Journal of Inherited Metabolic Disease

, Volume 39, Issue 2, pp 273–283 | Cite as

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

  • Christian Staufner
  • Martin Lindner
  • Carlo Dionisi-Vici
  • Peter Freisinger
  • Dries Dobbelaere
  • Claire Douillard
  • Nawal Makhseed
  • Beate K. Straub
  • Kimia Kahrizi
  • Diana Ballhausen
  • Giancarlo la Marca
  • Stefan Kölker
  • Dorothea Haas
  • Georg F. Hoffmann
  • Sarah C. Grünert
  • Henk J. Blom
Original Article

Abstract

Background

Adenosine kinase deficiency is a recently described defect affecting methionine metabolism with a severe clinical phenotype comprising mainly neurological and hepatic impairment and dysmorphism.

Methods

Clinical data of 11 additional patients from eight families with adenosine kinase deficiency were gathered through a retrospective questionnaire. Two liver biopsies of one patient were systematically evaluated.

Results

The main clinical symptoms are mild to severe liver dysfunction with neonatal onset, muscular hypotonia, global developmental retardation and dysmorphism (especially frontal bossing). Hepatic involvement is not a constant finding. Most patients have epilepsy and recurrent hypoglycemia due to hyperinsulinism. Major biochemical findings are intermittent hypermethioninemia, increased S-adenosylmethionine and S-adenosylhomocysteine in plasma and increased adenosine in urine. S-adenosylmethionine and S-adenosylhomocysteine are the most reliable biochemical markers. The major histological finding was pronounced microvesicular hepatic steatosis. Therapeutic trials with a methionine restricted diet indicate a potential beneficial effect on biochemical and clinical parameters in four patients and hyperinsulinism was responsive to diazoxide in two patients.

Conclusion

Adenosine kinase deficiency is a severe inborn error at the cross-road of methionine and adenosine metabolism that mainly causes dysmorphism, brain and liver symptoms, but also recurrent hypoglycemia. The clinical phenotype varies from an exclusively neurological to a multi-organ manifestation. Methionine-restricted diet should be considered as a therapeutic option.

Keywords

Intellectual Disability Diazoxide AdoMet Megaloblastic Anemia Hyperinsulinism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We especially thank Zlata Antoni, Elisabeth Specht and Johanna Kugele for excellent technical assistance.

Compliance with Ethical Standards

Funding

Part of the study was funded by grants of the German Research Foundation to BKS (DFG STR1160/1-1 and 1-2).

Conflict of interest

None.

Informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients or their parents in case of minor patients for being included in the study. Additional informed consent was obtained from all patients for whom identifying information is included in this article.

Supplementary material

10545_2015_9904_MOESM1_ESM.docx (214 kb)
ESM 1 (DOCX 213 kb)

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Copyright information

© SSIEM 2015

Authors and Affiliations

  • Christian Staufner
    • 1
  • Martin Lindner
    • 1
    • 2
  • Carlo Dionisi-Vici
    • 3
  • Peter Freisinger
    • 4
  • Dries Dobbelaere
    • 5
  • Claire Douillard
    • 5
  • Nawal Makhseed
    • 6
  • Beate K. Straub
    • 7
  • Kimia Kahrizi
    • 8
  • Diana Ballhausen
    • 9
  • Giancarlo la Marca
    • 10
  • Stefan Kölker
    • 1
  • Dorothea Haas
    • 1
  • Georg F. Hoffmann
    • 1
  • Sarah C. Grünert
    • 11
  • Henk J. Blom
    • 11
  1. 1.Department of General Pediatrics, Division of Pediatric Metabolic Medicine and NeuropediatricsUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Department of NeurologyUniversity Children’s Hospital FrankfurtFrankfurtGermany
  3. 3.Division of MetabolismBambino Gesù Children’s Hospital IRCCSRomeItaly
  4. 4.Children’s Hospital ReutlingenReutlingenGermany
  5. 5.Reference Center for Inherited Metabolic Diseases in Child and AdulthoodUniversity Children’s Hospital Jeanne de FlandreLille CedexFrance
  6. 6.Department of PediatricsJahra HospitalJahraKuwait
  7. 7.Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
  8. 8.Genetics Research CenterUniversity of Social Welfare and Rehabilitation SciencesTehranIran
  9. 9.Center for molecular diseasesCHUV LausanneLausanneSwitzerland
  10. 10.Newborn Screening, Clinical Chemistry and Pharmacology Lab, NeuroFarba DepartmentMeyer Children’s University HospitalFlorenceItaly
  11. 11.Center for Pediatrics and Adolescent MedicineUniversity Hospital FreiburgFreiburgGermany

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