Early diagnosis of adenylosuccinate lyase deficiency using a high-throughput screening method and a trial of oral S-adenosyl-l-methionine as a treatment method.
OBJECTIVE
The aim of this study was to develop a high-throughput urine screening technique for adenylosuccinate lyase (ADSL) deficiency and to evaluate S-adenosyl-l-methionine (SAMe) as a potential treatment for this disorder.


METHODS
Testing for succinyladenosine (S-Ado), a marker of ADSL deficiency, was incorporated into a screening panel for urine biomarkers for inborn errors of metabolism using electrospray tandem mass spectrometry. Liquid chromatography-mass spectrometry and high-performance liquid chromatography were used to confirm and monitor the response of metabolites to oral SAMe treatment.


RESULTS
Increased levels of S-Ado were detected in a 3-month-old male infant with hypotonia and seizures. ADSL gene sequencing revealed a previously described c.-49T>C mutation and a novel c.889_891dupAAT mutation, which was likely to disrupt enzyme function. After 9 months of SAMe treatment, there was no clear response evidenced in urine metabolite levels or clinical parameters.


CONCLUSIONS
These results demonstrate proof of the principle for the high-throughput urine screening technique, allowing earlier diagnosis of patients with ADSL deficiency. However, early treatment with SAMe does not appear to be effective in ADSL deficiency. It is suggested that although SAMe treatment may ameliorate purine nucleotide deficiency, it cannot correct metabolic syndromes in which a toxic nucleotide is present, in this case presumed to be succinylaminoimidazole carboxamide ribotide.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Vic., Australia.
Michiel A
MA
van Werkhoven
John A
JA
Duley
Ivan
I
McGown
Teresa
T
Munce
Jeremy L
JL
Freeman
James J
JJ
Pitt
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000264:Adenylosuccinate Lyase / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics / Q000652:urine; D000284:Administration, Oral; D001321:Autistic Disorder; D002675:Child, Preschool; D002853:Chromatography, Liquid; D004569:Electroencephalography; D005838:Genotype; D057166:High-Throughput Screening Assays; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation / Q000235:genetics; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics / Q000652:urine; D012436:S-Adenosylmethionine / Q000008:administration & dosage*; D021241:Spectrometry, Mass, Electrospray Ionization
C043565:succinyladenosine; D012436:S-Adenosylmethionine; D000264:Adenylosuccinate Lyase; D000241:Adenosine