X-linked cobalamin disorder (HCF1) mimicking nonketotic hyperglycinemia with increased both CSF glycine and methylmalonic acid

Publication date: Available online 7 January 2017
Source:Pediatric Neurology
Author(s): Emmanuel Scalais, Elise Osterheld, Christiane Weitzel, Linda De Meirleir, Frederic Mataigne, Geert Martens, Tamim H. Shaikh, Curtis R. Coughlin, Hung-Chun Yu, Michael Swanson, Marisa W. Friederich, Gunter Scharer, Daniel Helbling, Jamie Wendt-Andrae, Johan Van Hove
BackgroundAutosomal recessive or X-linked inborn errors of intracellular cobalamin metabolism can lead to methylmalonic aciduria and homocystinuria. In neonates, both increased cerebrospinal fluid (CSF) glycine and CSF/plasma glycine ratio is a biochemical feature of non-ketotic hyperglycinemia.Patient DescriptionWe 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. Increased CSF glycine and CSF/plasma glycine ratio were indicative of nonketotic hyperglycinemia. Early magnetic resonance imaging showed restricted diffusion and decreased apparent diffusion coefficient (ADC) 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 elevated CSF levels of glycine and methylmalonic acid (MMA) and increased urinary MMA 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. Additionally, a hemizygous mutation was found in the ATRX (c. 2728A>G, p. Lys910Glu). Retrospective review of two other patients with X-linked cobalamin also identified elevated CSF glycine levels.ConclusionThis boy had cobalamin X-linked (HCFC1 deficiency) with increased CSF glycine and MMA and increased CSF/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 elevated glycine.



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