Neurological insights on two siblings with GM3 synthase deficiency due to novel compound heterozygous ST3GAL5 variants



      ST3GAL5 encodes GM3 synthase (ST3 beta-galactoside alpha-2,3-sialyltransferase 5; ST3GAL5), which synthesizes GM3 by transferring sialic acid to lactosylceramide. GM3, a sialic acid-containing glycosphingolipid known as ganglioside, is a precursor to the biosynthesis of various more complex gangliosides that are active in the brain. Biallelic variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD), a rare congenital disorder of glycosylation. GM3SD was first identified in the Amish population in 2004.


      We report two siblings diagnosed with GM3SD due to novel compound heterozygous ST3GAL5 variants. The novel ST3GAL5 variants, detected by whole-exome sequencing in the patients, were confirmed to be pathogenic by GM3 synthase assay. The clinical courses of these patients, which began in infancy with irritability and growth failure, followed by developmental delay and hearing loss, were consistent with previous case reports of GM3SD. The older sibling underwent deep brain stimulation for severe involuntary movements at the age of 9 years. The younger sibling suffered from acute encephalopathy at the age of 9 months and subsequently developed refractory epilepsy.


      Reports of GM3SD outside the Amish population are rare, and whole-exome sequencing may be required to diagnose GM3SD in non-Amish patients. Since an effective treatment for GM3SD has not yet been established, we might select deep brain stimulation as a symptomatic treatment for involuntary movements in GM3SD.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Simpson M.A.
        • Cross H.
        • Proukakis C.
        • Priestman D.A.
        • Neville D.C.
        • Reinkensmeier G.
        • et al.
        Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.
        Nat Genet. 2004; 36: 1225-1229
        • Paprocka J.
        • Jezela-Stanek A.
        • Tylki-Szymanska A.
        • Grunewald S.
        Congenital Disorders of Glycosylation from a Neurological Perspective.
        Brain Sci. 2021; 11: 88
        • Schengrund C.L.
        Gangliosides: glycosphingolipids essential for normal neural development and function.
        Trends Biochem Sci. 2015; 40: 397-406
        • Schnaar R.L.
        Gangliosides of the vertebrate nervous system.
        J Mol Biol. 2016; 428: 3325-3336
        • Strekalova T.
        • Veniaminova E.
        • Svirin E.
        • Kopeikina E.
        • Veremeyko T.
        • Yung A.W.Y.
        • et al.
        Sex-Specific ADHD-like behaviour, altered metabolic functions, and altered EEG activity in sialyltransferase ST3GAL5-deficient mice.
        Biomolecules. 2021; 11: 1759
        • Strekalova T.
        • Svirin E.
        • Veniaminova E.
        • Kopeikina E.
        • Veremeyko T.
        • Yung A.W.Y.
        • et al.
        ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5.
        Brain Behav Immun Health. 2021; 16: 100306
        • Takahashi Y.
        • Date H.
        • Oi H.
        • Adachi T.
        • Imanishi N.
        • Kimura E.
        • et al.
        Six years' accomplishment of the Initiative on Rare and Undiagnosed Diseases: nationwide project in Japan to discover causes, mechanisms, and cures.
        J Hum Genet. 2022; 67: 505-513
        • Seyama R.
        • Tsuchida N.
        • Okada Y.
        • Sakata S.
        • Hamada K.
        • Azuma Y.
        • et al.
        Two families with TET3-related disorder showing neurodevelopmental delay with craniofacial dysmorphisms.
        J Hum Genet. 2022; 67: 157-164
        • Uemura S.
        • Yoshida S.
        • Shishido F.
        • Inokuchi J.
        The cytoplasmic tail of GM3 synthase defines its subcellular localization, stability, and in vivo activity.
        Mol Biol Cell. 2009; 20: 3088-3100
        • Nihei W.
        • Nagafuku M.
        • Hayamizu H.
        • Odagiri Y.
        • Tamura Y.
        • Kikuchi Y.
        • et al.
        NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains.
        J Lipid Res. 2018; 59: 2181-2187
      1. Inamori K, Nitta T, Shishido F, Watanabe S, Ohno I, Inokuchi J. Sialyltransferase activity assay for ganglioside GM3 synthase. Methods Mol. Biol. “Glycolipids: Methods and Protocols”: Springer; 2023. in press.

        • Harrus D.
        • Kellokumpu S.
        • Glumoff T.
        Crystal structures of eukaryote glycosyltransferases reveal biologically relevant enzyme homooligomers.
        Cell Mol Life Sci. 2018; 75: 833-848
        • Lee J.S.
        • Yoo Y.
        • Lim B.C.
        • Kim K.J.
        • Song J.
        • Choi M.
        • et al.
        GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome-like phenotype.
        Am J Med Genet A. 2016; 170: 2200-2205
        • Heide S.
        • Jacquemont M.L.
        • Cheillan D.
        • Renouil M.
        • Tallot M.
        • Schwartz C.E.
        • et al.
        GM3 synthase deficiency in non-Amish patients.
        Genet Med. 2022; 24: 492-498
        • Bowser L.E.
        • Young M.
        • Wenger O.K.
        • Ammous Z.
        • Brigatti K.W.
        • Carson V.J.
        • et al.
        Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier.
        Mol Genet Metab. 2019; 126: 475-488
        • Fragaki K.
        • Ait-El-Mkadem S.
        • Chaussenot A.
        • Gire C.
        • Mengual R.
        • Bonesso L.
        • et al.
        Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.
        Eur J Hum Genet. 2013; 21: 528-534
        • Tang F.L.
        • Wang J.
        • Itokazu Y.
        • Yu R.K.
        Enhanced susceptibility to chemoconvulsant-Induced seizures in ganglioside GM3 synthase knockout mice.
        ASN Neuro. 2020; 12 (1759091420938175)
        • Yoshikawa M.
        • Go S.
        • Takasaki K.
        • Kakazu Y.
        • Ohashi M.
        • Nagafuku M.
        • et al.
        Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti.
        Proc Natl Acad Sci U S A. 2009; 106: 9483-9488
        • Yoshikawa M.
        • Go S.
        • Suzuki S.
        • Suzuki A.
        • Katori Y.
        • Morlet T.
        • et al.
        Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells.
        Hum Mol Genet. 2015; 24: 2796-2807
        • Hiraoka M.
        • Ohkawa E.
        • Abe A.
        • Murata M.
        • Go S.
        • Inokuchi J.I.
        • et al.
        Visual function in mice lacking GM3 synthase.
        Curr Eye Res. 2019; 44: 664-670
        • Wang H.
        • Sency V.
        • McJarrow P.
        • Bright A.
        • Huang Q.
        • Cechner K.
        • et al.
        Oral ganglioside supplement improves growth and development in patients with ganglioside GM3 synthase deficiency.
        JIMD Rep. 2019; 45: 9-20
        • Wang H.
        • Wang A.
        • Wang D.
        • Bright A.
        • Sency V.
        • Zhou A.
        • et al.
        Early growth and development impairments in patients with ganglioside GM3 synthase deficiency.
        Clin Genet. 2016; 89: 625-629
        • Yang H.
        • Brown Jr., R.H.
        • Wang D.
        • Strauss K.A.
        • Gao G.
        AAV-mediated gene therapy for glycosphingolipid biosynthesis deficiencies.
        Trends Mol Med. 2021; 27: 520-523
        • Kabayama K.
        • Sato T.
        • Saito K.
        • Loberto N.
        • Prinetti A.
        • Sonnino S.
        • et al.
        Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance.
        Proc Natl Acad Sci U S A. 2007; 104: 13678-13683