Metabolic Brain Disease

, Volume 34, Issue 5, pp 1335–1340 | Cite as

Phenotypic and molecular spectrum of Korean patients with Lesch-Nyhan syndrome and attenuated clinical variants

  • Ja Hyang Cho
  • Jin-Ho Choi
  • Sun Hee Heo
  • Gu-Hwan Kim
  • Mi-Sun Yum
  • Beom Hee Lee
  • Han-Wook YooEmail author
Original Article


Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder caused by mutations in the HPRT1 gene. The clinical features and mutation spectrum of 26 Korean LNS patients from 23 unrelated families were retrospectively reviewed. The HPRT1 gene was analyzed by direct sequencing of genomic DNA. The median age at diagnosis was 2.3 years (range, 4 months–22.6 years) and the initial presenting features included developmental delay, orange colored urine, and self-injurious behaviors. Most patients were wheelchair-bound and suffered from urinary complications and neurologic problems such as self-mutilation and developmental delay. Twenty different mutations in HPRT1 were identified among 23 independent pedigrees, including six novel mutations. The most common mutation type was truncating mutations including nonsense and frameshift mutations (45%). Large deletions in the HPRT1 gene were identified in exon 1, exons 5–6, exons 1–9, and at chr X:134,459,540–134,467,241 (7702 bp) including the 5′-untranslated region, exon 1, and a portion of intron 1. In conclusion, this study describes the phenotypic spectrum of LNS and has identified 20 mutations from 23 Korean families, including six novel mutations in Korean patients with LNS.


HPRT1 Hypoxanthine guanine phosphoribosyltransferase Hyperuricemia Lesch-Nyhan syndrome 



This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1D1A1B03029638).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.


