Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the residual adenylosuccinate lyase activity in cultured lymphoblasts from a pair of siblings with infantile autism who have been previously shown to have a deficiency of the enzyme. The rates and distribution of de novo purine synthesis assessed by the utilization of radiolabeled formate by intact cells was nearly normal. We compared the steady-state kinetics and thermal stability of adenylosuccinate lyase in lysates from those cells and normal lymphoblasts. There is no evidence of inhibitory activity in the lysates of the mutant cells. The optimal pH was approximately 7.8 and was indistinguishable from that in control cells. The apparent Km in the two mutant cells lines (2.6 +/- 0.5 microM) is not significantly different from normal (3.3 +/- 0.8 microM), but the mutants displayed markedly decreased maximum steady-state velocities (6.7 +/- 1.1 compared to 13.8 +/- 0.9 nmol.mg-1.min-1). Residual activities in mutant cells show decreased thermal stability (t1/2 = 0.21 minutes at 60 degrees C as compared to 2.2 minutes), suggesting that there is a structural mutation of the adenylosuccinate lyase in the mutant cells.
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PMID:Studies of mutant human adenylosuccinate lyase. 262 96

Residual adenylosuccinase activity was studied in cultured lymphoblasts from a pair of siblings with infantile autism who have been previously shown to have a deficiency of the enzyme. The rates and distribution of de novo purine synthesis by intact cells were nearly normal. There was no evidence of inhibitory activity in the lysates of the mutant cells. The optimal pH was indistinguishable from that in control cells. The apparent Km in the two mutant cells lines is not significantly different from normal, but the mutants displayed markedly decreased maximum steady-state velocities. Residual activities in mutant cells show decreased thermal stability, suggesting that there is a structural mutation of the adenylosuccinase in the mutant cells.
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PMID:Kinetic studies of mutant human adenylosuccinase. 280 36

Succinyladenosine and succinylaminoimidazole carboxamide riboside were found in body fluids from 3 children, including a brother and sister, with severe psychomotor delay and autism. Both succinylpurines were identified by acid hydrolysis, anion-exchange chromatography, and ultraviolet spectrophotometry. Concentrations of both compounds were around 100 mumol/l in cerebrospinal fluid, between 5 and 10 mumol/l in plasma, and in the mmol/l range in urine. Succinylpurines were undetectable in cerebrospinal fluid and plasma from controls but there might be trace amounts in normal urine. The compounds are dephosphorylated derivatives of the intracellular metabolites adenylosuccinate and succinylaminoimidazole carboxamide ribotide, the two substrates of adenylosuccinase (adenylosuccinate lyase, EC 4.3.2.2). Their presence indicates a deficiency of this enzyme, which is involved in both de novo synthesis of purines and the formation of adenosine monophosphate from inosine monophosphate. Assays in one patient revealed markedly decreased adenylosuccinase activity in the liver and absence of activity in the kidney. The accumulation of both succinylpurines in the cerebrospinal fluid suggests that there is also a deficiency of this enzyme in the brain and that it may be the basic defect in a subgroup of children with genetically determined autism.
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PMID:An infantile autistic syndrome characterised by the presence of succinylpurines in body fluids. 615 Jan 39

We report a new screening method for adenylosuccinate lyase (ASase) deficiency using capillary electrophoresis (CE). This enzyme defect causes secondary autism and psychomotor retardation in early childhood. In all body fluids of these patients, two succinylpurine metabolites can be found that are normally not detectable: succinyladenosine and succinylaminoimidazole carboxamide (SAICA) riboside. A Beckman P/ACE 2050 capillary electrophoresis system was used with a 47.1 cm capillary, 75 microns ID, and the P/ACE Beckman UV absorbance detector. Untreated urine, injected for 1 s, was separated in a pH 8.63 borate buffer at 20 kV. The two succinylpurines (migration times 13.36 and 13.60 min) were detected at 254 nm only in urine of patients with ASase deficiency but not in control samples.
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PMID:Capillary electrophoresis for screening of adenylosuccinate lyase deficiency. 858 67

Autism is a heterogeneous neuropsychiatric syndrome of unknown etiology. There is evidence that a deficiency in the enzyme adenylosuccinate lyase (ADSL), essential for de novo purine biosynthesis, could be involved in the pathogenesis of certain cases. A point mutation in the ADSL gene, resulting in a predicted serine-to-proline substitution and conferring structural instability to the mutant enzyme, has been reported previously in 3 affected siblings. In order to determine the prevalence of the mutation, we PCR-amplified the exon spanning the site of this mutation from the genomic DNA of patients fulfilling DSM-III-R criteria for autistic disorder. None of the 119 patients tested were found to have this mutation. Furthermore, on preliminary screening using singlestrand conformation polymorphism (SSCP), no novel mutations were detected in the coding sequence of four ADSL exons, spanning approximately 50% of the cDNA. In light of these findings, it appears that mutations in the ADSL gene represent a distinctly uncommon cause of autism.
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PMID:Adenylosuccinate lyase (ADSL) and infantile autism: absence of previously reported point mutation. 882 95

