Clinical, neuroradiological, and biochemical features of SLC35A2-CDG patients
EPGEN Study
(2019) Journal of Inherited Metabolic Disease, volume 42, issue 3, pp. 553 - 564
(Article)
Abstract
SLC35A2-CDG is caused by mutations in the X-linked SLC35A2 gene encoding the UDP-galactose transporter. SLC35A2 mutations lead to hypogalactosylation of N-glycans. SLC35A2-CDG is characterized by severe neurological symptoms and, in many patients, early-onset epileptic encephalopathy. In view of the diagnostic challenges, we studied the clinical, neuroradiological, and biochemical features of
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15 patients (11 females and 4 males) with SLC35A2-CDG from various centers. We describe nine novel pathogenic variations in SLC35A2. All affected individuals presented with a global developmental delay, and hypotonia, while 70% were nonambulatory. Epilepsy was present in 80% of the patients, and in EEG hypsarrhythmia and findings consistent with epileptic encephalopathy were frequently seen. The most common brain MRI abnormality was cerebral atrophy with delayed myelination and multifocal inhomogeneous abnormal patchy white matter hyperintensities, which seemed to be nonprogressive. Thin corpus callosum was also common, and all the patients had a corpus callosum shorter than normal for their age. Variable dysmorphic features and growth deficiency were noted. Biochemically, normal mucin type O-glycosylation and lipid glycosylation were found, while transferrin mass spectrometry was found to be more specific in the identification of SLC35A2-CDG, as compared to routine screening tests. Although normal glycosylation studies together with clinical variability and genetic results complicate the diagnosis of SLC35A2-CDG, our data indicate that the combination of these three elements can support the pathogenicity of mutations in SLC35A2.
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Keywords: CDG, congenital glycosylation disorders, epileptic encephalopathy, infantile spasms, SLC35A2, Journal Article
ISSN: 0141-8955
Publisher: Springer Netherlands
Note: Funding Information: This work was supported and funded by the Estonian Research Council grant GARLA8175 and PUT355. Further financial support was obtained from the Netherlands Organization for Scientific Research (ZONMW Medium Investment grant 40-00506-98-9001 and VIDI grant 91713359 to DJL), and from the European Union's Horizon 2020 research and innovation program under the ERA-NET Cofund action N° 643578 (EURO-CDG-2), the Rocket Fund, and National Institutes of Health grant R01DK099551. Research study EPGEN is funded by the Canada Excellence Research Chair, leading Edge Endowment Fund, rare Diseases Foundation, Grocholski Foundation and Alva Foundations. Investigators in the EPGEN study, UBC, Canada include: Ilaria Guella, Shelin Adam, Cyrus Boelman, Corneliu Bolbocean, Sarah E. Buerki, Tara Candido, Patrice Eydoux, Daniel M.Evans, William Gibson, Gabriella Horvath, Linda Huh, Tanya N. Nelson, Graham Sinclair, Tam-sin Tarling, Eric B.Toyota, Katelin N. Townsend, Margot I. Van Allen, Clara van Karnebeek, and Susanne Vercauteren. Funding Information: Estonian Research Council, Grant/Award Numbers: GARLA8175, PUT355; H2020 European Institute of Innovation and Technology, Grant/Award Number: N° 643578; National Institutes of Health, Grant/ Award Number: R01DK099551; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: ZONMW Medium Investment grant 40-00506-98-9001, VIDI grant 91713359 Publisher Copyright: © 2019 SSIEM
(Peer reviewed)