title: Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany. christian.staufner@med.uni-heidelberg.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Staufner
authors.affiliation: Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.|Department of Neurology, University Children's Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.affiliation: Children's Hospital Reutlingen, Reutlingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.affiliation: Reference Center for Inherited Metabolic Diseases in Child and Adulthood, University Children's Hospital Jeanne de Flandre, Lille Cedex, France.
authors.forename: Dries
authors.initials: D
authors.lastname: Dobbelaere
authors.affiliation: Reference Center for Inherited Metabolic Diseases in Child and Adulthood, University Children's Hospital Jeanne de Flandre, Lille Cedex, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Douillard
authors.affiliation: Department of Pediatrics, Jahra Hospital, Jahra, Kuwait.
authors.forename: Nawal
authors.initials: N
authors.lastname: Makhseed
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Beate K
authors.initials: BK
authors.lastname: Straub
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.affiliation: Center for molecular diseases, CHUV Lausanne, Lausanne, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Ballhausen
authors.affiliation: Newborn Screening, Clinical Chemistry and Pharmacology Lab, NeuroFarba Department, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.affiliation: Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
authors.affiliation: Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Haas
authors.affiliation: Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Grünert
authors.affiliation: Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
mesh_terms: D000241:Adenosine / Q000378:metabolism / Q000652:urine; D000248:Adenosine Kinase / Q000172:deficiency* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000378:metabolism / Q000652:urine; D002648:Child; D002675:Child, Preschool; D004032:Diet; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism / Q000401:mortality; D007223:Infant; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism / Q000401:mortality*; D008715:Methionine / Q000378:metabolism; D012189:Retrospective Studies; D012435:S-Adenosylhomocysteine / Q000097:blood / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000097:blood / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D000248:Adenosine Kinase; D000241:Adenosine