J. Inher. Metab. Dis. 15 (1992) 790-79I © SSIEM and KluwerAcademicPublishers. Printed in the Netherlands
CASE REPORT Lesch-Nyhan syndrome in a girl P. van Bogaert 1, I. Ceballos 2, I. Desguerre 1, L. Telvi 3, P. Kamoun 2 and G. Ponsot 1
Lesch-Nyhan syndrome (McKusick 308000) is characterized by hyperuricaemia, choreoathetosis, spasticity, mental retardation, and self-mutilation. This disorder results from a complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT), an enzyme encoded by a single gene on the X chromosome (Xq26-q27) (Stout and Caskey 1989), and has already been identified in a female patient (Ogasawara et al 1989). We report a second case of a female Lesch-Nyhan patient. This girt was born from healthy non-consanguineous parents and had a healthy brother and sister. The circumstances of her birth were normal (weight 2720 g after 37 weeks of gestation; APGAR score at 10 after 1 min), but a transient hypoglycaemic episode was noticed on her first day of life. Hypotonia and developmental retardation appeared in her first months of life. Three febrile convulsive episodes occurred between 18 and 36 months of life. Self-mutilation of her fingers occurred when she was 4 years old and still persisted when we saw her at 7 years of age. Weight and height were three standard deviations below the normal range, but cranial circumference was in the normal range. There were severe biting lesions of her finger extremities. On neurological examination, the girl had excellent social contact but her language was dysarthic and poor for age. Examination of the cranial nerves was normal. A spastic quadriparesis was present, making the sitting position impossible without support. Prehension of objects was acquired but was dystonic and clumsy. There were no sensory disturbances. Electroencephalogram and cranial computed tomographic scan were unremarkabte. Hyperuricaemia (467 #tool/L) and elevated 24-h urinary uric acid to creatinine ratio (1.1) were consistent with H P R T deficiency, which was confirmed by measurement of enzyme activity in erythrocytes (0.11 nmol min-1 (mg haemoglobin)-1) for the patient, the normal value for our laboratory being 2.09 _+ 0.37). The karyotype was 46 XX and no morphological abnormalities could be identified by a high-resolution analysis of the chromosomes. In the case described by Ogasawara et al (1989), a Southern analysis of DNA identified a deletion that involved the entire H P R T gene and was not found in the parents. Furthermore, these authors showed that this de novo mutation occurred on the maternal X-chromosome; so it was concluded that there had been non-random inactivation of the cytologically normal paternal X-chromosome. We tried to determine the carrier status of our patient's mother by using cultured fibroblasts, since it has been demonstrated that obligate heterozygotes are mosaics Departments of Paediatric Neurology and 3Cytogenetics, Hopital Saint-Vincent-De-Paul, 82 avenue Denfert Rochereau, 75674 Paris Cedex 14, France; 2Biochemical Genetics Laboratory, H6pital Necker-Enfants Malades, 149 rue de S6vres, 75743 Paris Cedex 15, France 790
791
Case Report
in terms of H P R T activity (Stout and Caskey 1989). The mother's HPRT activity on cultured fibroblasts was 34.7 nmol h-1 (mg protein)- ~ (the mean value of 4 controls being 41.2 _+ 3.2). For our patient and her father, the enzymatic activities in clutured fibroblasts were respectively 4.4 and 50.5 nmol h - ~ (rag protein)- 1. The interpretation of this slightly reduced maternal value was hazardous, so to further investigate the carrier status a selection for HPRT-deficient fibroblasts took place in medium containing 6-thioguanine (Chen et al 1990). As expected, after 15 days in the selective medium, fibroblasts from the Lesch-Nyhan patient exhibited a resistance to 6-thioguanine, since we observed a 100% mortality of mother's and father's fibroblasts. These results strongly suggest that a de novo mutation accounted for our patient's disorder. The next step is the molecular analysis of the patient's DNA to investigate the parental origin of the abnormal gene as well as the inactivation of the X-chromosome in this patient. REFERENCES
Chen RH, Maher VM, McCormick JJ (1990) Effect of excision repair by diploid human fibroblasts on the kinds and locations of mutations induced by (+/-)-7/~-8~-dihydroxy9~,10~-epoxy-7,8,9,10-tetrahydroxybenzo(a)pyrenein the coding region of HPRT gene. Proc NatI Acad Sci USA 87: 8680-8684. Ogasawara N, Stout JT, Goto H, Sonta SI, Matsumoto A, Caskey CT (1989) Molecular analysis of a female Lesch-Nyhan patient. J Clin Invest 24: 1024-1027. Stout JT, Caskey CT (1989) Hypoxanthine phosphoribosyltransferase deficiency: The LeschNyhan syndrome and gouty arthritis. In Scriver CR, Beaudet AL, Sly WS, Valle DV, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, 1007-1028.
