allopurinol and Intellectual-Disability

Perinatal asphyxia is characterized by oxygen deprivation and lack of perfusion in the perinatal period, leading to hypoxic-ischemic encephalopathy and sequelae such as cerebral palsy, mental retardation, cerebral visual impairment, epilepsy and learning disabilities. On cellular level PA is associated with a decrease in oxygen and glucose leading to ATP depletion and a compromised mitochondrial function. Upon reoxygenation and reperfusion, the renewed availability of oxygen gives rise to not only restoration of cell function, but also to the activation of multiple detrimental biochemical pathways, leading to secondary energy failure and ultimately, cell death. The formation of reactive oxygen species, nitric oxide and peroxynitrite plays a central role in the development of subsequent neurological damage. In this review we give insight into the pathophysiology of perinatal asphyxia, discuss its clinical relevance and summarize current neuroprotective strategies related to therapeutic hypothermia, ischemic postconditioning and pharmacological interventions. The review will also focus on the possible neuroprotective actions and molecular mechanisms of the selective neuronal and inducible nitric oxide synthase inhibitor 2-iminobiotin that may represent a novel therapeutic agent for the treatment of hypoxic-ischemic encephalopathy, both in combination with therapeutic hypothermia in middle- and high-income countries, as well as stand-alone treatment in low-income countries.

Topics: Allopurinol; Asphyxia Neonatorum; Biotin; Cerebral Palsy; Clinical Trials as Topic; Epilepsy; Erythropoietin; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Intellectual Disability; Ischemic Postconditioning; Melatonin; Neuroprotective Agents; Pregnancy; Reactive Nitrogen Species; Reactive Oxygen Species

Topics: Allopurinol; Amniocentesis; Athetosis; Brain; Erythrocytes; Fibroblasts; Humans; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Pentosyltransferases; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Uric Acid

Topics: Allopurinol; Carbamazepine; Child, Preschool; DNA Mutational Analysis; Erythrocytes; Family Health; Female; Gout Suppressants; Humans; Hypoxanthine Phosphoribosyltransferase; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Mutation; Peritoneal Dialysis; Treatment Outcome

The impairment of the purinergic system, characterized by reduced adenosinergic activity, has been implicated in the neurobiology of aggressive behaviour. Since there are no direct adenosine agonists available for human use, inhibition of purine degradation by allopurinol was conceived as a possible strategy. We report two cases of adults with refractory aggressive behaviour due to a neurological condition (one mainly with self-inflicted behaviour) with dramatic response to therapy with allopurinol, 300 mg/day p.o. These preliminary results reinforce the involvement of the purinergic system in the neurobiology of aggression, warranting further testing of allopurinol as a new treatment for aggressive and self-inflicted behaviours.

Topics: Administration, Oral; Adult; Aggression; Allopurinol; Astrocytoma; Brain Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Intellectual Disability; Male; Meningitis; Neurocognitive Disorders; Parietal Lobe; Postoperative Complications; Radiotherapy, Adjuvant; Self-Injurious Behavior

A female patient is described with combined deficiency of sulphite, zanthine and aldehyde oxidase. She presented at the age of four weeks with intractable seizures. Initially the diagnosis was suspected because of a very low serum urate level (23 mumol/1-1). This condition can be easily missed and it is proposed that measurement of serum urate be included in the metabolic assessment of neonates with unexplained seizures and developmental delay.

Topics: Aldehyde Oxidase; Aldehyde Oxidoreductases; Chromosome Aberrations; Chromosome Disorders; Coenzymes; Female; Genes, Recessive; Humans; Infant; Intellectual Disability; Metalloproteins; Molybdenum Cofactors; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Uric Acid; Xanthine Oxidase

Topics: Female; Homozygote; Humans; Intellectual Disability; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Xanthine Oxidase; Xanthines

Topics: Allopurinol; Athetosis; Child; Compulsive Behavior; Diet Therapy; Humans; Huntington Disease; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Uric Acid

Topics: Allopurinol; Anticonvulsants; Child; Child, Preschool; Electroencephalography; Humans; Infant; Intellectual Disability; Male; Neurologic Manifestations; Purine-Pyrimidine Metabolism, Inborn Errors; Seizures; Uric Acid

