Contribution of tandem mass spectrometry to the diagnosis of lysosomal storage disorders

Abstract

Tandem mass spectrometry (MS/MS) is a highly sensitive and specific technique. Thanks to the development of triple quadrupole analyzers, it is becoming more widely used in laboratories working in the field of inborn errors of metabolism. We review here the state of the art of this technique applied to the diagnosis of lysosomal storage disorders (LSDs) and how MS/MS has changed the diagnostic rationale in recent years. This fine technology brings more sensitive, specific, and reliable methods than the previous biochemical ones for the analysis of urinary glycosaminoglycans, oligosaccharides, and sialic acid. In sphingolipidoses, the quantification of urinary sphingolipids (globotriaosylceramide, sulfatides) is possible. The measurement of new plasmatic biomarkers such as oxysterols, bile acids, and lysosphingolipids allows the screening of many sphingolipidoses and related disorders (Niemann-Pick type C), replacing tedious biochemical techniques. Applied to amniotic fluid, a more reliable prenatal diagnosis or screening of LSDs is now available for fetuses presenting with antenatal manifestations. Applied to enzyme measurements, it allows high throughput assays for the screening of large populations, even newborn screening. The advent of this new method can modify the diagnostic rationale behind LSDs.

Plasma and dried blood spot lysosphingolipids for the diagnosis of different sphingolipidoses: a comparative study

“…We reported a sensitive multiplex method to measure various lysosphingolipids in the plasma for the diagnosis of Fabry, Gaucher, Krabbe, Niemann-Pick type A, B and C diseases and prosaposin deficiency [20,24]. Similar studies were performed by other groups [5,[21][22][23]. Despite the different analytical approaches in terms of sample preparation, internal standard and LC-MS/MS analysis, all these studies confirmed that a simultaneous LysoSL quantification could be a useful first-tier test to screen patients suspected for sphingolipidoses.…”

“…LysoGM1 and LysoGM2 have been proposed to be biomarkers of other two ultra-rare lysosomal diseases, the GM1 and GM2 gangliosidoses. The sensitivity of these markers in the plasma has been reported to be poor and critical for later onset forms [5,21]. We analyzed these markers in a limited number of patients (GM1 n = 1; GM2 n = 2).…”

“…The enzymatic activity in DBS was recently measured by tandem mass spectrometry (MS/MS) [3,4]. The versatility of MS/ MS has enabled this technique to be applied not only for enzymatic determination but also for biomarker detection [5]. In this context, lysosphingolipids (LysoSLs), the N-deacylated forms of sphingolipids, have been identified as potential biomarkers of several LSDs, specifically the sphingolipidoses, such as Gaucher disease (GD), Fabry disease (FD), Krabbe disease (KD) and Niemann-Pick type A/B (NPA/B) and type C (NPC) diseases, and the GM1 and GM2 gangliosidoses.…”

Identification and Evaluation of Biomarkers for Niemann-Pick Disease Type C Based on Chemical Analysis Techniques

“…Later, the unknown peak was reported to be useful for NPC diagnostic screening [95] and immediately cited in many guidelines [3,96,97]. Multiplex analyses of Lyso-SM-509 were useful for differentiation from other lysosomal diseases [98]. The differentiation between NPC and NP-A/B [99,100] and correlations between cholenoic acids and Lyso-SM-509 have also been reported [101].…”

Niemann-Pick type C disease: The atypical sphingolipidosis

“…Measurements of plasma lysosphingomyelin levels also have been reported to be potentially useful in NPC disease (Welford et al, 2014). Lysosphingolipids, N-deacylated versions of their precursor sphingolipids, appear to be elevated in multiple disorders due to deficiencies of enzymes responsible for the breakdown of complex sphingolipids (Piraud et al, 2018). Moreover, lysosphingolipid measurements have attracted attention since compared to their acylated precursors, their accumulation is often up to an order of magnitude higher in these disease states, suggesting that they could be more reliable biomarkers than the other previously discussed sphingolipid metabolites (Welford et al, 2014).…”