This article includes discussion of adenylosuccinate lyase deficiency, ADSL, adenylosuccinase deficiency, adenylosuccinate lyase deficiency type I, and adenylosuccinate lyase deficiency type II. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
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 purinosome is a multienzyme complex of the de novo purine synthesis (DNPS) enzymes (including adenylosuccinate lyase) that cells transiently assemble in their cytosol on depletion or increased demand of purines. The study of purinosome formation in skin fibroblasts of the patients with adenylosuccinate lyase deficiency showed that significant differences of purinosome assembly exist among individual cases with adenylosuccinate lyase deficiency and that the ability to form purinosomes inversely correlates with the severity of the phenotype. This finding corroborates the hypothesis that the phenotypic severity of adenylosuccinate lyase deficiency is mainly determined by structural stability and residual catalytic capacity of the corresponding mutant adenylosuccinate lyase protein complex, as this is prerequisite for the formation and stability of the purinosome and at least partial channeling of SAICAR through the DNPS pathway.
• The clinical presentation of adenylosuccinate lyase (ADSL) deficiency varies greatly with respect to age of onset, clinical manifestations, and rate of disease progression.
• Due to lack of specific features and later onset of symptoms, diagnosis of patients is difficult, and simple selective screening procedures are indispensable in avoiding undiagnosed cases.
• Selective screening for adenylosuccinate lyase deficiency should be performed in patients who have neurologic disease without clear etiology, especially if MRI findings such as delayed or lack of myelination, white matter abnormal signal, and atrophy of the cerebrum and/or cerebellum are also present.
• Greater awareness of adenylosuccinate lyase deficiency among general pediatricians, neonatologists, pediatric neurologists, and radiologists is the key to identifying the disorder in the early stage.
Historical note and terminology
Adenylosuccinate lyase (ADSL, also termed adenylosuccinase) catalyzes 2 steps in the synthesis of purine nucleotides: the conversion of succinylaminoimidazolecarboxamide ribotide (SAICAR) into aminoimidazole-carboxamide ribotide (AICAR), the eighth step of the de novo pathway, and the formation of adenosine monophosphate (AMP) from adenylosuccinate (S-AMP), the second step in the conversion of inosine monophosphate (IMP) into AMP. Both reactions release fumarate. Together with adenylosuccinate synthetase and AMP deaminase, adenylosuccinate lyase also forms the purine nucleotide cycle.
Adenylosuccinate lyase deficiency, the first enzyme deficiency reported in the de novo pathway of purine synthesis in man, was discovered in the course of a systematic study of amino acids in cerebrospinal fluid before and after acid hydrolysis (Jaeken and Van den Berghe 1984). In 3 children with severe psychomotor retardation and autistic features, this procedure released abnormally large, equimolar amounts of aspartate and glycine. The additional identification by gas chromatography of an equimolar amount of ribose, led to a search for purine compounds. Anion-exchange high pressure liquid chromatography (HPLC) of deproteinized, but not hydrolyzed, cerebrospinal fluid, plasma, and urine revealed the presence of 2 UV absorbing compounds that were undetectable in control samples. They were identified as succinylaminoimidazolecarboxamide riboside (SAICA-riboside) and succinyl-adenosine (S-Ado). These succinylpurines are the products of the dephosphorylation, by 5'-nucleotidase(s), of SAICAR and S-AMP, respectively.
In profoundly intellectually disabled patients with adenylosuccinate lyase deficiency, cerebrospinal fluid (CSF) concentrations of both succinylpurines are 100 µmol/l to 200 µmol/l, and S-Ado/SAICA-riboside ratios are between 1 and 2. In adenylosuccinate lyase-deficient patients with milder clinical pictures, CSF concentrations of SAICA-riboside are in the same range, but those of S-Ado tend to be higher. This results in S-Ado/SAICA-riboside ratios above 2, even reaching 4 to 5 in a less intellectually impaired patient (Jaeken et al 1988). In urine, the concentrations of the succinylpurines can reach up to 5 µmol per mg creatinine, and their ratio reflects that in CSF.
Recent studies, however, have shown that the ratio of the accumulating S-Ado and SAICAr in body fluids is not predictive of phenotype severity; rather, it may be secondary to the degree of the patient's development (ie, to the age of the patient at the time of a sample collection) (Zikanova et al 2010). Recently, Ray and colleagues have shown a nonlinear dependence of the activities on the substrate ratios due to competitive binding, distinct difference in the behaviors of the different mutations, and S-Ado/SAICAr ratios in patients that could be explained by inherent properties of the mutant enzyme (Ray et al 2012; Ray et al 2013).
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