Topics: Allopurinol; Anemia; Anti-Bacterial Agents; Humans; Infant; Intellectual Disability; Lesch-Nyhan Syndrome; Neurologic Manifestations; Uric Acid; Urinary Calculi; Urinary Tract Infections

Topics: Adenine; Adolescent; Adult; Allopurinol; Athetosis; Australia; Child; Humans; Hypoxanthines; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Phosphotransferases; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Uric Acid; Xanthines

Topics: Allopurinol; Athetosis; Child, Preschool; Humans; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Sex Factors; Syndrome

Topics: Adolescent; Allopurinol; Athetosis; Child, Preschool; Humans; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Sex Chromosomes; Uric Acid

Topics: Adolescent; Athetosis; Brain; Child; Child, Preschool; Compulsive Behavior; Gout; Humans; Huntington Disease; Infant; Infant, Newborn; Intellectual Disability; Kidney Diseases; Liver; Prognosis; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Self Mutilation; Transferases; Uric Acid; Uricosuric Agents; Xanthine Oxidase

Topics: Allopurinol; Athetosis; Basal Ganglia; Diphosphates; Erythrocytes; Fibroblasts; Guanine; Humans; Hypoxanthines; Infant; Intellectual Disability; Lesch-Nyhan Syndrome; Liver; Pentosephosphates; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Ribose; Self Mutilation; Transferases; Xanthines

Topics: Adolescent; Allopurinol; Athetosis; Child; Humans; Hypoxanthines; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Probenecid; Purine-Pyrimidine Metabolism, Inborn Errors; Pyelonephritis; Self Mutilation; Uric Acid; Urinary Calculi; Xanthines

Topics: Allopurinol; Athetosis; Child; Chorea; Compulsive Behavior; Humans; Intellectual Disability; Orotic Acid; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Pyrimidines; Self Mutilation; Uric Acid

Topics: Allopurinol; Athetosis; Child; Child, Preschool; Chorea; Chromatography, Thin Layer; Densitometry; Humans; Hypoxanthines; Intellectual Disability; Male; Nucleosides; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Self Mutilation; Uric Acid; Xanthines

Certain gouty subjects with excessive de novo purine synthesis are deficient in hypoxanthineguanine phosphoribosyltransferase (HG-PRTase [EC 2.4.2.8]). The mechanism of accelerated uric acid formation in these patients was explored by measuring the incorporation of glycine-(14)C into various urinary purine bases of normal and enzyme-deficient subjects during treatment with the xanthine oxidase inhibitor, allopurinol. In the presence of normal HG-PRTase activity, allopurinol reduced purine biosynthesis as demonstrated by diminished excretion of total urinary purine or by reduction of glycine-(14)C incorporation into hypoxanthine, xanthine, and uric acid to less than one-half of control values. A boy with the Lesch-Nyhan syndrome was resistant to this effect of allopurinol while a patient with 12.5% of normal enzyme activity had an equivocal response. Three patients with normal HG-PRTase activity had a mean molar ratio of hypoxanthine to xanthine in the urine of 0.28, whereas two subjects who were deficient in HG-PRTase had reversal of this ratio (1.01 and 1.04). The patterns of (14)C-labeling observed in HG-PRTase deficiency reflected the role of hypoxanthine as precursor of xanthine. The data indicate that excessive uric acid in HG-PRTase deficiency is derived from hypoxanthine which is insufficiently reutilized and, as a consequence thereof, catabolized inordinately to uric acid. The data provide evidence for cyclic interconversion of adenine and hypoxanthine derivatives. Cleavage of inosinic acid to hypoxanthine via inosine does not contribute significantly to the formation of uric acid in either normal man or in patients with HG-PRTase deficiency.HG-PRTase was not completely absent in red blood cells from a boy with the Lesch-Nyhan syndrome; with hypoxanthine as substrate, the activity in erythrocyte hemolysates was 0.64% of normal values.

