This deficiency, discovered in 1984 (10), is the first enzyme deficiency reported on the de novo pathway of purine synthesis in man. It is characterized by the accumulation of the two succinylpurines, succinylaminoimidazolecarboxamide riboside (SAICA-riboside) and succinyladenosine (S-Ado), at 100 - 500 µM concentration in cerebrospinal fluid, and in amounts of 25 - 700 µmol/mmol of creatinine in urine. These succinylpurines are the dephosphorylated derivatives of, respectively, SAICAR and S-AMP, the two substrates of ADSL (Figure 1). SAICA-riboside is normally undetectable in cerebrospinal fluid, but S-Ado is found at approximately 1 µM concentration (11).
Symptoms
Most ADSL-deficient patients, often refered to as type I, display severe psychomotor retardation (10, 12, 13) frequently accompanied by epilepsy, and by autistic features (failure to make eye-to-eye contact, repetitive behavior, temper tantrums). Some of these patients also have severe growth retardation associated with muscular wasting. Dysmorphic features are absent. More recently, patients have been reported with even more severe neurological symptoms, namely convulsions starting within the first days or weeks of life, leading to death within a few months (14 - 17).
Other patients present with more moderate psychomotor delay, also often associated with epilepsy and autistic features (13, 18, 19). Finally, a number of patients, sometimes refered to as type II, display strikingly milder retardation: among them a girl with a psychomotor development at the level of 2.5 years at age 4 (12), another girl with profound muscle hypotonia accompanied by slightly delayed motor development (20), and children with high-functioning autism (21, and unpublished observations).
Diagnosis
The marked clinical heterogeneity of ADSL deficiency, and the absence of pathognomonic signs, justify systematic screening for the disorder in unexplained, profound as well as mild psychomotor retardation, in neurological disease with convulsions and/or hypotonia, and in children with autism.
Diagnostic tests are based on the presence in cerebospinal fluid and/or urine of SAICA-riboside and S-Ado. These can be identified by various techniques. For systematic screening, a modified Bratton-Marshall test (22) performed on urine appears most practical. False positives are, however, recorded in patients who receive sulphonamides, for the measurement of which the test was initially designed, and/or antiepileptic medications. Several thin-layer chromatographic methods are also available (23). Final diagnosis requires HPLC with UV detection and spectral analysis (10).
Interestingly, in the severely affected patients, concentrations of S-Ado are in the same range as those of SAICA-riboside, and the S-Ado/SAICA-riboside ratios are around 1. Ratios in urine (and also in plasma) reflect those in cerebrospinal fluid (12). In contrast, in the mildly affected patients, concentrations of S-Ado are distinctly higher than those of SAICA-riboside, which are in the same range as in the severely retarded patients. In the first reported Type II patient, cerebrospinal fluid S-Ado reached 475 µM and the S-Ado/SAICA-riboside ratio was 3.7 (12). In other mildly affected patients, S-Ado/SAICA-riboside ratios were around 2.5 (20, 21). In patients with intermediate symptomatology, S-Ado/SAICA-riboside ratios were between 1.8 and 2.2 (18, 24).
Prenatal diagnosis of ADSL deficiency has been performed by molecular analysis (25).
Enzyme studies
When performed, assays of ADSL in patients' tissues, with S-AMP as substrate, have shown that 15 25 % residual activity is most often found in liver and kidney, and that the enzyme defect is not generalized (12). In a number of profoundly retarded, type I patients, measurements of the activity of ADSL with both S-AMP and SAICAR as substrates have shown that both activities were decreased in parallel in liver (26) and fibroblasts (27), in the latter to approximately 30 % of normal. In fibroblasts of the first reported type II patient, activity with S-AMP was reduced to 3 % of normal, whereas that with SAICAR was 30 % of control (27). This nonparallel loss of both activities of ADSL, if also present in other tissues, provides an explanation for the higher S-Ado/SAICA-riboside ratio, reaching approximately 4 in the body fluids of this mildly retarded patient.
Pathophysiological mechanisms
Two main hypotheses could explain the symptoms of ADSL deficiency: impaired synthesis of purine nucleotides, and neurotoxic effects of the accumulating succinylpurines. Decreased concentrations of purine nucleotides could not be evidenced in various tissues of ADSL-deficient patients. This can be explained by residual activity of ADSL, and by supply of purines via the salvage enzymes, hypoxanthine-guanine phosphoribosyltransferase and adenine phosphoribosyltransferase (Figure 1). As discussed above, present evidence indicates that the more severe presentations of ADSL deficiency tend to be associated with S-Ado/SAICA-riboside ratios around 1, whereas in milder clinical pictures these ratios are comprised between 2 and 4. This suggests that SAICA-riboside is the neurotoxic compound, and that S-Ado could protect against its deleterious effects.
Genotype-phenotype correlations
Expression of a number of mutated ADSL enzymes as thioredoxin fusion proteins has shown that some were thermolabile, and others thermostable (28). Thermolabile mutations tended to display similar residual activities with SAICAR and S-AMP, whereas thermostable mutations had higher residual activities with SAICAR than with S-AMP. Patients homozygous for a thermolabile mutation displayed similarly decreased ADSL activities in their fibroblasts, S-Ado/SAICA-riboside ratios of approximately 1 in their cerebrospinal fluid, and profound mental retardation. Patients homozygous for a thermostable mutation displayed a much more 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 cerebrospinal fluid, and were mildly retarded. These data suggest that 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 and the patients' mental status.
Prognosis and treatment
Several patients, particularly those presenting with early epilepsy, have died in infancy. Other patients, particularly those with higher S-Ado/SAICA-riboside ratios, fare relatively well, and have reached adult age.
With the aim to replenish hypothetically decreased concentrations of adenine nucleotides in ADSL-deficient tissues, some patients have been treated for several months with oral adenine (10 mg/kg per day), associated with allopurinol (5 to 10 mg/kg per day) to avoid conversion into very poorly soluble 2,8-dihydroxyadenine. No clinical or biochemical improvement was recorded, with the exception of some acceleration of growth (12).
More recently, oral administration of D-ribose (1.5 g/kg per
day) has been reported to reduce seizure frequency and to improve
behaviour in a 13-year old patient (29).
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