Although the exact prevalence of metabolic abnormalities in autism spectrum disorders is unknown, several metabolic defects have been associated with autistic symptoms. These include phenylketonuria, histidinemia, adenylosuccinate lyase deficiency, dihydropyrimidine dehydrogenase deficiency, 5'-nucleotidase superactivity, and phosphoribosylpyrophosphate synthetase deficiency. When the metabolic consequences of an enzyme defect are well defined (e.g., phenylketonuria, 5'-nucleotidase superactivity), treatment with diet, drugs, or nutritional supplements may bring about a dramatic reduction in autistic symptoms. This review evaluates evidence for metabolic etiologies in autism spectrum disorders, as well as for the efficacy of dietary and vitamin treatments. The relationship between gastrointestinal abnormalities and autism spectrum disorders is also considered.
J Autism Dev Disord 2000 Oct
PMID:Metabolic approaches to the treatment of autism spectrum disorders. 1109 86

An Australian patient with autism was found to be heterozygous for two mutations in the gene encoding adenylosuccinate lyase (ASL), resulting in the protein mutations E80D and D87E. The patient's mother carried only the E80D mutation. The equivalent positions are 62 and 69 in Bacillus subtilis ASL. Although both human and B. subtilis enzymes normally have Asp at position 87 (or 69), the B. subtilis ASL has Ile and Asp at 62 and 65, respectively, whereas human ASL has Glu and Arg at the equivalent positions. We have constructed, expressed, and purified the double mutant I62E/D65R as a "humanized" normal B. subtilis enzyme to compare with enzymes with a single mutation at position 62 (I62D/D65R), at position 69 (I62E/D65R/D69E), or at both positions (I62D/D65R/D69E). V(max) for conversion of adenylosuccinate to AMP and fumarate is 0.57 micromol/min/mg for I62E/D65R, 0.064 micromol/min/mg for I62D/D65R, 0.27 micromol/min/mg for I62E/D65R/D69E, and 0.069 micromol/min/mg for I62D/D65R/D69E. The K(m) for adenylosuccinate is elevated in the X62D mutants, and I62D/D65R is the least stable of these ASLs at 37 degrees C. The CD spectra of mutant and wild type enzymes are similar; thus, there are no appreciable structural changes. Clearly the Asp(62) causes the most drastic effect on ASL function, whereas the Glu(69) mutation produces only modest change. These results emphasize the importance of expanding tests for ASL deficiency to individuals with developmental delay of any severity, including individuals with autistic spectrum disorder. This study further demonstrates the usefulness of the B. subtilis ASL as a model to mimic the defective enzyme in ASL deficiency.
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PMID:Two novel mutant human adenylosuccinate lyases (ASLs) associated with autism and characterization of the equivalent mutant Bacillus subtilis ASL. 1547 76

Autism is a heterogeneous disorder that can reveal a specific genetic disease. This paper describes several genetic diseases consistently associated with autism (fragile X, tuberous sclerosis, Angelman syndrome, duplication of 15q11-q13, Down syndrome, San Filippo syndrome, MECP2 related disorders, phenylketonuria, Smith-Magenis syndrome, 22q13 deletion, adenylosuccinate lyase deficiency, Cohen syndrome, and Smith-Lemli-Opitz syndrome) and proposes a consensual and economic diagnostic strategy to help practitioners to identify them. A rigorous initial clinical screening is presented to avoid unnecessary laboratory and imaging studies. Regarding psychiatric nosography, the concept of "syndromal autism"--autism associated with other clinical signs should be promoted because it may help to distinguish patients who warrant a multidisciplinary approach and further investigation.
J Autism Dev Disord 2005 Feb
PMID:Specific genetic disorders and autism: clinical contribution towards their identification. 1579 26

Mental retardation (MR) is a common disorder frequently of unknown origin. Because there are few studies regarding MR and inborn errors of metabolism (IEM), we aimed to identify patients with IEM from a cohort of 944 patients with unexplained MR. Biochemical examinations such as determination of creatine (Cr) metabolites, acylcarnitines, purine, and pyrimidines in urine were applied. We found seven patients with IEM [three with cerebral Cr deficiency syndromes (CCDS)], one with adenylosuccinate lyase (ADSL) deficiency, and three, born before the neonatal metabolic screening program in Catalonia, with phenylketonuria (PKU). All told, they represent 0.8% of the whole cohort. All of them had additional symptoms such as epilepsy, movement disorders, autism, and other psychiatric disturbances. In conclusion, in patients with MR, it is essential to perform a thorough appraisal of the associated signs and symptoms, and in most disorders, it is necessary to apply specific analyses. In some cases, it is important to achieve an early diagnosis and therapy, which may reduce the morbimortality, and to offer genetic counselling.
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PMID:Study of inborn errors of metabolism in urine from patients with unexplained mental retardation. 2004 33

A rhodamine based boronic acid linearly responds to increasing 5-aminoimidazole-4-carboxamide riboside (AICAr) concentrations in human urine. This method is thus an advance in detecting adenylosuccinate lyase (ADSL) deficiency as AICAr is a model riboside for the ADSL substrates succinyladenosine (S-Ado) and succinylaminoimidazolecarboxamide riboside (SAICAr). ADSL deficiency is a rare but devastating disease of de novo purine synthesis in infants. Its diagnosis is also significant as it is one of the autism spectrum disorders.
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PMID:Progress Towards Simple and Direct Detection of Adenylosuccinate Lyase Deficiency in Human Urine. 2271 7


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