MinireviewAdenylosuccinate lyase deficiency
Introduction
Adenylosuccinate lyase (ADSL, EC 4.3.2.2) deficiency is a defect of purine metabolism causing serious neurological and physiological symptoms. It was first described in 1984 by Jaeken and Van den Berghe [1], who found succinylpurines in the cerebrospinal fluid (CSF), plasma, and urine of three patients with severe psychomotor delay and autistic features. These succinylpurines, succinyladenosine (S-Ado) and succinylaminoimidazolecarboxamide riboside (SAICAr) are the dephosphorylated derivatives of ADSL substrates. This accumulation in their patients’ CSF suggested a deficiency in ADSL activity, and indeed, the investigators reported significantly reduced ADSL enzyme activity in these patients. ADSL catalyzes two steps in the de novo purine biosynthetic pathway, which consists of 13 metabolic steps in the conversion of ribose-5-phosphate into AMP or GMP (Fig. 1). These two steps are: the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) into aminoimidazolecarboxamide ribonucleotide (AICAR), and the conversion of succinyladenosine monophosphate (AMPS) to adenosine monophosphate (AMP).
Regulation of the de novo purine biosynthetic pathway is highly controlled and occurs at multiple steps. Disruption of this regulation is known to cause other syndromes with neurodevelopmental abnormalities. For example, levels of PRPP, a substrate for the second step of de novo purine synthesis, are very important in the regulation of the pathway (Fig. 1). Mutations in PRPP synthetase leading to elevated activity of this enzyme cause elevated de novo purine synthesis and, in some families, neurodevelopmental impairment [2].
Lesch–Nyhan syndrome is caused by a deficiency of HPRT, an enzyme in the purine salvage pathway [3], [4]. Since PRPP is a substrate in the reaction of HPRT, a deficiency of HPRT causes levels of free PRPP to rise and therefore stimulate flux through the de novo purine pathway [3], [4]. The hallmark of this disorder is compulsive self-mutilation, although other characteristics include hyperuricemia, choreoathetosis, spasticity, aggression, and sometimes, mental retardation [3], [4].
Another syndrome of purine synthesis is AICA-Ribosiduria, caused by a deficiency of the bifunctional enzyme AICAR transformylase/IMP cyclohydrase (ATIC) [5]. This enzyme acts in the two de novo pathway steps following the first ADSL step (Fig. 1). A deficiency of this enzyme causes psychomotor retardation, epilepsy, congenital blindness, and dysmorphic features [5]. Like patients with ADSL deficiency, this patient accumulates SAICAr and S-Ado, as well as AICA-riboside (AICAr), the nucleoside derivative of AICAR, one substrate of ATIC [5].
Clearly, perturbations in the de novo purine pathway have profound effects on many neurological functions, though the mechanisms are not understood.
Section snippets
Diagnosis and clinical features of ADSL deficiency
In general, patients with ADSL deficiency are discovered during screens of children with unexplained developmental delay using the Bratton–Marshall assay for diazotizable amines [6]. This assay reveals accumulation of SAICAr in body fluids, which is the main diagnosis criterion for this disease. However, since the Bratton–Marshall assay can cause false positive results if patients are taking certain medications, a diagnosis of ADSL deficiency is generally then made using HPLC analysis showing
The genetics of ADSL deficiency
The human ADSL gene has been mapped to chromosome 22q13.1-13.2 [15], [16], [17]. The gene is 23 kb in length, consists of 13 exons, and encodes a protein of 484 amino acids [18]. In 1992, Stone et al. [13] reported the first sequence of a mutation in the ADSL gene leading to this syndrome. To date, 38 different mutations have been reported in the ADSL gene that lead to ADSL deficiency (Table 1). Each mutation is a single base pair change that produces an altered ADSL protein. All are missense
Pathogenic mechanisms of ADSL deficiency
The mechanism(s) whereby ADSL deficiency causes psychomotor delay and behavioral abnormalities is unknown. Possibilities include: deficient synthesis of purine nucleotides; impairment of the purine nucleotide cycle; and toxic effects of the intracellular and/or extracellular accumulation of the ADSL substrate derivatives.
Patient enzyme activities
Measurements of ADSL activities in biopsy specimens show that the degree of enzyme deficiency is variable in patients and surprisingly is not present in all tissues [39], [40]. Most patients have deficient levels of enzyme activity in liver and kidney, but only some have deficient levels in skeletal muscle [40], [41]. Generally, ADSL activity in muscle is reduced in patients presenting with growth retardation and muscular wasting [14]. In some patients, low enzyme levels are also observed in
Model systems to study ADSL deficiency
Analyses of purified or recombinantly expressed enzymes have been presented as model systems to study ADSL. In one study, a set of ADSL—Trx (histidine tagged) fusion proteins were assayed [56]. Unfortunately, the Trx fusion protein has a different activity profile than the wild-type activity in fibroblasts. Specifically, the Trx protein shows higher activity with SAICAR than with AMPS, while the wild-type (non-fusion) protein shows higher activity with AMPS than with SAICAR [56]. Also, the
Acknowledgments
We thank Dr. Miles Brennan for useful discussions about ADSL deficiency and for critical reading of the manuscript. This work was supported by NIH Grant MH65431 and grants from the Bonfils–Stanton Foundation and the Ludlow-Griffith Foundation to D.P., and by NIH Grant DK60504 to R.F.C.
References (71)
- et al.
Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase
J. Biol. Chem.
(1999) - et al.
The biochemical basis of the behavioral disorder in the Lesch–Nyhan syndrome
Neurosci. Biobehav. Rev.
(1985) - et al.
AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC
Am. J. Hum. Genet.
(2004) - et al.
Detection of 5′-phosphoribosyl-4-(N-succinylcarboxamide)-5-aminoimidazole in urine by use of the Bratton–Marshall reaction: identification of patients deficient in adenylosuccinate lyase activity
Anal. Biochem.
(1986) - et al.
First U.S. case of adenylosuccinate lyase deficiency with severe hypotonia
Pediatr. Neurol.
(1997) - et al.
Failure of muscle energy metabolism in a patient with adenylosuccinate lyase deficiency. An in vivo study by phosphorus NMR spectroscopy
Biochim. Biophys. Acta
(1997) - et al.
Early amygdala damage in the rat as a model for neurodevelopmental psychopathological disorders
Eur. Neuropsychopharmacol.
(2001) - et al.
Mapping of human chromosome 22 with a panel of somatic cell hybrids
Genomics
(1991) - et al.
Adenylosuccinase deficiency: possibly underdiagnosed encephalopathy with variable clinical features
Eur. J. Paediatr. Neurol.
(1999) - et al.
Mutation of a nuclear respiratory factor 2 binding site in the 5′ untranslated region of the ADSL gene in three patients with adenylosuccinate lyase deficiency
Am. J. Hum. Genet.
(2002)
Autism and adenylosuccinase deficiency
J. Am. Acad. Child Adolesc. Psychiatry
Two novel mutant human adenylosuccinate lyases (ASLs) associated with autism and characterization of the equivalent mutant Bacillus subtilis ASL
J. Biol. Chem.
Adenylosuccinase deficiency: an unusual cause of early-onset epilepsy associated with acquired microcephaly
Brain Dev.
Brain regional levels of adenosine and adenosine nucleotides in rats killed by high-energy focused microwave irradiation
J. Neurosci. Methods
The purine nucleotide cycle and its molecular defects
Prog. Neurobiol.
Kinetic studies of mutant human adenylosuccinase
Biochim. Biophys. Acta
The structure of adenylosuccinate lyase, an enzyme with dual activity in the de novo purine biosynthetic pathway
Struct. Fold Des.
The crystal structure of adenylosuccinate lyase from Pyrobaculum aerophilum reveals an intracellular protein with three disulfide bonds
J. Mol. Biol.
Identification of His141 in the active site of Bacillus subtilis adenylosuccinate lyase by affinity labeling with 6-(4-bromo-2,3-dioxobutyl)thioadenosine 5′-monophosphate
J. Biol. Chem.
Expression, purification, and kinetic characterization of recombinant human adenylosuccinate lyase
J. Biol. Chem.
Adenylosuccinase deficiency: possibly underdiagnosed encephalopathy with variable clinical features
Eur. J. Paediatr. Neurol.
Identification of new mutations in the adenylosuccinate lyase gene associated with impaired enzyme activity in lymphocytes and red blood cells
Biochim. Biophys. Acta
An infantile autistic syndrome characterised by the presence of succinylpurines in body fluids
Lancet
Hypoxanthine–guanine phosphoribosyltransferase deficiency: Lesch–Nyhan syndrome and gout
Regional brain glucose utilization in adenylosuccinase-deficient patients measured by positron emission tomography
Pediatr. Res.
Effect of d-ribose administration to a patient with inherited deficit of adenylosuccinase
Adv. Exp. Med. Biol.
Psychopharmacology in autism
Psychosom. Med.
A mutation in adenylosuccinate lyase associated with mental retardation and autistic features
Nat. Genet.
Inborn errors of the purine nucleotide cycle: adenylosuccinase deficiency
J. Inherit. Metab. Dis.
A somatic cell hybrid with a single human chromosome 22 corrects the defect in the CHO mutant (Ade-I) lacking adenylosuccinase activity
Cytogenet. Cell Genet.
Mapping of the human adenylosuccinate lyase (ADSL) gene to chromosome 22q13.1 → q13.2
Cytogenet. Cell Genet.
Human adenylosuccinate lyase (ADSL), cloning and characterization of full-length cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in six patients
Hum. Mol. Genet.
Mutation analysis in adenylosuccinate lyase deficiency: eight novel mutations in the re-evaluated full ADSL coding sequence
Hum. Mutat.
Functional studies in fibroblasts of adenylosuccinase-deficient children
J. Inherit. Metab. Dis.
Residual adenylosuccinase activities in fibroblasts of adenylosuccinase-deficient children: parallel deficiency with adenylosuccinate and succinyl-AICAR in profoundly retarded patients and non-parallel deficiency in a mildly retarded girl
J. Inherit. Metab. Dis.
Cited by (81)
A Caenorhabditis elegans model of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology
2023, Molecular Genetics and MetabolismMulti-omics analysis reveals the influence of tetracycline on the growth of ryegrass root
2022, Journal of Hazardous MaterialsCellular and molecular mechanisms underlying autism spectrum disorders and associated comorbidities: A pathophysiological review
2022, Biomedicine and PharmacotherapyCitation Excerpt :In addition, defects in urea cycles and phenylketonuria, and subsequent increase in ammonia and phenylalanine, are associated with an elevation in the excitation-to-inhibition, seizure, and epilepsy due to overproduction of the cortical excitatory neurotransmitter, glutamate [174,196,202,203] (Fig. 1). Nonetheless, deficiency of some minerals contributes significantly to epilepsy but at very few rates [155,174,204]. Magnesium (Mg) is one of the most essential minerals that affect the neurotransmitter system.
The protective effect of Xanthoceras sorbifolia Bunge husks on cognitive disorder based on metabolomics and gut microbiota analysis
2021, Journal of Ethnopharmacology