Abstract
Adenylosuccinate lyase ADSL) deficiency is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways. Biochemically this defect manifests by the presence in the biologic fluids of two dephosphorylated substrates of ADSL enzyme: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). More than 80 individuals with ADSL deficiency have been identified, but incidence of the disease remains unknown. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The fatal neonatal form has onset from birth and presents with fatal neonatal encephalopathy with a lack of spontaneous movement, respiratory failure, and intractable seizures resulting in early death within the first weeks of life. Patients with type I (severe form) present with a purely neurologic clinical picture characterized by severe psychomotor retardation, microcephaly, early onset of seizures, and autistic features. A more slowly progressing form has also been described (type II, moderate or mild form), as having later onset, usually within the first years of life, slight to moderate psychomotor retardation and transient contact disturbances. Diagnosis is facilitated by demonstration of SAICAr and S-Ado in extracellular fluids such as plasma, cerebrospinal fluid and/or followed by genomic and/or cDNA sequencing and characterization of mutant proteins. Over 50 ADSL mutations have been identified and their effects on protein biogenesis, structural stability and activity as well as on purinosome assembly were characterized. To date there is no specific and effective therapy for ADSL deficiency.
Highlights
Adenylosuccinate lyase ADSL) deficiency is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways
The enzyme adenylosuccinate lyase (EC 4.3.2.2) catalyzes two non-sequential steps in the de novo synthesis of purine nucleotides leading to nonhydrolytic cleavage of succinyl groups to yield fumarate: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) into aminoimidazole carboxamide ribotide (AICAR) and the formation of adenosine monophosphate nucleotides (Fig. 1)
It has been suggested that the ratio of the accumulating succinyladenosine (S-Ado) and succinylaminoimidazolecarboxamide riboside (SAICAr) in body fluids is not predictive of phenotype severity; rather, it may be secondary to the degree of the patient’s development (Zikanova et al 2010)
Summary
Adenylosuccinate lyase deficiency (OMIM 103 050) is an autosomal recessive defect of purine metabolism. It was first described in 1984 by Jaeken and van den Berghe (Jaeken and Van den Berghe 1984), who found succinylpurines in the cerebrospinal fluid (CSF), plasma, and urine of three patients with severe psychomotor delay and autistic features. In addition to its role in purine biosynthesis, the enzyme is involved, together with adenylate deaminase and adenylosuccinate synthetase, in the purine nucleotide cycle This cycle prevents adenosine monophosphate (AMP) accumulation following adenosine triphosphate (ATP) catabolism, and this, in turn, displaces the adenylate kinase reaction toward adenosine triphosphate formation (Sabina et al 1980). Detailed and regularly updated information on identified patients may be found on ADSL database http://www1.lf1.cuni. cz/udmp/adsl
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