Metabolic improvement in patients with Niemann-Pick disease following intravenous trehalose administration: An untargeted pharmacometabolomic study

Abstract

Abstract Niemann-Pick (NP) types A (NPA) and B (NPB) are life-threatening and rare inherited lysosomal storage disorders, caused by a deficiency in the acid sphingomyelinase enzyme activity. The negative outcome of this deficiency is the sphingomyelin (SM) accumulation in different organs and tissues. Trehalose is a natural disaccharide with neuroprotective and autophagy-inducing abilities which has recently been shown to improve clinical and biochemical features of patients with NPA/B. Changes in the serum metabolome were assessed in five patients with NPA/B, who received 15 g/week of trehalose intravenously for three months, using an untargeted gas chromatography-mass spectrometry (GC-MS) method. MSDIAL was used for data processing, and PCA, and OPLS-DA were carried out using SIMCA. OPLS-DA model revealed significant changes in several serum metabolites including phosphate (P = .0019), sorbitol (P = .00009), myoinositol (P = .02), threonine (P = .01), lactic acid (P = .0001), 1-monopalmitin (P = .01), threitol (P = .002), ribitol (P = .008), and D-ribose (P = .007) following trehalose treatment. The findings revealed that the beneficial effects of trehalose in patients with NP are mediated by metabolic alterations. A clear shift in glucose metabolism in favor of less fatty acid production together with facilitating the breakdown of sphingomyelins is involved in the observed protective activity.