Abstract
Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GM3D) causes an absence of GM3 and all downstream biosynthetic derivatives. The affected individuals manifest with severe irritability, intractable seizures, and profound intellectual disability. The current study is to assess the effects of an oral ganglioside supplement to patients with GM3D, particularly on their growth and development during early childhood. A total of 13 young children, 11 of them under 40 months old, received oral ganglioside supplement through a dairy product enriched in gangliosides, for an average of 34 months. Clinical improvements were observed in most children soon after the supplement was initiated. Significantly improved growth and development were documented in these subjects as average percentiles for weight, height, and occipitofrontal circumference increased in 1–2 months. Three children with initial microcephaly demonstrated significant catch-up head growth and became normocephalic. We also illustrated brief improvements in developmental and cognitive scores, particularly in communication and socialization domains through Vineland-II. However, all improvements seemed transient and gradually phased out after 12 months of supplementation. Gangliosides GM1 and GM3, although measureable in plasma during the study, were not significantly changed with ganglioside supplementation for up to 30 months. We speculate that the downstream metabolism of ganglioside biosynthesis is fairly active and the potential need for gangliosides in the human body is likely substantial. As we search for new effective therapies for GM3D, approaches to reestablish endogenous ganglioside supplies in the affected individuals should be considered.
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Acknowledgments
We thank the families for their patience and support. We appreciate many physicians who provided outstanding and compassionate care to the children affected by the disease. The study was supported in part by Fonterra (via the New Zealand Primary Growth Partnership program, funded by Fonterra Co-operative Group Ltd and the NZ Ministry for Primary Industries) and the Zverina Family Foundation.
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Communicated by: Roberto Giugliani, MD, PhD
Electronic Supplementary Material
Supplementary Table 1
Study protocol and flowchart (DOCX 24 kb)
Supplementary Table 2
Extractions of comments from parents during the study (DOCX 19 kb)
Supplementary Table 3
Selective Vineland Adaptive Behavior Scales – Second Edition (Vineland-II) in GM3D patients receiving G500 (DOCX 20 kb)
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One Sentence Take-Home Message
Oral ganglioside supplement significantly improves growth and development in patients with ganglioside GM3 synthase deficiency; however, the improvements seem transient and gradually phase out after 12 months.
Contributions of Individual Authors
All authors participated in the conduct of the study, and Heng Wang, Paul McJarrow, Aimin Zhou, and Baozhong Xin contributed to the planning and reporting of the work.
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Heng Wang
Competing Interest
Heng Wang, as a principal investigator, received funding support from Fonterra Co-operative Group Ltd. to DDC Clinic for this study and also served as a speaker for a Fonterra-organized symposium. Paul McJarrow and Angela Rowan are employees of Fonterra.
Funding
The study was supported in part by Fonterra (via the New Zealand Primary Growth Partnership program, funded by Fonterra Co-operative Group Ltd and the NZ Ministry for Primary Industries) and Zverina Family Foundation. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.
Ethics Approval and Patients Consent
The study was approved by the DDC Clinic IRB, and written informed consent was obtained from the patients’ legal guardians and available upon request (ClinicalTrials.gov Identifier: NCT02234024).
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© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)
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Wang, H. et al. (2018). Oral Ganglioside Supplement Improves Growth and Development in Patients with Ganglioside GM3 Synthase Deficiency. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 45. JIMD Reports, vol 45. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_134
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DOI: https://doi.org/10.1007/8904_2018_134
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