Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG

doi:10.1038/s41436-020-0767-8

. 2020 Jun;22(6):1102-1107.

doi: 10.1038/s41436-020-0767-8. Epub 2020 Feb 27.

Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG

Peter Witters^{1

2}, Shawn Tahata³, Rita Barone⁴, Katrin Õunap^{5

6}, Ramona Salvarinova⁷, Sabine Grønborg⁸, George Hoganson⁹, Fernando Scaglia^{10

11

12}, Andrea Margaret Lewis¹⁰, Mari Mori¹³, Jolanta Sykut-Cegielska¹⁴, Andrew Edmondson^#¹⁵, Miao He^#¹⁶, Eva Morava^#^{17

18

19}

Affiliations

¹ Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium.
² Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
³ Department of Clinical Genomics, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
⁴ Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
⁵ Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
⁶ Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
⁷ Children's & Women's Health Centre of British Columbia, Vancouver, BC, Canada.
⁸ Center for Inherited Metabolic Diseases, Department of Pediatrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
⁹ Department of Pediatrics, University of Illinois, IL, Chicago, USA.
¹⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
¹¹ Texas Children's Hospital, Houston, TX, USA.
¹² Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Shatin, Hong Kong.
¹³ Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
¹⁴ Department of Inborn Errors of Metabolism and Paediatrics, Institute of Mother and Child, Warsaw, Poland.
¹⁵ Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁶ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁷ Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium. peter.witters@uzleuven.be.
¹⁸ Department of Development and Regeneration, KU Leuven, Leuven, Belgium. peter.witters@uzleuven.be.
¹⁹ Department of Clinical Genomics, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. peter.witters@uzleuven.be.

^# Contributed equally.

PMID: 32103184
PMCID: PMC7275909
DOI: 10.1038/s41436-020-0767-8

Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG

Peter Witters et al. Genet Med. 2020 Jun.

. 2020 Jun;22(6):1102-1107.

doi: 10.1038/s41436-020-0767-8. Epub 2020 Feb 27.

Authors

Affiliations

¹ Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium.
² Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
³ Department of Clinical Genomics, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
⁴ Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
⁵ Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
⁶ Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
⁷ Children's & Women's Health Centre of British Columbia, Vancouver, BC, Canada.
⁸ Center for Inherited Metabolic Diseases, Department of Pediatrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
⁹ Department of Pediatrics, University of Illinois, IL, Chicago, USA.
¹⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
¹¹ Texas Children's Hospital, Houston, TX, USA.
¹² Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Shatin, Hong Kong.
¹³ Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
¹⁴ Department of Inborn Errors of Metabolism and Paediatrics, Institute of Mother and Child, Warsaw, Poland.
¹⁵ Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁶ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁷ Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium. peter.witters@uzleuven.be.
¹⁸ Department of Development and Regeneration, KU Leuven, Leuven, Belgium. peter.witters@uzleuven.be.
¹⁹ Department of Clinical Genomics, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. peter.witters@uzleuven.be.

^# Contributed equally.

PMID: 32103184
PMCID: PMC7275909
DOI: 10.1038/s41436-020-0767-8

Abstract

Purpose: We studied galactose supplementation in SLC35A2-congenital disorder of glycosylation (SLC35A2-CDG), caused by monoallelic pathogenic variants in SLC35A2 (Xp11.23), encoding the endoplasmic reticulum (ER) and Golgi UDP-galactose transporter. Patients present with epileptic encephalopathy, developmental disability, growth deficiency, and dysmorphism.

Methods: Ten patients with SLC35A2-CDG were supplemented with oral D-galactose for 18 weeks in escalating doses up to 1.5 g/kg/day. Outcome was assessed using the Nijmegen Pediatric CDG Rating Scale (NPCRS, ten patients) and by glycomics (eight patients).

Results: SLC35A2-CDG patients demonstrated improvements in overall Nijmegen Pediatric CDG Rating Scale (NPCRS) score (P = 0.008), the current clinical assessment (P = 0.007), and the system specific involvement (P = 0.042) domains. Improvements were primarily in growth and development with five patients resuming developmental progress, which included postural control, response to stimuli, and chewing and swallowing amelioration. Additionally, there were improvements in gastrointestinal symptoms and epilepsy. One patient in our study did not show any clinical improvement. Galactose supplementation improved patients' glycosylation with decreased ratios of incompletely formed to fully formed glycans (M-gal/disialo, P = 0.012 and monosialo/disialo, P = 0.017) and increased levels of a fully galactosylated N-glycan (P = 0.05).

