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Metabolic Brain Disease

, Volume 32, Issue 6, pp 2131–2137 | Cite as

A homozygous PIGO mutation associated with severe infantile epileptic encephalopathy and corpus callosum hypoplasia, but normal alkaline phosphatase levels

  • Yoav Zehavi
  • Anja von Renesse
  • Etty Daniel-Spiegel
  • Yonatan Sapir
  • Luci Zalman
  • Ilana Chervinsky
  • Markus Schuelke
  • Rachel Straussberg
  • Ronen Spiegel
Original Article

Abstract

We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.

Keywords

PIGO gene Exome sequencing Autozygosity mapping Epileptic encephalopathy 

Notes

Acknowledgements

We thank the patients and their family for their participation in this study.

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 and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study or their LARs. Additional informed consent was obtained from all individual participants or their LARs for whom identifying information is included in this article.The signed forms of LARs consent for publication of this case study are enclosed to the manuscript.

Supplementary material

11011_2017_109_MOESM1_ESM.pdf (334 kb)
ESM 1 (PDF 333 kb)

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Yoav Zehavi
    • 1
  • Anja von Renesse
    • 2
  • Etty Daniel-Spiegel
    • 3
    • 4
  • Yonatan Sapir
    • 5
  • Luci Zalman
    • 6
  • Ilana Chervinsky
    • 7
  • Markus Schuelke
    • 2
  • Rachel Straussberg
    • 8
  • Ronen Spiegel
    • 1
    • 4
  1. 1.Pediatric Department BEmek Medical CenterAfulaIsrael
  2. 2.NeuroCure Clinical Research Center and Department of NeuropediatricsCharité UniversitätsmedizinBerlinGermany
  3. 3.Department of Obstetrics and Gynecology, Ultrasound UnitEmek Medical CenterAfulaIsrael
  4. 4.Rappaport Faculty of MedicineTechnionHaifaIsrael
  5. 5.Department of RadiologyEmek Medical CenterAfulaIsrael
  6. 6.Hematology-Oncology ServiceEmek Medical CenterAfulaIsrael
  7. 7.Genetic InstituteEmek Medical CenterAfulaIsrael
  8. 8.Pediatric Neurology UnitSchneider Children’s Medical CenterPetach TikvaIsrael

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