Plasma GM2 ganglioside potential biomarker for diagnosis, prognosis and disease monitoring of GM2-Gangliosidosis

Amélie Blondel; Ichraf Kraoua; Chloé Marcelino; Walid Khrouf; Dimitri Schlemmer; Benjamin Ganne; Catherine Caillaud; Gorka Fernández-Eulate; Ilhem Ben Youssef Turki; Benjamin Dauriat; Dominique Bonnefont-Rousselot; Yann Nadjar; Foudil Lamari

doi:10.1016/j.ymgme.2022.106983

Plasma G_M2 ganglioside potential biomarker for diagnosis, prognosis and disease monitoring of GM2-Gangliosidosis

Mol Genet Metab. 2023 Feb;138(2):106983. doi: 10.1016/j.ymgme.2022.106983. Epub 2022 Dec 26.

Affiliations

¹ Metabolic Biochemistry Department, Neurometabolic unit, DMU Biogem, Pitié-Salpêtrière University Hospital, AP-HP, Sorbonne University, 75013 Paris, France.
² University of Tunis El Manar, Faculty of Medicine of Tunis, Tunis, Tunisia; Neurology Department, LR18SP04, National Institute Mongi Ben Hamida of Neurology, Tunis, Tunisia.
³ Cytogenetic and Medical Genetic Department, Hôpital de la mère et de l'enfant, 87042 Limoges, France.
⁴ Biochemistry, Metabolomics, and Proteomics Department, Necker Enfants Malades University Hospital, AP-HP, Center-Paris University, 75015 Paris, France.
⁵ Neurology Department, Reference Center for Lysosomal Diseases, Pitié-Salpêtrière University Hospital, AP-HP Sorbonne University, 75013 Paris, France; Institut Necker-Enfants Malades, INSERM U1151, BioSPC (ED562), Université Paris Cité, Paris, France.
⁶ Metabolic Biochemistry Department, Neurometabolic unit, DMU Biogem, Pitié-Salpêtrière University Hospital, AP-HP, Sorbonne University, 75013 Paris, France; Paris University, UTCBS, U 1022 Inserm, UMR 88 CNRS, Paris, France.
⁷ Neurology Department, Reference Center for Lysosomal Diseases, Pitié-Salpêtrière University Hospital, AP-HP Sorbonne University, 75013 Paris, France.
⁸ Metabolic Biochemistry Department, Neurometabolic unit, DMU Biogem, Pitié-Salpêtrière University Hospital, AP-HP, Sorbonne University, 75013 Paris, France. Electronic address: foudil.lamari@aphp.fr.

PMID: 36709536
DOI: 10.1016/j.ymgme.2022.106983

Abstract

GM2-Gangliosidosis are a group of inherited lysosomal storage pathologies characterized by a large accumulation of G_M2 ganglioside in the lysosome. They are caused by mutation in HEXA or HEXB causing reduced or absent activity of a lysosomal β-hexosaminidase A, or mutation in GM2A causing defect in GM2 activator protein (GM2AP), an essential protein for the activity of the enzyme. Biochemical diagnosis relies on the measurement of β-hexosaminidases A and B activities, which is able to detect lysosomal enzyme deficiency but fails to identify defects in GM2AP. We developed a rapid, specific and sensitive liquid chromatography-mass spectrometry-based method to measure simultaneously G_M1, G_M2, G_M3 and G_D3 molecular species. Gangliosides were analysed in plasma from 19 patients with GM2-Gangliosidosis: Tay-Sachs (n = 9), Sandhoff (n = 9) and AB variant of GM2-Gangliosidosis (n = 1) and compared to 20 age-matched controls. Among patients, 12 have a late adult-juvenile-onset and 7 have an infantile early-onset of the disease. Plasma G_M2 molecular species were increased in all GM2-Gangliosidosis patients (19/19), including the patient with GM2A mutation, compared to control individuals and compared to patients with different other lysosomal storage diseases. G_M234:1 and G_M234:1/G_M334:1 ratio discriminated patients from controls with 100% sensitivity and specificity. G_M234:1 and G_M234:1/G_M334:1 were higher in patients with early-onset compared to those with late-onset of the disease, suggesting a relationship with severity. Longitudinal analysis in one adult with Tay-Sachs disease over 9 years showed a positive correlation of G_M234:1 and G_M234:1/G_M334:1 ratio with age at sampling. We propose that plasma G_M2 34:1 and its ratio to G_M3 34:1 could be sensitive and specific biochemical diagnostic biomarkers for GM2-Gangliosidosis including AB variant and could be useful as a first line diagnostic test and potential biomarkers for monitoring upcoming therapeutic efficacy.

Keywords: AB variant; GM2 activator protein; GM2-Gangliosidosis; Hexosaminidases; Mass spectrometry; Plasma gangliosides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Biomarkers
G(M2) Ganglioside / metabolism
Gangliosides / metabolism
Gangliosidoses, GM2* / diagnosis
Gangliosidoses, GM2* / genetics
Hexosaminidase A
Humans
Sandhoff Disease* / diagnosis
Sandhoff Disease* / genetics
Sandhoff Disease* / metabolism
Tay-Sachs Disease* / diagnosis
Tay-Sachs Disease* / genetics
beta-N-Acetylhexosaminidases / metabolism

Substances

Gangliosides
G(M2) Ganglioside
Hexosaminidase A
Biomarkers
beta-N-Acetylhexosaminidases