title: X-Linked Cobalamin Disorder (HCFC1) Mimicking Nonketotic Hyperglycinemia With Increased Both Cerebrospinal Fluid Glycine and Methylmalonic Acid.
abstract: BACKGROUND
  Autosomal recessive or X-linked inborn errors of intracellular cobalamin metabolism can lead to methylmalonic aciduria and homocystinuria. In neonates, both increased cerebrospinal fluid glycine and cerebrospinal fluid/plasma glycine ratio are biochemical features of nonketotic hyperglycinemia.
  
  
  METHODS
  We describe a boy presenting in the neonatal period with hypotonia, tonic, clonic, and later myoclonic seizures, subsequently evolving into refractory epilepsy and severe neurocognitive impairment.
  
  
  RESULTS
  Increased cerebrospinal fluid glycine and cerebrospinal fluid to plasma glycine ratio were indicative of nonketotic hyperglycinemia. Early magnetic resonance imaging showed restricted diffusion and decreased apparent diffusion coefficient values in posterior limb of internal capsules and later in entire internal capsules and posterior white matter. Sequencing did not show a mutation in AMT, GLDC, or GCSH. Biochemical analysis identified persistently increased cerebrospinal fluid levels of glycine and methylmalonic acid and increased urinary methylmalonic acid and plasma homocysteine levels, which improved on higher parenteral hydroxocobalamin dose. Exome sequencing identified a known pathogenic sequence variant in X-linked cobalamin (HCFC1), c.344C>T, p. Ala115Val. In addition, a hemizygous mutation was found in the ATRX (c. 2728A>G, p. Lys910Glu). Retrospective review of two other patients with X-linked cobalamin deficiency also identified increased cerebrospinal fluid glycine levels.
  
  
  CONCLUSIONS
  This boy had X-linked cobalamin deficiency (HCFC1) with increased cerebrospinal fluid glycine and methylmalonic acid and increased cerebrospinal fluid to plasma glycine ratio suggesting a brain hyperglycinemia. Putative binding sites for HCFC1 and its binding partner THAP11 were identified near genes of the glycine cleavage enzyme, providing a potential mechanistic link between HCFC1 mutations and increased glycine.
authors.affiliation: Division of Pediatric Neurology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg; Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg. Electronic address: Emmanuel.scalais@gmail.com.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Scalais
authors.affiliation: Division of Pediatric Neurology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg; Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
authors.forename: Elise
authors.initials: E
authors.lastname: Osterheld
authors.affiliation: Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
authors.forename: Christiane
authors.initials: C
authors.lastname: Weitzel
authors.affiliation: Pediatric Neurology and Metabolism, Universitair Ziekenhuis, Brussel, Belgium.
authors.forename: Linda
authors.initials: L
authors.lastname: De Meirleir
authors.affiliation: Department of Neuroradiology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
authors.forename: Frederic
authors.initials: F
authors.lastname: Mataigne
authors.affiliation: VUB Metabolomics Platform, Department of Clinical Biology, Universitair Ziekenhuis, Brussel, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Martens
authors.affiliation: Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado.
authors.forename: Tamim H
authors.initials: TH
authors.lastname: Shaikh
authors.affiliation: Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Coughlin
authors.affiliation: Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado.
authors.forename: Hung-Chun
authors.initials: HC
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado.
authors.forename: Michael
authors.initials: M
authors.lastname: Swanson
authors.affiliation: Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado.
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Friederich
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Genetics Supervisor, Sequencing Core Diagnostic Manager, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Gunter
authors.initials: G
authors.lastname: Scharer
authors.affiliation: Molecular Genetics Supervisor, Sequencing Core Diagnostic Manager, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Daniel
authors.initials: D
authors.lastname: Helbling
authors.affiliation: Molecular Genetics Supervisor, Sequencing Core Diagnostic Manager, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Jamie
authors.initials: J
authors.lastname: Wendt-Andrae
authors.affiliation: Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado. Electronic address: Johan.Vanhove@childrenscolorado.org.
authors.forename: Johan L K
authors.initials: JLK
authors.lastname: Van Hove
mesh_terms: D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D001921:Brain / Q000000981:diagnostic imaging; D003937:Diagnosis, Differential; D040181:Genetic Diseases, X-Linked / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D005998:Glycine / Q000097:blood / Q000134:cerebrospinal fluid*; D006801:Humans; D020158:Hyperglycinemia, Nonketotic / Q000175:diagnosis*; D007231:Infant, Newborn; D008297:Male; D008764:Methylmalonic Acid / Q000134:cerebrospinal fluid*; D014806:Vitamin B 12 Deficiency / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics
chemical_list: D015415:Biomarkers; D008764:Methylmalonic Acid; D005998:Glycine
keywords: cobalamin metabolism; glycine; leukoencephalopathy; methylmalonic acid; refractory seizures; restricted diffusion