SOCIETY FOR THE STUDY OF INBORN ERRORS OF METABOLISM The SSIEM was founded in 1963 by a small group in the North of England but now has more than 70% of its members outside the UK. The aim of the Society is to promote the exchange of ideas between professional workers in different disciplines who are interested in inherited metabolic disorders. This aim is pursued in scientific meetings and publications. The Society holds an annum symposium concentrating on different topics each year with facilities for poster presentations. There is always a clinical aspect as well as a laboratory component. The meeting is organized so that there is ample time for informal discussion; this feature has allowed the formation of a network of contacts throughout the world. The international and multidisciptinary approach is also reflected in the Journal of Inherited Metabolic Disease. If you are interested in joining the SSIEM then contact the Treasurer: Dr. D. Isherwood, Department of Clinical Biochemistry, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, L12 2AP, UK. The current subscription is £30 per year payable January Ist each year. This subscription includes the 6 issues of the Journal of Inherited Metabolic Disease as well as the regular circulation of a newsletter.
J. Inher. Metab, Dis. 15 (1992)
CASE REPORT Lesch-Nyhan syndrome in a girl P. van Bogaert 1, I. Ceballos 2, I. Desguerre 1, L. Telvi 3, P. Kamoun 2 and G. Ponsot 1
Lesch-Nyhan syndrome (McKusick 308000) is characterized by hyperuricaemia, choreoathetosis, spasticity, mental retardation, and self-mutilation. This disorder results from a complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT), an enzyme encoded by a single gene on the X chromosome (Xq26-q27) (Stout and Caskey 1989), and has already been identified in a female patient (Ogasawara et al 1989). We report a second case of a female Lesch-Nyhan patient. This girt was born from healthy non-consanguineous parents and had a healthy brother and sister. The circumstances of her birth were normal (weight 2720 g after 37 weeks of gestation; APGAR score at 10 after 1 min), but a transient hypoglycaemic episode was noticed on her first day of life. Hypotonia and developmental retardation appeared in her first months of life. Three febrile convulsive episodes occurred between 18 and 36 months of life. Self-mutilation of her fingers occurred when she was 4 years old and still persisted when we saw her at 7 years of age. Weight and height were three standard deviations below the normal range, but cranial circumference was in the normal range. There were severe biting lesions of her finger extremities. On neurological examination, the girl had excellent social contact but her language was dysarthic and poor for age. Examination of the cranial nerves was normal. A spastic quadriparesis was present, making the sitting position impossible without support. Prehension of objects was acquired but was dystonic and clumsy. There were no sensory disturbances. Electroencephalogram and cranial computed tomographic scan were unremarkabte. Hyperuricaemia (467 #tool/L) and elevated 24-h urinary uric acid to creatinine ratio (1.1) were consistent with H P R T deficiency, which was confirmed by measurement of enzyme activity in erythrocytes (0.11 nmol min-1 (mg haemoglobin)-1) for the patient, the normal value for our laboratory being 2.09 _+ 0.37). The karyotype was 46 XX and no morphological abnormalities could be identified by a high-resolution analysis of the chromosomes. In the case described by Ogasawara et al (1989), a Southern analysis of DNA identified a deletion that involved the entire H P R T gene and was not found in the