Screening for Adenylosuccinate Lyase Deficiency: Clinical, Biochemical and Molecular Findings in Four Patients

Abstract

Adenylosuccinate lyase deficiency is an autosomal recessive defect of purine metabolism. Succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) are the disease marker metabolites in physiological fluids. The Bratton-Marshall test for detection of SAICAr in urine has been added to the selective screening for inborn errors of metabolism that is carried out in our lab. During the last three years, around 2000 patients have been screened by this method, resulting in the detection of four new cases with this disease. They all presented with severe psychomotor delay, hypotonia and refractory epilepsy since the neonatal period. The S-Ado/SAICAr ratio in cerebrospinal fluid was below 2, indicating that they correspond to the most severe form of the disease. New missense mutations were found in a heterozygous fashion in three patients. The study of purines in all patients with neurological disease of unknown etiology is highly recommended.

Adenylosuccinate Lyase (ADSL) - Purine Metabolism - Refractory Epilepsy - Mental Retardation

References

• 1 Bowling F G, McGill J J, Moxon-Lester L, Broe D, Cowley D M. ¹H-NMR spectroscopy monitoring of ribose treatment in ADSL deficiency.  J Inher Metab Dis. 2000;  23 (Suppl 1) 381
• 2 Ciardo F, Salerno C, Curatolo P. Neurologic aspects of adenylosuccinate lyase deficiency.  J Child Neurol. 2001;  16 301-308
• 3 Jaeken J, Van den Berghe G. An infantile autistic syndrome characterised by the presence of succinylpurines in body fluids.  Lancet. 1984;  2 1058-1061
• 4 Köhler M, Assmann B, Bräutigam C, Storm W, Marie S. et al . Adenylosuccinase deficiency: possibly underdiagnosed encephalopathy with variable clinical features.  Eur J Pediatr Neurol. 1999;  3 3-6
• 5 Krijt J, Kmoch S, Hartmannova H, Havlícek V, Sebesta I. Identification and determination of succinyladenosine in human cerebrospinal fluid.  J Chromatrogr B. 1999;  726 53-58
• 6 Laikind P K, Seegmiller J E, Gruber H E. Detection of 5′-phosphoribosyl-4-(N-succinylcarboxamide)-5-aminoimidazole in urine by use of the Bratton-Marshall reaction: identification of patients deficient in adenylosuccinate lyase activity.  Anal Biochem. 1986;  156 81-90
• 7 Marie S, Cuppens H, Heuterspreute M, Jaspers M, Zambrano E, Gu X X. et al . Mutation analysis in adenylosuccinate lyase deficiency. Eight novel mutations in the re-evaluated full ADSL coding sequence.  Hum Mut. 1999;  13 197-202
• 8 Marie S, Flipsen J WAM, Duran M, Poll-The B T, Beemer F A, Bosschaart A N. et al . Prenatal diagnosis in adenylosuccinate lyase deficiency.  Prenat Diagn. 2000;  20 33-36
• 9 Salerno C, D'Eufemia P, Finocchiaro R, Celli M, Spalice A, Iannetti P. et al . Effect of D-ribose on purine synthesis and neurological symptoms in a patient with adenylosuccinase deficiency.  Biochim Biophys Acta. 1999;  1453 135-140
• 10 Sebesta I, Krijt J, Kmoch S, Hartmannova H, Wojda M, Zeman J. Adenylosuccinase deficiency: clinical and biochemical findings in 5 Czech patients.  J Inher Metab Dis. 1997;  20 343-344
• 11 Simmonds H A, Duley J A, Davies P M. Analysis of purines and pyrimidines in blood, urine and other physiological fluids. Hommes F Techniques in Diagnostic Human Biochemical Genetics: a Laboratory Manual. New York; Wiley-Liss 1991: 397-424
• 12 Stone T W, Roberts L A, Morris B J, Jones P A, Ogilvy H A, Behan W MH. et al . Succinylpurines induce neuronal damage in the rat brain. Griesmacher et al Purine and Pyrimidine Metabolism in Man. IX. New York; Plenum Press 1998: 185-189
• 13 Valik D, Miner P T, Jones J D. First U. S. case of adenylosuccinate lyase deficiency with severe hypotonia.  Pediatr Neurol. 1997;  16 252-255
• 14 Van den Berghe G, Jaeken J. Adenylosuccinate lyase deficiency. Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York; McGraw-Hill 2000: 2653-2662