Chapter 112

## Abstract

Abstract

1. The deficiency of adenylosuccinate lyase (ADSL) (MIM 103050) causes variable degrees of psychomotor retardation, often accompanied by epileptic seizures and/or autistic features. About half of the patients display moderate to severe retardation and epilepsy after the first year, occasionally associated with growth retardation and muscular wasting. Others present with convulsions within the first days to weeks of life. Rarely, patients display only mild psychomotor retardation or profound muscle hypotonia.

2. ADSL deficiency is characterized by the appearance in cerebrospinal fluid and urine, and to a much smaller extent in plasma, of succinylaminoimidazolecarboxamide riboside (SAICAriboside) and succinyladenosine (S-Ado). These succinylpurines are the dephosphorylated derivatives of, respectively, SAICAribotide (SAICAR) and adenylosuccinate (S-AMP), the two substrates of ADSL. This enzyme intervenes twice in the synthesis of purine nucleotides; it catalyzes the eighth step of their de novo synthesis, and the second step of the conversion of IMP into AMP.

3. To date, about 60 patients have been identified. Most of them have been diagnosed in the low countries, Belgium and The Netherlands, and in the Czech Republic. Other patients have been identified in Australia, France, Germany, Italy, Morocco, Norway, Portugal, Spain, Turkey, and the USA. The marked clinical heterogeneity of ADSL deficiency justifies systematic screening for the disorder in patients with unexplained psychomotor retardation and/or neurologic disease.

4. ADSL deficiency is inherited in an autosomal recessive manner. The ADSL gene is located on chromosome 22q. Thirty-seven ADSL gene mutations have been identified to date. Most seem to lead to structural instability of the enzyme, without modifications of its kinetic properties.

5. Although ADSL intervenes twice in purine biosynthesis, 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 purine salvage pathway. The symptoms of ADSL deficiency might thus be caused by neurotoxic effects of the accumulating succinylpurines. In most patients, S-Ado/SAICAriboside ratios are around 1. The observation of generally less severe mental retardation in patients with similar SAICAriboside levels but S-Ado/SAICAriboside ratios above 2, suggests that SAICAriboside is the offending compound, and that S-Ado could protect against its toxic effects. To date, however, all attempts to evidence neurotoxicity of the succinylpurines have failed.

6. The prognosis of ADSL-deficient subjects is generally poor. Several patients, particularly those presenting with early epilepsy, have died in early infancy. Nevertheless, some patients, particularly those with higher S-Ado/SAICAriboside ratios, fare relatively well. With the aim to replenish hypothetically decreased concentrations of purine nucleotides in ADSL-deficient tissues, some patients have been treated with oral supplements of adenine and allopurinol, the latter to avoid conversion of adenine into minimally soluble 2,8-dihydroxyadenine. No clinical or biochemical improvement was recorded, with the exception of some acceleration of growth.More recently, therapeutic trials have been initiated with ribose and uridine.

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