title: Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function.
abstract: Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.
authors.affiliation: Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus K
authors.initials: MK
authors.lastname: Bjursell
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
authors.forename: Jordi Asin
authors.initials: JA
authors.lastname: Cayuela
authors.forename: Martin L
authors.initials: ML
authors.lastname: Engvall
authors.forename: Nicole
authors.initials: N
authors.lastname: Lesko
authors.forename: Shanti
authors.initials: S
authors.lastname: Balasubramaniam
authors.forename: Göran
authors.initials: G
authors.lastname: Brandberg
authors.forename: Maria
authors.initials: M
authors.lastname: Halldin
authors.forename: Maria
authors.initials: M
authors.lastname: Falkenberg
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Desiree
authors.initials: D
authors.lastname: Smith
authors.forename: Eduard
authors.initials: E
authors.lastname: Struys
authors.forename: Ulrika
authors.initials: U
authors.lastname: von Döbeln
authors.forename: Claes M
authors.initials: CM
authors.lastname: Gustafsson
authors.forename: Joakim
authors.initials: J
authors.lastname: Lundeberg
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
mesh_terms: D000248:Adenosine Kinase / Q000172:deficiency*; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002658:Developmental Disabilities / Q000235:genetics; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006710:Homocysteine / Q000097:blood / Q000235:genetics; D006801:Humans; D008107:Liver Diseases / Q000235:genetics / Q000473:pathology*; D008297:Male; D008715:Methionine / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D012435:S-Adenosylhomocysteine / Q000097:blood; D012436:S-Adenosylmethionine / Q000097:blood / Q000235:genetics
chemical_list: D006710:Homocysteine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D000248:Adenosine Kinase