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

doi:10.1016/j.braindev.2023.01.002

. 2023 May;45(5):270-277.

doi: 10.1016/j.braindev.2023.01.002. Epub 2023 Jan 21.

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

Shiena Watanabe¹, Ming Lei², Eiji Nakagawa³, Eri Takeshita¹, Kei-Ichiro Inamori⁴, Fumi Shishido⁵, Masayuki Sasaki¹, Satomi Mitsuhashi⁶, Naomichi Matsumoto², Yuiko Kimura⁷, Masaki Iwasaki⁷, Yuji Takahashi⁸, Hidehiro Mizusawa⁸, Ohsuke Migita⁹, Isao Ohno⁵, Jin-Ichi Inokuchi¹⁰

Affiliations

¹ Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan.
² Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan.
³ Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan. Electronic address: nakagawa@ncnp.go.jp.
⁴ Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Japan.
⁵ Center for Medical Education, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Japan.
⁶ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan; Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Japan.
⁷ Department of Neurosurgery, National Center Hospital, National Center of Neurology and Psychiatry, Japan.
⁸ Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan.
⁹ Department of Laboratory Medicine, St. Marianna University, School of Medicine, Japan.
¹⁰ Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Japan; Forefront Research Center, Graduate School of Science, Osaka University, Japan.

PMID: 36690566
DOI: 10.1016/j.braindev.2023.01.002

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

Shiena Watanabe et al. Brain Dev. 2023 May.

. 2023 May;45(5):270-277.

doi: 10.1016/j.braindev.2023.01.002. Epub 2023 Jan 21.

Authors

Affiliations

¹ Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan.
² Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan.
³ Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan. Electronic address: nakagawa@ncnp.go.jp.
⁴ Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Japan.
⁵ Center for Medical Education, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Japan.
⁶ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan; Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Japan.
⁷ Department of Neurosurgery, National Center Hospital, National Center of Neurology and Psychiatry, Japan.
⁸ Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan.
⁹ Department of Laboratory Medicine, St. Marianna University, School of Medicine, Japan.
¹⁰ Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Japan; Forefront Research Center, Graduate School of Science, Osaka University, Japan.

PMID: 36690566
DOI: 10.1016/j.braindev.2023.01.002

Abstract

Background: 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.

Case: 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.

Discussion: 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.

Keywords: Deep brain stimulation; Developmental delay; Epilepsy; GM3 synthase deficiency; Ganglioside; Involuntary movement; ST3GAL5.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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

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

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