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J Inherit Metab Dis. 2019 May;42(3):553-564. doi: 10.1002/jimd.12055. Epub 2019 Feb 11.

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

Author information

1
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
2
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
3
Children's Clinic, Tartu University Hospital, Tartu, Estonia.
4
Donders Institute for Brain, Cognition, and Behavior, Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Radiology Clinic, Tartu University Hospital, Tartu, Estonia.
6
Department of Radiology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
7
GlycoScience Group, National Institute for Bioprocessing Research & Training, Dublin, Ireland.
8
Child Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
9
Department of Clinical and Experimental Medicine, Referral Centre for Inherited Metabolic Diseases, University of Catania, Catania, Italy.
10
Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
11
Department of Inborn Errors of Metabolism and Paediatrics, Institute of Mother and Child, Warsaw, Poland.
12
Child Developmental Center, Hospital Pediátrico, Center for Inherited Metabolic Diseases, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
13
Department of Medical Genetics, Shodair Children's Hospital, Helena, Montana.
14
Department of Neurology, University of North Carolina School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
15
Metabolic Unit, Great Ormond Street Hospital and Institute of Child Health, University College London, NHS Trust, London, UK.
16
Division Pediatrics, Metabolic Diseases, Wilhelmina Children's Hospital (Part of UMC Utrecht), Utrecht, The Netherlands.
17
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
18
Department of Clinical Genetics, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
19
Clinic of Children and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland.
20
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
21
Division of Biochemical Diseases, Department of Pediatrics, British Columbia Children's Hospital, UBC BC Children's Hospital Research Institute, Vancouver, Canada.
22
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
23
Department of Child Neurology and Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands.
24
Division of Neurology, Department of Pediatrics, University of British Columbia, Vancouver, Canada.
25
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.

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 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.

KEYWORDS:

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

PMID:
30746764
DOI:
10.1002/jimd.12055

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