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Severe infantile epileptic encephalopathy associated with D-glyceric aciduria: report of a novel case and review

  • Yoav Zehavi
  • Hanna Mandel
  • Ayelet Eran
  • Sarit Ravid
  • Muhammad Abu Rashid
  • Erwin E. W. Jansen
  • Mirjam M. C. Wamelink
  • Ann Saada
  • Avraham Shaag
  • Orly Elpeleg
  • Ronen SpiegelEmail author
Original Article

Abstract

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.

Keywords

Epileptic encephalopathy D-glyceric aciduria Whole exome sequencing Autosomal recessive GLYCTK gene D-glycerate kinase enzyme 

Notes

Acknowledgments

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.

Ethical approval

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

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).

Supplementary material

11011_2019_384_MOESM1_ESM.docx (335 kb)
ESM 1 (DOCX 334 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yoav Zehavi
    • 1
  • Hanna Mandel
    • 2
  • Ayelet Eran
    • 3
    • 4
  • Sarit Ravid
    • 4
    • 5
  • Muhammad Abu Rashid
    • 6
  • Erwin E. W. Jansen
    • 7
  • Mirjam M. C. Wamelink
    • 7
  • Ann Saada
    • 8
    • 9
  • Avraham Shaag
    • 8
  • Orly Elpeleg
    • 8
  • Ronen Spiegel
    • 1
    • 4
    Email author
  1. 1.Department of Pediatrics BEmek Medical CenterAfulaIsrael
  2. 2.Institute of Human Genetics and Metabolic DiseasesGalilee Medical CenterNahariyaIsrael
  3. 3.Neuroradiology Unit Department of RadiologyRambam Health Care CampusHaifaIsrael
  4. 4.Rappaport School of Medicine, TechnionHaifaIsrael
  5. 5.Pediatric Neurology UnitRuth Rappaport Children’s HospitalHaifaIsrael
  6. 6.Clalit Health ServicesHaifaIsrael
  7. 7.Metabolic Unit, Department of Clinical ChemistryAmsterdam UMC, Vrije Universiteit AmsterdamAmsterdamThe Netherlands
  8. 8.Monique and Jacques Roboh Department of Genetic ResearchHadassah-Hebrew University Medical CenterJerusalemIsrael
  9. 9.Metabolic Laboratory, Department of Genetics and Metabolic DiseasesHadassah-Hebrew University Medical CenterJerusalemIsrael

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