parents. Furthermore, these authors showed that this de novo mutation occurred on the maternal X-chromosome; so it was concluded that there had been non-random inactivation of the cytologically normal paternal X-chromosome. We tried to determine the carrier status of our patient's mother by using cultured fibroblasts, since it has been demonstrated that obligate heterozygotes are mosaics Departments of Paediatric Neurology and 3Cytogenetics, Hopital Saint-Vincent-De-Paul, 82 avenue Denfert Rochereau, 75674 Paris Cedex 14, France; 2Biochemical Genetics Laboratory, H6pital Necker-Enfants Malades, 149 rue de S6vres, 75743 Paris Cedex 15, France 790
791
Case Report
in terms of H P R T activity (Stout and Caskey 1989). The mother's HPRT activity on cultured fibroblasts was 34.7 nmol h-1 (mg protein)- ~ (the mean value of 4 controls being 41.2 _+ 3.2). For our patient and her father, the enzymatic activities in clutured fibroblasts were respectively 4.4 and 50.5 nmol h - ~ (rag protein)- 1. The interpretation of this slightly reduced maternal value was hazardous, so to further investigate the carrier status a selection for HPRT-deficient fibroblasts took place in medium containing 6-thioguanine (Chen et al 1990). As expected, after 15 days in the selective medium, fibroblasts from the Lesch-Nyhan patient exhibited a resistance to 6-thioguanine, since we observed a 100% mortality of mother's and father's fibroblasts. These results strongly suggest that a de novo mutation accounted for our patient's disorder. The next step is the molecular analysis of the patient's DNA to investigate the parental origin of the abnormal gene as well as the inactivation of the X-chromosome in this patient. REFERENCES
Chen RH, Maher VM, McCormick JJ (1990) Effect of excision repair by diploid human fibroblasts on the kinds and locations of mutations induced by (+/-)-7/~-8~-dihydroxy9~,10~-epoxy-7,8,9,10-tetrahydroxybenzo(a)pyrenein the coding region of HPRT gene. Proc NatI Acad Sci USA 87: 8680-8684. Ogasawara N, Stout JT, Goto H, Sonta SI, Matsumoto A, Caskey CT (1989) Molecular analysis of a female Lesch-Nyhan patient. J Clin Invest 24: 1024-1027. Stout JT, Caskey CT (1989) Hypoxanthine phosphoribosyltransferase deficiency: The LeschNyhan syndrome and gouty arthritis. In Scriver CR, Beaudet AL, Sly WS, Valle DV, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, 1007-1028.
SOCIETY FOR THE STUDY OF INBORN ERRORS OF METABOLISM The SSIEM was founded in 1963 by a small group in the North of England but now has more than 70% of its members outside the UK. The aim of the Society is to promote the exchange of ideas between professional workers in different disciplines who are interested in inherited metabolic disorders. This aim is pursued in scientific meetings and publications. The Society holds an annum symposium concentrating on different topics each year with facilities for poster presentations. There is always a clinical aspect as well as a laboratory component. The meeting is organized so that there is ample time for informal discussion; this feature has allowed the formation of a network of contacts throughout the world. The international and multidisciptinary approach is also reflected in the Journal of Inherited Metabolic Disease. If you are interested in joining the SSIEM then contact the Treasurer: Dr. D. Isherwood, Department of Clinical Biochemistry, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, L12 2AP, UK. The current subscription is £30 per year payable January Ist each year. This subscription includes the 6 issues of the Journal of Inherited Metabolic Disease as well as the regular circulation of a newsletter.
J. Inher. Metab, Dis. 15 (1992)
