title: A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders.
abstract: SLC39A8 variants have recently been reported to cause a type II congenital disorder of glycosylation (CDG) in patients with intellectual disability and cerebellar atrophy. Here we report a novel SLC39A8 variant in siblings with features of Leigh-like mitochondrial disease. Two sisters born to consanguineous Lebanese parents had profound developmental delay, dystonia, seizures and failure to thrive. Brain MRI of both siblings identified bilateral basal ganglia hyperintensities on T2-weighted imaging and cerebral atrophy. CSF lactate was elevated in patient 1 and normal in patient 2. Respiratory chain enzymology was only performed on patient 1 and revealed complex IV and II + III activity was low in liver, with elevated complex I activity. Complex IV activity was borderline low in patient 1 muscle and pyruvate dehydrogenase activity was reduced. Whole genome sequencing identified a homozygous Chr4(GRCh37):g.103236869C>G; c.338G>C; p.(Cys113Ser) variant in SLC39A8, located in one of eight regions identified by homozygosity mapping. SLC39A8 encodes a manganese and zinc transporter which localises to the cell and mitochondrial membranes. Patient 2 blood and urine manganese levels were undetectably low. Transferrin electrophoresis of patient 2 serum revealed a type II CDG defect. Oral supplementation with galactose and uridine led to improvement of the transferrin isoform pattern within 14 days of treatment initiation. Oral manganese has only recently been added to the treatment. These results suggest SLC39A8 deficiency can cause both a type II CDG and Leigh-like syndrome, possibly via reduced activity of the manganese-dependent enzymes β-galactosyltransferase and mitochondrial manganese superoxide dismutase.
authors.affiliation: Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, KRI, Level 3, Locked Bag 4001, Westmead, NSW, 2145, Australia. lisa.riley@health.nsw.gov.au.|Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. lisa.riley@health.nsw.gov.au.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Riley
authors.affiliation: Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.affiliation: Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Velimir
authors.initials: V
authors.lastname: Gayevskiy
authors.affiliation: Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, Australia.|Department of Medical Genetics, Sydney Children's Hospital, Randwick, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
authors.affiliation: Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: Medical Imaging Department, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Prelog
authors.affiliation: Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.|Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.|Department of Neurogenetics, Kolling Institute of Medical Research, University of Sydney and Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
authors.affiliation: Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia.|Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Shanti
authors.initials: S
authors.lastname: Balasubramaniam
authors.affiliation: Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, KRI, Level 3, Locked Bag 4001, Westmead, NSW, 2145, Australia.|Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.|Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia.|Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D018981:Congenital Disorders of Glycosylation / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000235:genetics; D008345:Manganese / Q000172:deficiency*; D028361:Mitochondrial Diseases / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; C530151:SLC39A8 protein, human; D008345:Manganese