Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency

Adenylosuccinate lyase (ADSL) deficiency (MIM 103050) is an autosomal reces sive inborn error of purine synthesis characterized by the accumulation in body fluids of succinylaminoimidazolecarboxamide (SAICA) riboside and succi nyladenosine (S-Ado), the dephosphorylated derivatives of the two substrate s of the enzyme, Because ADSL-deficient patients display widely variable de grees of psychomotor retardation, we have expressed eight mutated ADSL enzy mes as thioredoxin fusions and compared their properties with the clinical and biochemical characteristics of 10 patients. Three expressed mutated ADS L enzymes (M26L, R426H and T450S) were thermolabile, four (A2V, R141W, R303 C and S395R) were thermostable and one (del206-218), was inactive. Thermola bile mutations decreased activities with SAICA ribotide (SAICAR) and adenyl osuccinate (SAMP) in parallel, or more with SAICAR than with S-AMP, Patient s homozygous for one of these mutations, R426H, displayed similarly decreas ed ADSL activities in their fibroblasts, S-Ado:SAICA riboside ratios of sim ilar to 1 in their cerebrospinal fluid and were profoundly retarded. With t he exception of A2V, thermostable mutations decreased activity with S-AMP t o a much more marked extent than with SAICAR, Two unrelated patients homozy gous for one of the thermostable mutations, R303C, also displayed a much mo re marked decrease in the activity of fibroblast ADSL with S-AMP than with SAICAR, had S-Ado:SAICA riboside ratios between 3 and 4 in their cerebrospi nal fluid and were mildly retarded. These results suggest that, in some cas es, the genetic lesion of ADSL determines the ratio of its activities with S-AMP versus SAICAR, which in turn defines the S-Ado:SAICA riboside ratio a nd the patients' mental status,