title: Mutations in SLC25A22: hyperprolinaemia, vacuolated fibroblasts and presentation with developmental delay.
abstract: Mutations in SLC25A22 are known to cause neonatal epileptic encephalopathy and migrating partial seizures in infancy. Using whole exome sequencing we identified four novel SLC25A22 mutations in six children from three families. Five patients presented clinical features similar to those in the literature including hypotonia, refractory neonatal-onset seizures and developmental delay. However, the sixth patients presented atypically with isolated developmental delay, developing late-onset (absence) seizures only at 7 years of age. Abnormal metabolite levels have not been documented in the nine patients described previously. One patient in our series was referred to the metabolic clinic because of persistent hyperprolinaemia and another three had raised plasma proline when tested. Analysis of the post-prandial plasma amino acid response in one patient showed abnormally high concentrations of several amino acids. This suggested that, in the fed state, when amino acids are the preferred fuel for the liver, trans-deamination of amino acids requires transportation of glutamate into liver mitochondria by SLC25A22 for deamination by glutamate dehydrogenase; SLC25A22 is an important mitochondrial glutamate transporter in liver as well as in brain. Electron microscopy of patient fibroblasts demonstrated widespread vacuolation containing neutral and phospho-lipids as demonstrated by Oil Red O and Sudan Black tinctorial staining; this might be explained by impaired activity of the proline/pyrroline-5-carboxylate (P5C) shuttle if SLC25A22 transports pyrroline-5-carboxylate/glutamate-γ-semialdehyde as well as glutamate.
authors.affiliation: Centre for Translational Omics, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Emma S
authors.initials: ES
authors.lastname: Reid
authors.affiliation: Centre for Translational Omics, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Hywel
authors.initials: H
authors.lastname: Williams
authors.affiliation: Histopathology Department, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.
authors.forename: Glenn
authors.initials: G
authors.lastname: Anderson
authors.affiliation: Histopathology Department, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.
authors.forename: Malika
authors.initials: M
authors.lastname: Benatti
authors.affiliation: Radiology Department, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.
authors.forename: Kling
authors.initials: K
authors.lastname: Chong
authors.affiliation: Centre for Translational Omics, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Chela
authors.initials: C
authors.lastname: James
authors.affiliation: Centre for Translational Omics, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Ocaka
authors.affiliation: Neurology Department, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Hemingway
authors.affiliation: Centre for Translational Omics, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.|The Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Little
authors.affiliation: Peterborough and Stamford Hospitals NHS Foundation Trust, Edith Cavell Campus, Bretton Gate, Peterborough, PE3 9GZ, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Brown
authors.affiliation: Child Development Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Parker
authors.affiliation: Clinical Genetics, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Holden
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Footitt
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.|Mitochondrial Research Group, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.affiliation: Centre for Translational Omics, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.|The Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.|Metabolic Medicine Department, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.affiliation: Centre for Translational Omics, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.affiliation: Centre for Translational Omics, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. peter.clayton@ucl.ac.uk.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011392:Proline / Q000378:metabolism; D012640:Seizures / Q000235:genetics / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; C499215:SLC25A22 protein, human; D018698:Glutamic Acid; D011392:Proline