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.
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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
Article: Adenylosuccinate lyase deficiency[Show abstract] [Hide abstract]
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.Journal of Inherited Metabolic Disease 08/2014; 38(2). DOI:10.1007/s10545-014-9755-y · 4.14 Impact Factor
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ABSTRACT: The Angelman syndrome is caused by disruption of the UBE3A gene and is clinically delineated by the combination of severe mental disability, seizures, absent speech, hypermotoric and ataxic movements, and certain remarkable behaviors. Those with the syndrome have a predisposition toward apparent happiness and paroxysms of laughter, and this finding helps distinguish Angelman syndrome from other conditions involving severe developmental handicap. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the critical 15q11.2-q13 genomic region identifies 75-80% of all individuals with the syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy. In the remaining group, UBE3A sequence analysis identifies an additional percentage of patients, but 5-10% will remain who appear to have the major clinical phenotypic features but do not have any identifiable genetic abnormalities. Genetic counseling for recurrence risk is complicated because multiple genetic mechanisms can disrupt the UBE3A gene, and there is also a unique inheritance pattern associated with UBE3A imprinting. Angelman syndrome is a prototypical developmental syndrome due to its remarkable behavioral phenotype and because UBE3A is so crucial to normal synaptic function and neural plasticity.Molecular syndromology 04/2012; 2(3-5):100-112. DOI:10.1159/000328837