Adenylosuccinate lyase deficiency
ABSTRACT Adenylosuccinate lyase deficiency is a disease of purine metabolism which affects patients both biochemically and behaviorally. The symptoms are variable and include psychomotor retardation, autistic features, hypotonia, and seizures. Patients also accumulate the substrates of ADSL in body fluids. Both the presence of normal levels of ADSL enzyme activities in some patient tissues and the absence of a clear correlation between mutations, biochemistry, and behavior show that the system has unexplored biochemical and/or genetic complexity. It is unclear whether the pathological mechanisms of this disease result from a deficiency of purines, a toxicity of intermediates, or perturbation of another pathway or system. A patient with autistic features and mild psychomotor delay carries two novel mutations in this gene, E80D and D87E. The creation of a mouse model of this disease will be an important step in elucidating the in vivo mechanisms of the disease. Mice carrying mutations that cause ADSL deficiency in humans will be informative as to the effects of these mutations both during embryogenesis and on the brain, possibly leading to therapies for this disease in the future.
SourceAvailable from: Richard E Frye[Show abstract] [Hide abstract]
ABSTRACT: Many children with ASD have underlying metabolic conditions.•Metabolic disorders are also commonly associated with epilepsy.•Treating metabolic disorders may optimize seizure management.Epilepsy & Behavior 11/2014; DOI:10.1016/j.yebeh.2014.08.134 · 2.06 Impact Factor
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ABSTRACT: Autism is a childhood neurodevelopmental disorder with high heterogeneity. Following our genome-wide associated loci with autism, we performed sequencing analysis of the coding regions, UTR and flanking splice junctions of AMPD1 in 830 Chinese autism individuals as well as 514 unrelated normal controls. Fourteen novel variants in the coding sequence were identified, including 11 missense variants and 3 synonymous mutations. Among these missense variants, 10 variants were absent in 514 control subjects, and conservative and functional prediction was carried out. Mitochondria activity and lactate dehydrogenase assay were performed in 5 patients' lymphoblast cell lines; p.P572S and p.S626C showed decreased mitochondrial complex I activity, and p.S626C increased lactate dehydrogenase release in medium. Conclusively, our data suggested that mutational variants in AMPD1 contribute to autism risk in Han Chinese population, uncovering the contribution of mutant protein to disease development that operates via mitochondria dysfunction and cell necrosis.European Archives of Psychiatry and Clinical Neuroscience 08/2014; DOI:10.1007/s00406-014-0524-6 · 3.36 Impact Factor
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ABSTRACT: The preparation of isotopically labelled standards of succinylpurines is presented.•LC–MS/MS method for determination of succinylpurines in neonatal DBS was developed.•Patients with ADSL deficiency have elevated levels of succinylpurines in DBS.•The new screening method may be used for retrospective diagnosis of ADSL deficiency.Clinical Biochemistry 10/2014; DOI:10.1016/j.clinbiochem.2014.10.004 · 2.23 Impact Factor