Emmanuel Scalais1, Elise Osterheld2, Christiane Weitzel3, Linda De Meirleir4, Frederic Mataigne5, Geert Martens6, Tamim H Shaikh7, Curtis R Coughlin7, Hung-Chun Yu7, Michael Swanson7, Marisa W Friederich7, Gunter Scharer8, Daniel Helbling9, Jamie Wendt-Andrae9, Johan L K Van Hove10. 1. 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. 2. Division of Pediatric Neurology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg; Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg. 3. Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg. 4. Pediatric Neurology and Metabolism, Universitair Ziekenhuis, Brussel, Belgium. 5. Department of Neuroradiology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg. 6. VUB Metabolomics Platform, Department of Clinical Biology, Universitair Ziekenhuis, Brussel, Belgium. 7. Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado. 8. 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. 9. Molecular Genetics Supervisor, Sequencing Core Diagnostic Manager, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin. 10. Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado. Electronic address: Johan.Vanhove@childrenscolorado.org.
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.
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: Emmanuel Scalais; Elise Osterheld; Christine Geron; Charlotte Pierron; Ronit Chafai; Vincent Schlesser; Patricia Borde; Luc Regal; Hilde Laeremans; Koen L I van Gassen; L Bert van den Heuvel; Linda De Meirleir Journal: JIMD Rep Date: 2019-07-01