D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.
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We thank Cindy Cohen for professional language editing.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Emek Medical Center ethics committee (study no. EMC-0067-09).
Informed consent for participation in the study and publication of the study case was obtained from all individual participants included in the study or their legally authorized representative (parents).
Bonham JR, Stephenson TJ, Carpenter KH, Rattenbury JM, Cromby CH, Pollitt RJ, Hull D (1990) D(+)-glyceric aciduria: etiology and clinical consequences. Pediatr Res 28(1):38–41CrossRefGoogle Scholar
Brandt NJ, Brandt S, Rasmussen K, Schnoheyder F (1974) Letter: Hyperglycericacidaemia with hyperglycinaemia: a new inborn error of metabolism. Br Med J 4(5940):344CrossRefGoogle Scholar
Cramer SD, Ferree PM, Lin K, Milliner DS, Holmes RP (1999) The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II. Hum Mol Genet 8(11):2063–2069CrossRefGoogle Scholar
Dimer NW, Schuck PF, Streck EL, Ferreira GC (2015) D-glyceric aciduria. An Acad Bras Cienc 87(2 Suppl):1409–1414CrossRefGoogle Scholar
Duran M, Beemer FA, Bruinvis L, Ketting D, Wadman SK (1987) D-glyceric acidemia: an inborn error associated with fructose metabolism. Pediatr Res 21(5):502–506CrossRefGoogle Scholar
Finsterer J (2017) Toxicity of antiepileptic drugs to mitochondria. Handb Exp Pharmacol 240:473–488CrossRefGoogle Scholar
Fontaine M, Porchet N, Largilliere C, Marrakchi S, Lhermitte M, Aubert JP, Degand P (1989) Biochemical contribution to diagnosis and study of a new case of D-glyceric acidemia/aciduria. Clin Chem 35(10):2148–2151PubMedGoogle Scholar
Grandgeorge D, Favier A, Bost M, Frappat P, Bon-Jet C, Garnel S (1980) L'acidemie D-glycerique: a propos d'une nouvelle obsevation anatomo-clinique. Arch Fr Pediatr (37):577–584Google Scholar
Guo JH, Hexige S, Chen L, Zhou GJ, Wang X, Jiang JM, Kong YH, Ji GQ, Wu CQ, Zhao SY, Yu L (2006) Isolation and characterization of the human D-glyceric acidemia related glycerate kinase gene GLYCTK1 and its alternatively splicing variant GLYCTK2. DNA Seq 17(1):1–7CrossRefGoogle Scholar
Insuga VMS, Requena PT, Bermejo AM, Merino M, De La Puente AJA, Viana H, Murias S, Garcia MJ (2010) Aciduria D- glicerica. A proposito de un caso y revision de la bibiliografia. Acta Pediatr Esp (68):79–83Google Scholar
Kalim A, Fitzsimons P, Till C, Fernando M, Mayne P, Sass JO, Crushell E (2017) Further evidence that d-glycerate kinase (GK) deficiency is a benign disorder. Brain and Development 39(6):536–538CrossRefGoogle Scholar
Kehrer D, Ahmed H, Brinkmann H, Siebers B (2007) Glycerate kinase of the hyperthermophilic archaeon Thermoproteus tenax: new insights into the phylogenetic distribution and physiological role of members of the three different glycerate kinase classes. BMC Genomics 8:301CrossRefGoogle Scholar
Rashed MS, Aboul-Enein HY, AlAmoudi M, Jakob M, Al-Ahaideb LY, Abbad A, Shabib S, Al-Jishi E (2002) Chiral liquid chromatography tandem mass spectrometry in the determination of the configuration of glyceric acid in urine of patients with D-glyceric and L-glyceric acidurias. Biomed Chromatogr 16(3):191–198CrossRefGoogle Scholar
Saada A, Bar-Meir M, Belaiche C, Miller C, Elpeleg O (2004) Evaluation of enzymatic assays and compounds affecting ATP production in mitochondrial respiratory chain complex I deficiency. Anal Biochem 335(1):66–72CrossRefGoogle Scholar
Sass JO, Fischer K, Wang R, Christensen E, Scholl-Burgi S, Chang R, Kapelari K, Walter M (2010) D-glyceric aciduria is caused by genetic deficiency of D-glycerate kinase (GLYCTK). Hum Mutat 31(12):1280–1285CrossRefGoogle Scholar
Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11(4):361–362CrossRefGoogle Scholar
Struys EA, Jansen EE, Verhoeven NM, Jakobs C (2004) Measurement of urinary D- and L-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after derivatization with diacetyl-L-tartaric anhydride. Clin Chem 50(8):1391–1395CrossRefGoogle Scholar
Swanson MA, Garcia SM, Spector E, Kronquist K, Creadon-Swindell G, Walter M, Christensen E, Van Hove JLK, Sass JO (2017) D-Glyceric aciduria does not cause nonketotic hyperglycinemia: a historic co-occurrence. Mol Genet Metab 121(2):80–82CrossRefGoogle Scholar
Topcu M, Saatci I, Haliloglu G, Kesimer M, Coskun T (2002) D-glyceric aciduria in a six-month-old boy presenting with west syndrome and autistic behaviour. Neuropediatrics 33(1):47–50CrossRefGoogle Scholar
Van Schaftingen E (1989) D-glycerate kinase deficiency as a cause of D-glyceric aciduria. FEBS Lett 243(2):127–131CrossRefGoogle Scholar
Wadman SK, Duran M, Ketting D, Bruinvis L, De Bree PK, Kamerling JP, Gerwig GJ, Vliegenthart JF, Przyrembel H, Becker K, Bremer HJ (1976) D-Glyceric acidemia in a patient with chronic metabolic acidosis. Clin Chim Acta 71(3):477–484CrossRefGoogle Scholar