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Congenital Hyperuricemia: Title and subTitle BreakAn Inborn Error of Purine Metabolism Associated With Psychomotor Retardation, Athetosis, and Self-Mutilation

Peter H. Berman, MD; M. Earl Balis, PhD; Joseph Dancis, MD
[+] Author Affiliations

Submitted for publication July 29, 1968; accepted Aug 19.

Reprint requests to Department of Pediatrics, NYU Medical Center, 550 First Ave, New York 10016 (Dr. Berman).


Arch Neurol. 1969;20(1):44-53. doi:10.1001/archneur.1969.00480070054006
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RESENT reports have established the existence of a sex-linked, recessive inborn error of purine metabolism in which hyperuricemia and hyperuricosuria are associated with a distinctive clinical syndrome.1-6 Stunting of growth, retardation of mental and motor development, choreoathetosis, generalized spasticity, and compulsive selfmutilation characterize the clinical defect.3-6 The metabolic abnormalities have been attributed to a deficiency of the enzyme inosinate phosphoribosy pyrophosphate transferase (IMP:PRPP transferase).7 This enzyme mediates the conversion of hypoxanthine to inosinate (hypoxanthine ribosylphosphate), a reaction that permits the reutilization of hypoxanthine for nucleotide synthesis. Since hypoxanthine cannot be reutilized in patients with the disease, whatever hypoxan-thine is formed is either excreted or further catabolized to xanthine and uric acid. The hyperuricemia and hyperuricosuria in these patients also reflect a marked increase in de novo purine synthesis associated with an exceedingly rapid turnover of purine nucleotides.3