Conclusions: Oral D-galactose supplementation results in clinical and biochemical improvement in SLC35A2-CDG. Galactose supplementation may partially overcome the Golgi UDP-galactose deficiency and improves galactosylation. Oral galactose is well tolerated and shows promise as dietary therapy.

Keywords: Nijmegen Pediatric CDG Rating Scale (NPCRS); SLC35A2-CDG; galactose; glycan; glycosylation.

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Conflict of interest statement

Conflict of interests

There are no conflicts of interests for any of the authors.

Figures

**Figure 1**
a Total score in Nijmegen pediatric CDG rating scale (before and after galactose supplementation) Mean total NPCRS score improved from 28.7 ± 9.7 to 24.6 ± 9.6 (P = 0.008) b System specific involvement in NCPRS (before and after galactose supplementation) System specific involvement improved from 5.1 ± 2.7 to 3.6 ± 2.6 (P = 0.042) c Current clinical assessment in NCPRS (before and after galactose supplementation) Current clinical assessment improved from 12.1 ± 3.8 to 10.2 ± 3.7 (P = 0.007)

**Figure 2. Glycomics before and after galactose supplementation**
a: A decrease in the mono-Gal/Di sialo upon treatment from 0.74 ± 1.27 to 0.45 ± 0.68 (p=0.011) b: A decrease in mono-sialic/disialic upon treatment from 0.51 ± 0.1 to 0.42 ± 0.09 (p=0.017)

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References

1. Kodera H, Nakamura K, Osaka H, et al. De novo mutations in SLC35A2 encoding a UDP-galactose transporter cause early-onset epileptic encephalopathy. Hum Mutat. 2013;34:1708–1714. - PubMed
1. Ng BG, Buckingham KJ, Raymond K, et al. Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation. Am J Hum Genet. 2013;92:632–636. - PMC - PubMed
1. Ng BG, Sosicka P, Agadi S, et al. SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals. Hum Mutat. 2019;40:908–925. - PMC - PubMed
1. Dörre K, Olczak M, Wada Y, et al. A new case of UDP-galactose transporter deficiency (SLC35A2-CDG): molecular basis, clinical phenotype, and therapeutic approach. J Inherit Metab Dis. 2015;38:931–940. - PubMed
1. Kimizu T, Takahashi Y, Oboshi T, et al. A case of early onset epileptic encephalopathy with de novo mutation in SLC35A2: Clinical features and treatment for epilepsy. Brain Dev. 2017;39:256–260. - PubMed

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[1] Kodera H, Nakamura K, Osaka H, et al. De novo mutations in SLC35A2 encoding a UDP-galactose transporter cause early-onset epileptic encephalopathy. Hum Mutat. 2013;34:1708–1714. - PubMed

[2] Kodera H, Nakamura K, Osaka H, et al. De novo mutations in SLC35A2 encoding a UDP-galactose transporter cause early-onset epileptic encephalopathy. Hum Mutat. 2013;34:1708–1714. - PubMed

[3] Ng BG, Buckingham KJ, Raymond K, et al. Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation. Am J Hum Genet. 2013;92:632–636. - PMC - PubMed

[4] Ng BG, Buckingham KJ, Raymond K, et al. Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation. Am J Hum Genet. 2013;92:632–636. - PMC - PubMed

[5] Ng BG, Sosicka P, Agadi S, et al. SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals. Hum Mutat. 2019;40:908–925. - PMC - PubMed

[6] Ng BG, Sosicka P, Agadi S, et al. SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals. Hum Mutat. 2019;40:908–925. - PMC - PubMed

[7] Dörre K, Olczak M, Wada Y, et al. A new case of UDP-galactose transporter deficiency (SLC35A2-CDG): molecular basis, clinical phenotype, and therapeutic approach. J Inherit Metab Dis. 2015;38:931–940. - PubMed

[8] Dörre K, Olczak M, Wada Y, et al. A new case of UDP-galactose transporter deficiency (SLC35A2-CDG): molecular basis, clinical phenotype, and therapeutic approach. J Inherit Metab Dis. 2015;38:931–940. - PubMed

[9] Kimizu T, Takahashi Y, Oboshi T, et al. A case of early onset epileptic encephalopathy with de novo mutation in SLC35A2: Clinical features and treatment for epilepsy. Brain Dev. 2017;39:256–260. - PubMed

[10] Kimizu T, Takahashi Y, Oboshi T, et al. A case of early onset epileptic encephalopathy with de novo mutation in SLC35A2: Clinical features and treatment for epilepsy. Brain Dev. 2017;39:256–260. - PubMed

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Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG

Affiliations

Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG

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