease due to the combined effects of the lysosomal calcium defect and sphingosine storage. In an NPC1 mouse model, we found the frequency of NK cells was altered and phenocopied S1P5-deficient mice, consistent with defects in S1P levels. NK cells from NPC1 mice also had a defect in cytotoxicity due to a failure in degranulation of cytotoxic granules, which was associated with reduced lysosomal calcium levels. Affected NPC1 patients and NPC1 heterozygote carriers had reduced NK-cell numbers in their blood and showed similar phenotypic and developmental changes to those observed in the NPC1 mouse. These findings highlight the effects of lysosomal storage on the peripheral immune system.

Niemann-Pick type C (NPC) is a neurodegenerative lysosomal storage disorder caused by defects in the lysosomal proteins NPC1 or NPC2. NPC cells are characterized by reduced lysosomal calcium levels and impaired sphingosine transport from lysosomes. Natural killer (NK) cells kill virally infected/transformed cells via degranulation of lysosome-related organelles. Their trafficking from lymphoid tissues into the circulation is dependent on sphingosine-1-phosphate (S1P) gradients, sensed by S1P receptor 5 (S1P5). We hypothesized that NK-cell function and trafficking could be affected in NPC disease due to the combined effects of the lysosomal calcium defect and sphingosine storage. In an NPC1 mouse model, we found the frequency of NK cells was altered and phenocopied S1P5-deficient mice, consistent with defects in S1P levels. NK cells from NPC1 mice also had a defect in cytotoxicity due to a failure in degranulation of cytotoxic granules, which was associated with reduced lysosomal calcium levels. Affected NPC1 patients and NPC1 heterozygote carriers had reduced NK-cell numbers in their blood and showed similar phenotypic and developmental changes to those observed in the NPC1 mouse. These findings highlight the effects of lysosomal storage on the peripheral immune system.

AbstractObjective:Niemann-Pick disease type C (NP-C) is a rare and devastating genetic disorder characterised by a range of progressive neurological symptoms, which imposes a burden on patients, family members, the healthcare system and society overall. The objective of this study was to assess direct and indirect costs associated with NP-C in the UK.Methods:This was a non-interventional, retrospective, cross-sectional cohort study based on responses from patients and/or their carers/guardians recruited from a UK NP-C database. Resource use and direct medical, direct non-medical and indirect costs were evaluated using data collected via postal survey in October 2007, which included a Medical Resource Use questionnaire. Total annual costs per patient were estimated.Results:In total, 18 Medical Resource Use questionnaires (29% response rate) were received and analysed. The mean total annual cost (SD) of NP-C per patient was £39,168 (£50,315); 46% were direct medical costs, to which home visits and residential care contributed 68% and 15%, respectively. Direct non-medical costs accounted for 24% of the average annual cost per patient, mainly due to specialist education, and indirect costs 30%. If only direct medical costs were considered, the mean annual cost (SD) per patient was reduced to £18,012 (£46,536).Conclusions:The direct annual per-patient cost of NP-C illness in 2007 appears moderate when compared with other rare and severely disabling diseases. However, cost estimates may be conservative, since findings are limited by a small sample size, low survey response rate and potential recall bias. As demonstrated by this study, a substantial proportion of the cost is shifted from the healthcare system to the patient, family and non-medical providers. These findings highlight the need for treatments that can slow or stop disease progression in NP-C.