Proc. Natl. Acad. Sci. USA Vol. 94, pp. 11601–11606, October 1997 Medical Sciences Developmental disorder associated with increased cellular nucleotidase activity (purine-pyrimidine metabolismyuridineybrain diseases) THEODORE PAGE*†,ALICE YU‡,JOHN FONTANESI‡, AND WILLIAM L. NYHAN‡ Departments of *Neurosciences and ‡Pediatrics, University of California at San Diego, La Jolla, CA 92093 Communicated by J. Edwin Seegmiller, University of California at San Diego, La Jolla, CA, August 7, 1997 (received for review June 26, 1997) ABSTRACT Four unrelated patients are described with a represent defects of purine metabolism, although no specific syndrome that included developmental delay, seizures, ataxia, enzyme abnormality has been identified in these cases (6). In recurrent infections, severe language deficit, and an unusual none of these disorders has it been possible to delineate the behavioral phenotype characterized by hyperactivity, short mechanism through which the enzyme deficiency produces the attention span, and poor social interaction. These manifesta- neurological or behavioral abnormalities. Therapeutic strate- tions appeared within the first few years of life. Each patient gies designed to treat the behavioral and neurological abnor- displayed abnormalities on EEG. No unusual metabolites were malities of these disorders by replacing the supposed deficient found in plasma or urine, and metabolic testing was normal metabolites have not been successful in any case. except for persistent hypouricosuria. Investigation of purine This report describes four unrelated patients in whom and pyrimidine metabolism in cultured fibroblasts derived developmental delay, seizures, ataxia, recurrent infections, from these patients showed normal incorporation of purine speech deficit, and an unusual behavioral phenotype were bases into nucleotides but decreased incorporation of uridine. associated with highly elevated activity of cytosolic 59nucle- De novo synthesis of purines and cellular phosphoribosyl otidase. Metabolic therapy with pyrimidine compounds ap- pyrophosphate content also were moderately decreased. The peared to be highly effective in reversing these manifestations. distribution of incorporated purines and pyrimidines did not reveal a pattern suggestive of a deficient enzyme activity. CLINICAL PRESENTATION Assay of individual enzymes in fibroblast lysates showed no deficiencies. However, the activity of cytosolic 5*-nucleotidase The clinical presentation of four patients is given below and is was elevated 6- to 10-fold. Based on the possibility that the summarized in Table 1. Details of the clinical course of each observed increased catabolic activity and decreased pyrimi- patient as well as results of neuropsychological testing and dine salvage might be causing a deficiency of pyrimidine treatment protocols will be published in a separate clinical nucleotides, the patients were treated with oral pyrimidine paper. nucleoside or nucleotide compounds. All patients showed The presentation was fairly consistent. All patients were remarkable improvement in speech and behavior as well as markedly delayed in their developmental milestones, especially decreased seizure activity and frequency of infections. A language. All had seizures, ataxia, an awkward gait, and mildly double-blind placebo trial was undertaken to ascertain the impaired fine motor control. All four displayed an unusual efficacy of this supplementation regimen. Upon replacement behavioral phenotype that was characterized by extreme hy- of the supplements with placebo, all patients showed rapid peractivity, distractability, a strange ‘‘delirious’’ quality to their regression to their pretreatment states. These observations affect, and abnormal social interaction. All four patients suggest that increased nucleotide catabolism is related to the experienced frequent ear and sinus infections, but no consis- symptoms of these patients, and that the effects of this tent reason for immunodeficiency (such as reduced antibody increased catabolism are reversed by administration of uri- titre or abnormal T cell response) could be found. It was noted dine. that during infection, behavioral, language, and neurological abnormalities would worsen. All patients excreted reduced Behavioral abnormalities, seizures, developmental delay, and quantities of uric acid when compared with age-matched immunodeficiency are known to be associated with several controls (7). A number of laboratory tests were performed and defects of purine and pyrimidine metabolism (1). Seizures and found to be within normal limits. These included plasma amino autistic behavior are seen in some patients with dihydropyri- acids and organic acids, urinary amino acids and organic acids, midine dehydrogenase