Academic Journal
Novel HEXB variant and first evidence of urinary Gb4 isoforms in Sandhoff disease: Biochemical and bioinformatic characterization in two Moroccan families.
| Τίτλος: | Novel HEXB variant and first evidence of urinary Gb4 isoforms in Sandhoff disease: Biochemical and bioinformatic characterization in two Moroccan families. |
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| Συγγραφείς: | Hammoud M; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco; Moroccan Association for Inherited Metabolic Diseases, Morocco. Electronic address: miloud.hammoud343@gmail.com., Rodrigues AMS; Sorbonne Université, CNRS, Laboratoire de Biodiversité et Biotechnologies Microbiennes, LBBM, Observatoire Océanologique, USR3579, Banyuls-sur-Mer, 66650, France., Assiri I; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco; Moroccan Association for Inherited Metabolic Diseases, Morocco., Najeh S; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco; Moroccan Association for Inherited Metabolic Diseases, Morocco., Jakani M; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco; Moroccan Association for Inherited Metabolic Diseases, Morocco., Berrachid A; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco; Moroccan Association for Inherited Metabolic Diseases, Morocco., Sabir ES; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco; Moroccan Association for Inherited Metabolic Diseases, Morocco., Lafhal K; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco; Moroccan Association for Inherited Metabolic Diseases, Morocco., El Foutat S; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco; Moroccan Association for Inherited Metabolic Diseases, Morocco., Bourrous M; Cadi Ayyad University, Faculty of Medicine and Pharmacy, Paediatrics' Department, Mohammed VI Hospital University, Marrakesh, Morocco., Elamiri MA; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco., Houël E; Sorbonne Université, CNRS, Laboratoire de Biodiversité et Biotechnologies Microbiennes, LBBM, Observatoire Océanologique, USR3579, Banyuls-sur-Mer, 66650, France., Stien D; Sorbonne Université, CNRS, Laboratoire de Biodiversité et Biotechnologies Microbiennes, LBBM, Observatoire Océanologique, USR3579, Banyuls-sur-Mer, 66650, France., Fdil N; Cadi Ayyad University, UCA, Faculty of Medicine and Pharmacy, Team for Childhood, Health and Development, Biochemistry Laboratory, Metabolic Platform, B.P. 7010, Marrakesh, Morocco; Moroccan Association for Inherited Metabolic Diseases, Morocco. Electronic address: naima.fdil@uca.ac.ma. |
| Πηγή: | Analytical biochemistry [Anal Biochem] 2026 Sep; Vol. 716, pp. 116157. Date of Electronic Publication: 2026 May 20. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: United States NLM ID: 0370535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0309 (Electronic) Linking ISSN: 00032697 NLM ISO Abbreviation: Anal Biochem Subsets: MEDLINE |
| Imprint Name(s): | Publication: <2000- > : San Diego, CA : Elsevier Original Publication: Orlando Fl : Academic Press |
| Ιατρικοί όροι (MeSH): | Sandhoff Disease*/genetics , Sandhoff Disease*/urine , beta-Hexosaminidase beta Chain*/genetics , beta-Hexosaminidase beta Chain*/metabolism , Globosides*/urine, Protein Isoforms/urine ; Protein Isoforms/genetics ; Biomarkers/urine ; Humans ; Female ; Male ; Morocco ; Computational Biology ; Chromatography, High Pressure Liquid ; Pedigree ; Chromatography, Thin Layer ; Tandem Mass Spectrometry ; Mutation ; Glycolipids ; Sphingolipids |
| Περίληψη: | Sandhoff disease is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of β-hexosaminidases A and B. These enzymes play a key role in the degradation of ganglioside GM2, GA2, globoside Gb4, and other glycolipids in neuronal and visceral tissues. Clinically, it is almost indistinguishable from Tay-Sachs disease, another disorder affecting hexosaminidase activity. We investigated two Moroccan families affected by Sandhoff disease through a multidisciplinary approach combining biochemical, chromatographic, bio-informatic, and genetic analyses. Urinary sphingolipids were characterized as potential biomarkers using thin-layer chromatography (TLC), high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS), and molecular networking. Enzyme activity of β-hexosaminidase A and total β-hexosaminidase were measured, and next-generation sequencing (NGS) was performed to identify disease-causing mutations in the HEXB gene. Lipidomic profiling of urinary extracts demonstrated accumulation of Gb4 and lactosylceramides. This is the first report showing that Gb4 isoforms are excreted in the urine of Sandhoff patients, highlighting their value as reliable, accessible and non-invasive biomarkers for resource-limited settings. Representative Gb4 isoforms were structurally assigned, and their exact molecular formulas were determined in patient urine. Enzyme essay revealed a marked reduction of β-hexosaminidase activity, consistent with Sandhoff disease. Molecular networking confirmed the abnormal sphingolipid signature. Genetic analysis identified a novel homozygous variant in the HEXB gene (c.1543A > C; p.Ser515Arg), associated with a severe clinical phenotype and early mortality. Our study expands the mutation spectrum of HEXB and provides first evidence of urinary Gb4 isoform excretion as potential biomarkers, demonstrating the utility of integrating urinary sphingolipid profiling with NGS. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Ganglioside GM2; Globoside Gb4; Molecular networking; Novel HEXB variant; Sandhoff disease; Thin-layer chromatography |
| Substance Nomenclature: | EC 3.2.1.52 (beta-Hexosaminidase beta Chain) EC 3.2.1.52 (HEXB protein, human) 126550-86-5 (globotriaosyl lysosphingolipid) 0 (Protein Isoforms) 0 (Biomarkers) 0 (Globosides) 0 (Glycolipids) 0 (Sphingolipids) |
| Entry Date(s): | Date Created: 20260521 Date Completed: 20260611 Latest Revision: 20260611 |
| Update Code: | 20260611 |
| DOI: | 10.1016/j.ab.2026.116157 |
| PMID: | 42167572 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1096-0309 |
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| DOI: | 10.1016/j.ab.2026.116157 |