In the present report, the results of

REFERENCES

Catel, W., and Schmidt, J.:  Über familiare gichtische Diathese in Verbindung mit zerebralen und renalen Symptomen bei einem Kleinkind , Deutsch Med Wschr 84:2145-2147 ( (Nov 27) ) 1959;.
Riley, I.D.:  Gout and Cerebral Palsy in a Three-Year-Old Boy , Arch Dis Child 35:293-295 ( (June) ) 1960;.
Lesch, M., and Nyhan, W.L.:  A Familial Disorder of Uric Acid Metabolism and Central Nervous System Function , Amer J Med 36:561-570 ( (April) ) 1964;.
Hoefnagel, D., et al:  Hereditary Choreoathetosis, Self-Mutilation, and Hyperuricemia in Young Males , New Eng J Med 273:130-135 ( (July 15) ) 1965;.
Michener, W.M.:  Hyperuricemia and Mental Retardation , Amer J Dis Child 113:195-206 ( (Feb) ) 1967;.
Partington, M.W., and Hennen, B.K.E.:  The Lesch-Nyhan Syndrome: Self-Destructive Biting, Mental Retardation, Neurological Disorder and Hyperuricemia , Devel Med Child Neurol 9:563-573 ( (Oct) ) 1967;.
Seegmiller, J.E.; Rosenbloom, F.M.; and Kelley, W.N.:  Enzyme Defect Associated With a SexLinked Human Neurologic Disorder and Excessive Purine Synthesis , Science 155:1682-1684 ( (March 31) ) 1967;.
Caraway, W.T.:  Determination of Uric Acid in Serum by a Carbonate Method , Amer J Clin Path 25:840-845 ( (July) ) 1955;.
Ayvazian, J.H., and Skupp, S.:  The Study of Purine Utilization and Excretion In a Xanthinuric Man , J Clin Invest 44:1248-1260 ( (July) ) 1965;.
Hamilton, L.:  Utilization of Purines for Nucleic Acid Synthesis in Man , Nature 172:457 ( (Sept 5) ) 1953;.
Banaschak, H.:  Untersuchungen Über eine Inosinkinase in roten Blutkörperchen , Folia Haematol 83:433-437 ( (Dec) ) 1965;.
Rudles, R.W.; Wyngaarden, J.B.; and Hitchings, G.H.:  Effects of Xanthine Oxidase Inhibitor on Thiopurine Metabolism, Hyperuricemia and Gout , Trans Assoc Amer Physicians 76:126-140, 1963;.
Balis, M.E., et al:  Urinary Metabolites in Congenital Hyperuricosuria , Science 156:1122-1123 ( (May 26) ) 1967;.
Sweetman, L., and Nyhan, W.L.:  Excretion of Hypoxanthine and Xanthine in Genetic Disease of Purine Metabolism , Nature 215:859-860 ( (Aug 19) ) 1967;.
Krakoff, I.H., and Meyer, R.L.:  Prevention of Hyperuricemia in Leukemia and Lymphoma , JAMA 193:1-6 ( (July 5) ) 1965;.
Gillespie, J.B., and Perucca, L.G.:  Congenital Generalized Indifference to Pain (Congenital Analgia) , J Dis Child 100:124-126 ( (July) ) 1960;.
Sass, J.K.; Itabashi, H.H.; and Dexter, R.A.:  Juvenile Gout With Brain Involvement , Arch Neurol 13:639-655 ( (Dec) ) 1965;.
Olsen, S.:  The Brain in Uremia , Acta Psychiat Scand 156 ( (suppl) ):1-128, 1961;.
Nyhan, W.L., et al:  Genetics of an X-Linked Disorder of Uric Acid Metabolism and Cerebral Function , Pediat Res 1:5-13 ( (Jan) ) 1967;.
Dancis, J., et al:  Absence of Mosaicism in the Lymphocyte in X-Linked Congenital Hyperuricosuria , Life Sci 7:587-591 ( (June 15) ) 1968;.
Benke, P.J., and Pitot, H.: Hypoxanthine-Guanine Phosphoribosyl Transferase Activity in Women Heterozygous for Juvenile Hyperuricemia, presented at the Society of Pediatric Research, Atlantic City, NJ, May 3-4, 1968.
Lyon, M.F.:  Gene Action in the X-Chromose of the Mouse , Nature 190:372-373 ( (April 22) ) 1961;.
Davidson, R.G.; Nitowsky, H.M.; and Childs, B.:  Demonstration of Two Populations of Cells in the Human Female for Glucose-6-Phosphate Dehydrogenase Variants , Proc Nat Acad Sci: USA 50:481-485, 1963;.
Danes, B.S., and Bearn, R.G.:  Hurler's Syndrome: A Genetic Study of Clones in Cell Culture With Particular Reference of the Lyon Hypothesis , J Exp Med 126:509-521 ( (Sept) ) 1967;.
Rosenbloom, F.M., et al:  Lyon Hypothesis and X-Linked Disease , Lancet 2:305-306 ( (Aug 5) ) 1967;.
Migeon, B.R., et al:  X-Linked Hypoxanthine-Guanine Phosphoribosyl Transferase Deficiency: Heterozygote Has Two Clonal Populations , Science 160:425-427 ( (April 26) ) 1968;.
Salzmann, J.; DeMars, R.; and Bewke, P.:  Single-Allele Expression at an X-Linked Hyperuricemia Locus in Heterozygous Human Cells , Proc Nat Acad Sci: USA 60:545-552, 1968;.
Rosenbloom, F.M., et al:  Biochemical Basis of Accelerated Purine Biosynthesis De Novo in Human Fibroblasts Lacking Hypoxanthine-Guanine Phosphoribosyl Transferase , J Biol Chem 243:1166-1173 ( (March 25) ) 1968;.
Berman, P.H.; Balis, M.E.; and Dancis, J.:  Diagnostic Test for Congenital Hyperuricemia With Central Nervous System Dysfunction , J Lab Clin Med 71:247-253 ( (Feb) ) 1968;.
Nyhan, quoted by Partington, M.W., and Hennen, B.K.E.:  The Lesch-Nyhan Syndrome: Self-Destructive Biting, Mental Retardation, Neurological Disorder, and Hyperuricemia , Devel Med Child Neurol 9:563-573 ( (Oct) ) 1967;.
Marks, J.F., et al: Uric Acid Levels in Infancy, presented at the Society of Pediatric Research, Atlantic City, NJ, May 3-4, 1968.

