Virchows Archiv

, Volume 472, Issue 6, pp 1029–1039 | Cite as

Variable X-chromosome inactivation and enlargement of pericentral glutamine synthetase zones in the liver of heterozygous females with OTC deficiency

  • Dita Musalkova
  • Eva Sticova
  • Martin Reboun
  • Jitka Sokolova
  • Jakub Krijt
  • Jitka Honzikova
  • Jiri Gurka
  • Magdalena Neroldova
  • Tomas Honzik
  • Jiri Zeman
  • Milan Jirsa
  • Lenka Dvorakova
  • Martin Hrebicek
Original Article


Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder that causes recurrent and life-threatening episodes of hyperammonemia. The clinical picture in heterozygous females is highly diverse and derives from the genotype and the degree of inactivation of the mutated X chromosome in hepatocytes. Here, we describe molecular genetic, biochemical, and histopathological findings in the livers explanted from two female patients with late-onset OTC deficiency. Analysis of X-inactivation ratios by DNA methylation-based assays showed remarkable intra-organ variation ranging from 46:54 to 82:18 (average 70:30, n = 37), in favor of the active X chromosome carrying the mutation c.583G>C (p.G195R), in the first patient and from 75:25 to 90:10 (average 82:18, n = 20) in favor of the active X chromosome carrying the splicing mutation c.663+1G>A in the second patient. The X-inactivation ratios in liver samples correlated highly with the proportions of OTC-positive hepatocytes calculated from high-resolution image analyses of the immunohistochemically detected OTC in frozen sections that was performed on total area > 5 cm2. X-inactivation ratios in blood in both female patients corresponded to the lower limit of the liver values. Our data indicate that the proportion of about 20–30% of hepatocytes expressing the functional OTC protein is not sufficient to maintain metabolic stability. X-inactivation ratios assessed in liver biopsies taken from heterozygous females with X-linked disorders should not be considered representative of the whole liver.


Ornithine transcarbamylase X chromosome inactivation Glycogen storage Liver Liver zonation Glutamine synthetase 



The authors would like to thank the patients and their families. We acknowledge the help and advice provided by Marketa Novakova, Michaela Hnizdova Bouckova, Michaela Fialova, Gabriela Storkanova, Ondrej Luksan, Karolina Peskova, and particularly, by Lenka Piherova and Jakub Sikora.


This study was supported by the projects GA UK No. 42314 and No. 580716 from the Grant Agency of Charles University in Prague, and also by projects SVV 260367, UNCE 204011/2012, Progres Q26, and MH CZ-DRO VFN 64165.

Compliance with ethical standards

The study was approved by the local ethics committee and conducted in agreement with institutional guidelines. Written informed consent was obtained from all adult study participants. On behalf of the patient written informed consent was obtained from her parents.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

428_2018_2345_MOESM1_ESM.pdf (169 kb)
ESM 1 (PDF 168 kb)
428_2018_2345_MOESM2_ESM.pdf (704 kb)
ESM 2 (PDF 704 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Dita Musalkova
    • 1
  • Eva Sticova
    • 2
  • Martin Reboun
    • 1
  • Jitka Sokolova
    • 1
  • Jakub Krijt
    • 1
  • Jitka Honzikova
    • 1
  • Jiri Gurka
    • 1
    • 3
  • Magdalena Neroldova
    • 4
  • Tomas Honzik
    • 5
  • Jiri Zeman
    • 5
  • Milan Jirsa
    • 4
  • Lenka Dvorakova
    • 1
  • Martin Hrebicek
    • 1
  1. 1.Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of MedicineCharles University and General University Hospital in PraguePrague 2Czech Republic
  2. 2.Department of Clinical and Transplant PathologyInstitute for Clinical and Experimental Medicine (IKEM)PragueCzech Republic
  3. 3.Institute of Histology and Embryology, First Faculty of MedicineCharles UniversityPragueCzech Republic
  4. 4.Laboratory of Experimental HepatologyInstitute for Clinical and Experimental Medicine (IKEM)PragueCzech Republic
  5. 5.Department of Pediatrics and Adolescent Medicine, First Faculty of MedicineCharles University and General University Hospital in PraguePragueCzech Republic

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