Topics: Adult; Allopurinol; Athetosis; Carbon Isotopes; Child; Chorea; Compulsive Behavior; Deficiency Diseases; Glycine; Gout; Guanine; Humans; Hypoxanthines; Inositol; Intellectual Disability; Metabolism, Inborn Errors; Nucleosides; Purines; Self Mutilation; Transferases; Uric Acid

Topics: Adenine; Allopurinol; Athetosis; Bone Marrow; Carbon Isotopes; Child; Child, Preschool; Chorea; Compulsive Behavior; Diet Therapy; Erythrocytes; Folic Acid; Glycine; Humans; Intellectual Disability; Male; Metabolism, Inborn Errors; Movement Disorders; Purines; Self Mutilation; Transferases; Uric Acid; Vitamin B 12

Topics: Allopurinol; Amino Acids; Athetosis; Carbon Isotopes; Child, Preschool; Chorea; Compulsive Behavior; Diet Therapy; Glutamates; Glycine; Humans; Infant; Intellectual Disability; Male; Metabolism, Inborn Errors; Movement Disorders; Purines; Self Mutilation; Uric Acid

Topics: Adolescent; Adult; Alkaptonuria; Allopurinol; Amniotic Fluid; Athetosis; Carbohydrates; Chorea; Chromatography, Ion Exchange; Compulsive Behavior; Female; Gout; Humans; Hypertension; Infant; Infant, Newborn; Intellectual Disability; Male; Maple Syrup Urine Disease; Methods; Middle Aged; Nephritis; Nicotinic Acids; Phenols; Pregnancy; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Self Mutilation; Spectrophotometry; Sulfuric Acids; Ultraviolet Rays; Uric Acid; Xanthines

Topics: Allopurinol; Athetosis; Benzofurans; Brain; Child; Child, Preschool; Chorea; Compulsive Behavior; Erythrocytes; Female; Guanine; Humans; Hypoxanthines; Infant; Intellectual Disability; Japan; Kidney; Lesch-Nyhan Syndrome; Liver; Male; Proteinuria; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Transferases; Uric Acid

Topics: Allopurinol; Athetosis; Azathioprine; Benzofurans; Child; Child, Preschool; Guanine; Humans; Hypoxanthines; Intellectual Disability; Japan; Ketones; Lesch-Nyhan Syndrome; Male; Paraplegia; Pentosyltransferases; Phenols; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Spasm; Uric Acid; Xanthines

Topics: Adenine; Allopurinol; Autistic Disorder; Carbon Isotopes; Child Behavior Disorders; Child, Preschool; Erythrocytes; Glucosyltransferases; Glycine; Gout; Guanine; Humans; Hypoxanthines; Intellectual Disability; Male; Mutism; Nucleotides; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Uric Acid; Xanthenes

Topics: Allopurinol; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Metabolism, Inborn Errors; Muscle Cramp; Self Mutilation; Uric Acid

Topics: Allopurinol; Athetosis; Child; Genes, Recessive; Guanine Nucleotides; Humans; Hypoxanthines; Intellectual Disability; Locomotion; Male; Neurologic Manifestations; Posture; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Sex Chromosomes; Speech Disorders; Transferases; Uric Acid

Topics: Allopurinol; Guanine; Humans; Hypoxanthines; Intellectual Disability; Kidney Diseases; Metabolism, Inborn Errors; Nervous System Diseases; Sex Chromosomes; Transferases; Uremia; Uric Acid; Xanthine Oxidase

Topics: Adenosine Triphosphate; Allopurinol; Anemia; Brain Diseases; Carbon Isotopes; Child, Preschool; Erythrocytes; Fibroblasts; Humans; Infant; Intellectual Disability; Kidney Diseases; Male; Metabolism, Inborn Errors; Purines; Self Mutilation; Transferases; Uric Acid

Topics: Allopurinol; Athetosis; Body Height; Body Weight; Child; Child, Preschool; Chorea; Humans; Infant; Intellectual Disability; Male; Probenecid; Self Mutilation; Uric Acid; Xanthine Oxidase

Topics: Adolescent; Allopurinol; Anemia, Macrocytic; Athetosis; Chorea; Gout; Humans; Intellectual Disability; Male; Nephritis, Interstitial; Neurologic Manifestations; Uric Acid

Topics: Adolescent; Allopurinol; Aminohydrolases; Athetosis; Brain; Central Nervous System Diseases; Cerebral Palsy; Chorea; Erythrocytes; Fibroblasts; Glucosyltransferases; Humans; Hypoxanthines; Intellectual Disability; Liver; Male; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Self Mutilation; Spasm; Xanthines