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Catel, W., and Schmidt, J.:  Über familiare gichtische Diathese in Verbindung mit zerebralen und renalen Symptomen bei einem Kleinkind , Deutsch Med Wschr 84:2145-2147 ( (Nov 27) ) 1959;.
Riley, I.D.:  Gout and Cerebral Palsy in a Three-Year-Old Boy , Arch Dis Child 35:293-295 ( (June) ) 1960;.
Lesch, M., and Nyhan, W.L.:  A Familial Disorder of Uric Acid Metabolism and Central Nervous System Function , Amer J Med 36:561-570 ( (April) ) 1964;.
Hoefnagel, D., et al:  Hereditary Choreoathetosis, Self-Mutilation, and Hyperuricemia in Young Males , New Eng J Med 273:130-135 ( (July 15) ) 1965;.
Michener, W.M.:  Hyperuricemia and Mental Retardation , Amer J Dis Child 113:195-206 ( (Feb) ) 1967;.
Partington, M.W., and Hennen, B.K.E.:  The Lesch-Nyhan Syndrome: Self-Destructive Biting, Mental Retardation, Neurological Disorder and Hyperuricemia , Devel Med Child Neurol 9:563-573 ( (Oct) ) 1967;.
Seegmiller, J.E.; Rosenbloom, F.M.; and Kelley, W.N.:  Enzyme Defect Associated With a SexLinked Human Neurologic Disorder and Excessive Purine Synthesis , Science 155:1682-1684 ( (March 31) ) 1967;.
Caraway, W.T.:  Determination of Uric Acid in Serum by a Carbonate Method , Amer J Clin Path 25:840-845 ( (July) ) 1955;.
Ayvazian, J.H., and Skupp, S.:  The Study of Purine Utilization and Excretion In a Xanthinuric Man , J Clin Invest 44:1248-1260 ( (July) ) 1965;.
Hamilton, L.:  Utilization of Purines for Nucleic Acid Synthesis in Man , Nature 172:457 ( (Sept 5) ) 1953;.
Banaschak, H.:  Untersuchungen Über eine Inosinkinase in roten Blutkörperchen , Folia Haematol 83:433-437 ( (Dec) ) 1965;.
Rudles, R.W.; Wyngaarden, J.B.; and Hitchings, G.H.:  Effects of Xanthine Oxidase Inhibitor on Thiopurine Metabolism, Hyperuricemia and Gout , Trans Assoc Amer Physicians 76:126-140, 1963;.
Balis, M.E., et al:  Urinary Metabolites in Congenital Hyperuricosuria , Science 156:1122-1123 ( (May 26) ) 1967;.
Sweetman, L., and Nyhan, W.L.:  Excretion of Hypoxanthine and Xanthine in Genetic Disease of Purine Metabolism , Nature 215:859-860 ( (Aug 19) ) 1967;.
Krakoff, I.H., and Meyer, R.L.:  Prevention of Hyperuricemia in Leukemia and Lymphoma , JAMA 193:1-6 ( (July 5) ) 1965;.
Gillespie, J.B., and Perucca, L.G.:  Congenital Generalized Indifference to Pain (Congenital Analgia) , J Dis Child 100:124-126 ( (July) ) 1960;.
Sass, J.K.; Itabashi, H.H.; and Dexter, R.A.:  Juvenile Gout With Brain Involvement , Arch Neurol 13:639-655 ( (Dec) ) 1965;.
Olsen, S.:  The Brain in Uremia , Acta Psychiat Scand 156 ( (suppl) ):1-128, 1961;.
Nyhan, W.L., et al:  Genetics of an X-Linked Disorder of Uric Acid Metabolism and Cerebral Function , Pediat Res 1:5-13 ( (Jan) ) 1967;.
Dancis, J., et al:  Absence of Mosaicism in the Lymphocyte in X-Linked Congenital Hyperuricosuria , Life Sci 7:587-591 ( (June 15) ) 1968;.
Benke, P.J., and Pitot, H.: Hypoxanthine-Guanine Phosphoribosyl Transferase Activity in Women Heterozygous for Juvenile Hyperuricemia, presented at the Society of Pediatric Research, Atlantic City, NJ, May 3-4, 1968.
Lyon, M.F.:  Gene Action in the X-Chromose of the Mouse , Nature 190:372-373 ( (April 22) ) 1961;.
Davidson, R.G.; Nitowsky, H.M.; and Childs, B.:  Demonstration of Two Populations of Cells in the Human Female for Glucose-6-Phosphate Dehydrogenase Variants , Proc Nat Acad Sci: USA 50:481-485, 1963;.
Danes, B.S., and Bearn, R.G.:  Hurler's Syndrome: A Genetic Study of Clones in Cell Culture With Particular Reference of the Lyon Hypothesis , J Exp Med 126:509-521 ( (Sept) ) 1967;.
Rosenbloom, F.M., et al:  Lyon Hypothesis and X-Linked Disease , Lancet 2:305-306 ( (Aug 5) ) 1967;.
Migeon, B.R., et al:  X-Linked Hypoxanthine-Guanine Phosphoribosyl Transferase Deficiency: Heterozygote Has Two Clonal Populations , Science 160:425-427 ( (April 26) ) 1968;.
Salzmann, J.; DeMars, R.; and Bewke, P.:  Single-Allele Expression at an X-Linked Hyperuricemia Locus in Heterozygous Human Cells , Proc Nat Acad Sci: USA 60:545-552, 1968;.
Rosenbloom, F.M., et al:  Biochemical Basis of Accelerated Purine Biosynthesis De Novo in Human Fibroblasts Lacking Hypoxanthine-Guanine Phosphoribosyl Transferase , J Biol Chem 243:1166-1173 ( (March 25) ) 1968;.
Berman, P.H.; Balis, M.E.; and Dancis, J.:  Diagnostic Test for Congenital Hyperuricemia With Central Nervous System Dysfunction , J Lab Clin Med 71:247-253 ( (Feb) ) 1968;.
Nyhan, quoted by Partington, M.W., and Hennen, B.K.E.:  The Lesch-Nyhan Syndrome: Self-Destructive Biting, Mental Retardation, Neurological Disorder, and Hyperuricemia , Devel Med Child Neurol 9:563-573 ( (Oct) ) 1967;.
Marks, J.F., et al: Uric Acid Levels in Infancy, presented at the Society of Pediatric Research, Atlantic City, NJ, May 3-4, 1968.

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