  1. Ceballos-Picot I, Augé F, Fu R, Olivier-Bandini A, Cahu J, Chabrol B, Aral B, de Martinville B, Lecain JP, Jinnah HA (2013) Phenotypic variation among seven members of one family with deficiency of hypoxanthine-guanine phosphoribosyltransferase. Mol Genet Metab 110:268–274. CrossRefGoogle Scholar
  2. Crawhall JC, Henderson JF, Kelley WN (1972) Diagnosis and treatment of the Lesch-Nyhan syndrome. Pediatr Res 6:504–513. CrossRefGoogle Scholar
  3. de Gemmis P, Anesi L, Lorenzetto E, Gioachini I, Fortunati E, Zandonà G, Fanin E, Fairbanks L, Andrighetto G, Parmigiani P, Dolcetta D, Nyhan WL, Hladnik U (2010) Analysis of the HPRT1 gene in 35 Italian Lesch-Nyhan families: 45 patients and 77 potential female carriers. Mutat Res 692:1–5. CrossRefGoogle Scholar
  4. Fu R, Ceballos-Picot I, Torres RJ, Larovere LE, Yamada Y, Nguyen KV, Hegde M, Visser JE, Schretlen DJ, Nyhan WL, Puig JG, O'Neill PJ, Jinnah HA, Lesch-Nyhan Disease International Study Group (2014a) Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain 137:1282–1303. CrossRefGoogle Scholar
  5. Fu R, Chen CJ, Jinnah HA (2014b) Genotypic and phenotypic spectrum in attenuated variants of Lesch-Nyhan disease. Mol Genet Metab 112:280–285. CrossRefGoogle Scholar
  6. Fu R, Sutcliffe D, Zhao H, Huang X, Schretlen DJ, Benkovic S, Jinnah HA (2015) Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways. Mol Genet Metab 114:55–61. CrossRefGoogle Scholar
  7. Fujimori S, Tagaya T, Yamaoka N, Saito H, Kamatani N, Akaoka I (1994) Direct evidence for a hot spot of germline mutation at HPRT locus. Adv Exp Med Biol 370:679–682CrossRefGoogle Scholar
  8. Hladnik U, Nyhan WL, Bertelli M (2008) Variable expression of HPRT deficiency in 5 members of a family with the same mutation. Arch Neurol 65:1240–1243. CrossRefGoogle Scholar
  9. Jinnah HA, De Gregorio L, Harris JC, Nyhan WL, O'Neill JP (2000) The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 463:309–326CrossRefGoogle Scholar
  10. Jinnah HA, Harris JC, Nyhan WL, O'Neill JP (2004) The spectrum of mutations causing HPRT deficiency: an update. Nucleosides Nucleotides Nucleic Acids 23:1153–1160. CrossRefGoogle Scholar
  11. Jinnah HA, Ceballos-Picot I, Torres RJ, Visser JE, Schretlen DJ, Verdu A, Larovere LE, Chen CJ, Cossu A, Wu CH, Sampat R, Chang SJ, de Kremer RD, Nyhan W, Harris JC, Reich SG, Puig JG, for the Lesch-Nyhan Disease International Study Group (2010) Attenuated variants of Lesch-Nyhan disease. Brain 133:671–689. CrossRefGoogle Scholar
  12. Jurecka A, Popowska E, Tylki-Szymanska A, Kubalska J, Ciara E, Krumina Z, Sykut-Cegielska J, Pronicka E (2008) Hypoxanthine-guanine phosphoribosylotransferase deficiency--the spectrum of polish mutations. J Inherit Metab Dis 31(Suppl 2):S447–S451. CrossRefGoogle Scholar
  13. Kelley WN, Rosenbloom FM, Henderson JF, Seegmiller JE (1967) A specific enzyme defect in gout associated with overproduction of uric acid. Proc Natl Acad Sci U S A 57:1735–1739CrossRefGoogle Scholar
  14. Kim KJ, Yamada Y, Suzumori K, Choi Y, Yang SW, Cheong HI, Hwang YS, Goto H, Ogasawara N (1997) Molecular analysis of hypoxanthine guanine phosphoribosyltransferase (HPRT) gene in five Korean families with Lesch-Nyhan syndrome. J Korean Med Sci 12:332–339. CrossRefGoogle Scholar
  15. Lesch M, Nyhan WL (1964) A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36:561–570CrossRefGoogle Scholar
  16. Neychev VK, Jinnah HA (2006) Sudden death in Lesch-Nyhan disease. Dev Med Child Neurol 48:923–926. CrossRefGoogle Scholar
  17. Nguyen KV, Naviaux RK, Paik KK, Nyhan WL (2012) Lesch-Nyhan syndrome: mRNA expression of HPRT in patients with enzyme proven deficiency of HPRT and normal HPRT coding region of the DNA. Mol Genet Metab 106:498–501. CrossRefGoogle Scholar
  18. Oh MM, Ham BK, Kang SH, Bae JH, Kim JJ, Yoo KH, Yoon DK, Moon DG (2011) Urine alkalinization may be enough for the treatment of bilateral renal pelvis stones associated with Lesch-Nyhan syndrome. Urol Res 39:417–419. CrossRefGoogle Scholar
  19. O'Neill JP, Rogan PK, Cariello N, Nicklas JA (1998) Mutations that alter RNA splicing of the human HPRT gene: a review of the spectrum. Mutat Res 411:179–214CrossRefGoogle Scholar
  20. Patel PI, Framson PE, Caskey CT, Chinault AC (1986) Fine structure of the human hypoxanthine phosphoribosyltransferase gene. Mol Cell Biol 6:393–403CrossRefGoogle Scholar
  21. Rebai I, Kraoua I, Benrhouma H, Rouissi A, Turki I, Ceballos-Picot I, Gouider-Khouja N (2014) Lesch Nyhan syndrome: a novel complex mutation in a Tunisian child. Brain and Development 36:921–923. CrossRefGoogle Scholar
  22. Rojahn J, Matson JL, Lott D, Esbensen AJ, Smalls Y (2001) The behavior problems inventory: an instrument for the assessment of self-injury, stereotyped behavior, and aggression/destruction in individuals with developmental disabilities. J Autism Dev Disord 31:577–588CrossRefGoogle Scholar
  23. Torres RJ, Puig JG (2007) Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet J Rare Dis 2:48. CrossRefGoogle Scholar
  24. Wehnert M, Herrmann FH (1990) Characterization of three new deletions at the 5′ end of the HPRT structural gene. J Inherit Metab Dis 13:178–183CrossRefGoogle Scholar
  25. Zennaro C et al (2017) The renal phenotype of allopurinol-treated HPRT-deficient mouse. PLoS One 12:e0173512. CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PediatricsKyung Hee University Hospital at GangdongSeoulSouth Korea
  2. 2.Department of Pediatrics, Asan Medical Center Children’s HospitalUniversity of Ulsan College of MedicineSeoulSouth Korea
  3. 3.Genome Research Center for Birth Defects and Genetic Diseases, Asan Institute for Life SciencesAsan Medical CenterSeoulSouth Korea
  4. 4.Medical Genetics CenterAsan Medical CenterSeoulSouth Korea

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