title: Pediatric neurological syndromes and inborn errors of purine metabolism.
abstract: This review is devised to gather the presently known inborn errors of purine metabolism that manifest neurological pediatric syndromes. The aim is to draw a comprehensive picture of these rare diseases, characterized by unexpected and often devastating neurological symptoms. Although investigated for many years, most purine metabolism disorders associated to psychomotor dysfunctions still hide the molecular link between the metabolic derangement and the neurological manifestations. This basically indicates that many of the actual functions of nucleosides and nucleotides in the development and function of several organs, in particular central nervous system, are still unknown. Both superactivity and deficiency of phosphoribosylpyrophosphate synthetase cause hereditary disorders characterized, in most cases, by neurological impairments. The deficiency of adenylosuccinate lyase and 5-amino-4-imidazolecarboxamide ribotide transformylase/IMP cyclohydrolase, both belonging to the de novo purine synthesis pathway, is also associated to severe neurological manifestations. Among catabolic enzymes, hyperactivity of ectosolic 5'-nucleotidase, as well as deficiency of purine nucleoside phosphorylase and adenosine deaminase also lead to syndromes affecting the central nervous system. The most severe pathologies are associated to the deficiency of the salvage pathway enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase: the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to a clear impairment of mitochondrial functions. The assessment of hypo- or hyperuricemic conditions is suggestive of purine enzyme dysfunctions, but most disorders of purine metabolism may escape the clinical investigation because they are not associated to these metabolic derangements. This review may represent a starting point stimulating both scientists and physicians involved in the study of neurological dysfunctions caused by inborn errors of purine metabolism with the aim to find novel therapeutical approaches.
authors.affiliation: Dipartimento di Biologia, Unità di Biochimica, Via S Zeno 51, 56127 Pisa, Italy. mcamici@biologia.unipi.it
authors.forename: Marcella
authors.initials: M
authors.lastname: Camici
authors.forename: Vanna
authors.initials: V
authors.lastname: Micheli
authors.forename: Piero Luigi
authors.initials: PL
authors.lastname: Ipata
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tozzi
mesh_terms: D000367:Age Factors; D020739:Brain Diseases, Metabolic, Inborn / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053858:Metabolic Networks and Pathways / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009711:Nucleotides / Q000378:metabolism; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D011687:Purines / Q000378:metabolism*
chemical_list: D004798:Enzymes; D009711:Nucleotides; D011687:Purines