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Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study.

Welford RW, Garzotti M, Marques Lourenço C, Mengel E, Marquardt T, Reunert J, Amraoui Y, Kolb SA, Morand O, Groenen P - PLoS ONE (2014)

Bottom Line: Lysosphingolipids have been shown to be excellent biomarkers of sphingolipidosis in several enzyme deficient lysosomal storage disorders.Plasma SPC and GlcSph are stable and can be measured accurately, precisely and reproducibly.Plasma GlcSph did not correlate with SPC levels in NP-C patients.

View Article: PubMed Central - PubMed

Affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.

ABSTRACT
Niemann-Pick disease type C (NP-C) is a devastating, neurovisceral lysosomal storage disorder which is characterised by variable manifestation of visceral signs, progressive neuropsychiatric deterioration and premature death, caused by mutations in the NPC1 and NPC2 genes. Due to the complexity of diagnosis and the availability of an approved therapy in the EU, improved detection of NP-C may have a huge impact on future disease management. At the cellular level dysfunction or deficiency of either the NPC1 or NPC2 protein leads to a complex intracellular endosomal/lysosomal trafficking defect, and organ specific patterns of sphingolipid accumulation. Lysosphingolipids have been shown to be excellent biomarkers of sphingolipidosis in several enzyme deficient lysosomal storage disorders. Additionally, in a recent study the lysosphingolipids, lysosphingomyelin (SPC) and glucosylsphingosine (GlcSph), appeared to be elevated in the plasma of three adult NP-C patients. In order to investigate the clinical utility of SPC and GlcSph as diagnostic markers, an in-depth fit for purpose biomarker assay validation for measurement of these biomarkers in plasma by liquid chromatography-tandem mass spectrometry was performed. Plasma SPC and GlcSph are stable and can be measured accurately, precisely and reproducibly. In a retrospective analysis of 57 NP-C patients and 70 control subjects, median plasma SPC and GlcSph were significantly elevated in NP-C by 2.8-fold and 1.4-fold respectively. For miglustat-naïve NP-C patients, aged 2-50 years, the area under the ROC curve was 0.999 for SPC and 0.776 for GlcSph. Plasma GlcSph did not correlate with SPC levels in NP-C patients. The data indicate excellent potential for the use of lysosphingomyelin in NP-C diagnosis, where it could be used to identify NP-C patients for confirmatory genetic testing.

No MeSH data available.


Related in: MedlinePlus

Plasma SPC and GlcSph in NP-C patients and controls.One sample per patient is shown, where multiple samples from one patient were available the first was used. The dotted horizontal line represents the 95% percentile of the entire control group for SPC (10.3 nM) and GlcSph (2.4 nM). The bar is the median. A and B, SPC and GlcSph in the entire cohort; C and D, SPC and GlcSph separated by age (years); E and F, SPC and GlcSph separated by miglustat status (0–50 years). The miglustat treated patients had been on treatment for 2.8±1.4 years (average ± standard deviation), 0.7–6 years (Min-Max).
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pone-0114669-g003: Plasma SPC and GlcSph in NP-C patients and controls.One sample per patient is shown, where multiple samples from one patient were available the first was used. The dotted horizontal line represents the 95% percentile of the entire control group for SPC (10.3 nM) and GlcSph (2.4 nM). The bar is the median. A and B, SPC and GlcSph in the entire cohort; C and D, SPC and GlcSph separated by age (years); E and F, SPC and GlcSph separated by miglustat status (0–50 years). The miglustat treated patients had been on treatment for 2.8±1.4 years (average ± standard deviation), 0.7–6 years (Min-Max).

Mentions: Median plasma SPC was 2.8-fold higher in NP-C patients than controls, with almost no overlap between the two groups (Figure 3A and Table S3 in File S1). Median plasma GlcSph was 1.4-fold significantly elevated in the NP-C group compared to the control group (Mann-Whitney), although there were a significant number of NP-C patients with GlcSph within the normal range (Figure 3B). When the groups were split based on age, SPC was seen to be elevated independently (Figure 3C), with the exception of the single patient in the >50 years age sub-group. There was also no obvious influence of age on the GlcSph elevation (Figure 3D). The NP-C group in the age range 0–50 years was subsequently split based on treatment with the glucosylceramide synthase inhibitor miglustat (Figure 3E and 3F). SPC was not significantly affected by miglustat treatment (Kruksal-Wallis test). The miglustat-treated NP-C sub-group had lower GlcSph than the miglustat-naïve sub-group (Figure 3F). This comparison in itself did not reach significance (Kruksal-Wallis test with Dunn's multiple comparison test). However, only the miglustat-naïve sub-group had significantly more GlcSph than the controls.


Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study.

Welford RW, Garzotti M, Marques Lourenço C, Mengel E, Marquardt T, Reunert J, Amraoui Y, Kolb SA, Morand O, Groenen P - PLoS ONE (2014)

Plasma SPC and GlcSph in NP-C patients and controls.One sample per patient is shown, where multiple samples from one patient were available the first was used. The dotted horizontal line represents the 95% percentile of the entire control group for SPC (10.3 nM) and GlcSph (2.4 nM). The bar is the median. A and B, SPC and GlcSph in the entire cohort; C and D, SPC and GlcSph separated by age (years); E and F, SPC and GlcSph separated by miglustat status (0–50 years). The miglustat treated patients had been on treatment for 2.8±1.4 years (average ± standard deviation), 0.7–6 years (Min-Max).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257710&req=5

pone-0114669-g003: Plasma SPC and GlcSph in NP-C patients and controls.One sample per patient is shown, where multiple samples from one patient were available the first was used. The dotted horizontal line represents the 95% percentile of the entire control group for SPC (10.3 nM) and GlcSph (2.4 nM). The bar is the median. A and B, SPC and GlcSph in the entire cohort; C and D, SPC and GlcSph separated by age (years); E and F, SPC and GlcSph separated by miglustat status (0–50 years). The miglustat treated patients had been on treatment for 2.8±1.4 years (average ± standard deviation), 0.7–6 years (Min-Max).
Mentions: Median plasma SPC was 2.8-fold higher in NP-C patients than controls, with almost no overlap between the two groups (Figure 3A and Table S3 in File S1). Median plasma GlcSph was 1.4-fold significantly elevated in the NP-C group compared to the control group (Mann-Whitney), although there were a significant number of NP-C patients with GlcSph within the normal range (Figure 3B). When the groups were split based on age, SPC was seen to be elevated independently (Figure 3C), with the exception of the single patient in the >50 years age sub-group. There was also no obvious influence of age on the GlcSph elevation (Figure 3D). The NP-C group in the age range 0–50 years was subsequently split based on treatment with the glucosylceramide synthase inhibitor miglustat (Figure 3E and 3F). SPC was not significantly affected by miglustat treatment (Kruksal-Wallis test). The miglustat-treated NP-C sub-group had lower GlcSph than the miglustat-naïve sub-group (Figure 3F). This comparison in itself did not reach significance (Kruksal-Wallis test with Dunn's multiple comparison test). However, only the miglustat-naïve sub-group had significantly more GlcSph than the controls.

Bottom Line: Lysosphingolipids have been shown to be excellent biomarkers of sphingolipidosis in several enzyme deficient lysosomal storage disorders.Plasma SPC and GlcSph are stable and can be measured accurately, precisely and reproducibly.Plasma GlcSph did not correlate with SPC levels in NP-C patients.

View Article: PubMed Central - PubMed

Affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.

ABSTRACT
Niemann-Pick disease type C (NP-C) is a devastating, neurovisceral lysosomal storage disorder which is characterised by variable manifestation of visceral signs, progressive neuropsychiatric deterioration and premature death, caused by mutations in the NPC1 and NPC2 genes. Due to the complexity of diagnosis and the availability of an approved therapy in the EU, improved detection of NP-C may have a huge impact on future disease management. At the cellular level dysfunction or deficiency of either the NPC1 or NPC2 protein leads to a complex intracellular endosomal/lysosomal trafficking defect, and organ specific patterns of sphingolipid accumulation. Lysosphingolipids have been shown to be excellent biomarkers of sphingolipidosis in several enzyme deficient lysosomal storage disorders. Additionally, in a recent study the lysosphingolipids, lysosphingomyelin (SPC) and glucosylsphingosine (GlcSph), appeared to be elevated in the plasma of three adult NP-C patients. In order to investigate the clinical utility of SPC and GlcSph as diagnostic markers, an in-depth fit for purpose biomarker assay validation for measurement of these biomarkers in plasma by liquid chromatography-tandem mass spectrometry was performed. Plasma SPC and GlcSph are stable and can be measured accurately, precisely and reproducibly. In a retrospective analysis of 57 NP-C patients and 70 control subjects, median plasma SPC and GlcSph were significantly elevated in NP-C by 2.8-fold and 1.4-fold respectively. For miglustat-naïve NP-C patients, aged 2-50 years, the area under the ROC curve was 0.999 for SPC and 0.776 for GlcSph. Plasma GlcSph did not correlate with SPC levels in NP-C patients. The data indicate excellent potential for the use of lysosphingomyelin in NP-C diagnosis, where it could be used to identify NP-C patients for confirmatory genetic testing.

No MeSH data available.


Related in: MedlinePlus