deficiency (2). Individuals with a defi- plasma and urinary HPLC analysis, biotin, carnitine, folate, ciency of adenylosuccinate lyase activity also display autistic and B12. All patients had unaffected parents and siblings; one behavior, seizures, and other neurological abnormalities (3). A patient’s history was positive for a similarly affected cousin. deficiency of either adenosine deaminase or purine nucleoside Patient 1, a white female, was first studied at 2 years of age phosphorylase causes severe immunodeficiency; neurological because of recurrent sinus infections, seizures, and develop- symptoms also have been reported with these two enzyme mental delay. A preliminary report of her case has been deficiencies (4). Finally, deficiency of hypoxanthine phospho- published (8). At 20 months, height and weight were both at the 10th percentile, and head circumference was at the 50% ribosyltransferase causes Lesch–Nyhan syndrome with its char- percentile. Seizures began at 19 months of age and consisted acteristic self-injurious behavior, mental retardation, and dys- predominantly of jerking of the upper extremities, head tilt, tonic posturing (5). Cases of excessive uric acid excretion and eye deviation. Seizures were not well controlled by car- associated with seizures and autistic behavior are likely to bamazapine or valproate. EEG revealed seizure activity over The publication costs of this article were defrayed in part by page charge Abbreviations: PRPP, phosphoribosyl pyrophosphate; FBS, fetal bo- payment. This article must therefore be hereby marked ‘‘advertisement’’ in vine serum. accordance with 18 U.S.C. §1734 solely to indicate this fact. †To whom reprint requests should be addressed at: Department of © 1997 by The National Academy of Sciences 0027-8424y97y9411601-6$2.00y0 Neurosciences 0624, University of California at San Diego, La Jolla, PNAS is available online at http:yywww.pnas.org. CA 92093. e-mail: [email protected]. 11601 Downloaded by guest on September 29, 2021 11602 Medical Sciences: Page et al. Proc. Natl. Acad. Sci. USA 94 (1997) Table 1. Clinical presentation of four patients Patient Patient Patient Patient Symptom 1 2 3 4 General Sex F F MM Age first studied, years 3428 Growth retardation 1211 Behavior Hyperactive 1111 Inability to focus 1111 Extreme distractibility 1111 Occasionally aggressive 1211 Impulsive 1111 ‘‘Delirious’’ affect 1111 Compulsiveness 1111 Abnormal social interaction 1111 Speech Speech delay 1111 Slurred speech 1111 Tremulous speech 1111 Short, telegraphic sentences 1111 Neurological Seizures 1111 Abnormal EEG 1111 Ataxia 1111 Impaired fine motor control 1111 Awkward gait 1111 Immunological Frequent infections 1111 Abnormal immunoglobulins 1122 Abnormal T cell response 1122 Other Developmentally delayed 1111 Sparse hairyhair loss 1122 Skin rash 1112 Hypouricosuria 1111 the right temporal region. Neurological examination also the cheeks, as well as keratosis follicularis on the trunk. The revealed truncal ataxia, an awkward gait, and mild impairment patient suffered from frequent bouts of sinusitis and otitis of fine motor control. Hair loss began at approximately 22 media and had been treated with antibiotics almost continu- months and continued until age 3.5 years. An intermittant ously since birth. Speech at 4 years was delayed, with a small erythema was noted on her forehead and cheeks. Severe vocabulary, slurred and tremulous pronunciation, and im- recurrent sinusitis required aggressive antibiotic therapy and proper syntax. Behavior was characterized by hyperactivity, repeated surgical drainage and lavage. short attention span, and lack of perseverance. Social inte- Speech began at 3 years with monosyllables only and re- reaction with other children was poor, but not notably aggres- mained profoundly delayed. An unusual behavioral phenotype sive. Intelligence as measured by the Leiter International was noted, which was characterized by extreme hyperactivity, Performance Scale was 85. marked impulsivity, perseveration, short attention span, and Ig studies were notable for slightly decreased IgG2 at 50, IgM inability to focus on tasks. She was noted to have a ‘‘delirious’’ at 96, and IgA at 14 (normal for age: 631 6 125, 58 6 19, and quality to her affect. Poor social intereaction was noted with 97 6 15 mgydl, respectively). After pneumovax she responded occasional aggression in the form of hitting, poking, pinching, only to type IV pneumococcal polysaccharide antigen. How- or biting others. Intelligence as measured by the Leiter Inter- ever, she had a strong response to haemophilus influenza national Performance Scale gave a value of 84. vaccine. Phytohemagglutinin stimulation index was within Immunological studies were undertaken to find a cause for normal