4.4 Article

Clinical, neuroradiological, and biochemical features of SLC35A2-CDG patients

Journal

JOURNAL OF INHERITED METABOLIC DISEASE
Volume 42, Issue 3, Pages 553-564

Publisher

WILEY
DOI: 10.1002/jimd.12055

Keywords

CDG; congenital glycosylation disorders; epileptic encephalopathy; infantile spasms; SLC35A2

Funding

  1. Estonian Research Council [GARLA8175, PUT355]
  2. Netherlands Organization for Scientific Research (ZONMW Medium Investment grant) [40-00506-98-9001]
  3. Netherlands Organization for Scientific Research (VIDI grant) [91713359]
  4. European Union's Horizon 2020 research and innovation program under the ERA-NET Cofund action [643578]
  5. Rocket Fund
  6. National Institutes of Health [R01DK099551]
  7. Canada Excellence Research Chair
  8. leading Edge Endowment Fund
  9. rare Diseases Foundation
  10. Grocholski Foundation
  11. Alva Foundations

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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 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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