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Lesch-Nyhan Syndrome

Synonyms: HGPRT Deficiency, HPRT Deficiency, Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency, Lesch-Nyhan Disease

, MD, PhD, , PhD, , MD, PhD, and , MD.

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Initial Posting: ; Last Update: May 15, 2014.

Estimated reading time: 21 minutes


Clinical characteristics.

Lesch-Nyhan syndrome is characterized by motor dysfunction that resembles cerebral palsy, cognitive and behavioral disturbances, and uric acid overproduction (hyperuricemia). The most common presenting features, hypotonia and developmental delay, are evident by age three to six months. Affected children are delayed in sitting and most never walk. Within the first few years, extrapyramidal involvement (e.g., dystonia, choreoathetosis, opisthotonos) and pyramidal involvement (e.g., spasticity, hyperreflexia, extensor plantar reflexes) become evident. Cognitive impairment and behavioral disturbances emerge between ages two and three years. Persistent self-injurious behavior (biting the fingers, hands, lips, and cheeks; banging the head or limbs) is a hallmark of the disease. Overproduction of uric acid may lead to deposition of uric acid crystals or calculi in the kidneys, ureters, or bladder. Gouty arthritis may occur later in the disease. Related disorders with less severe manifestations include hyperuricemia with neurologic dysfunction but no self-injurious behavior and hyperuricemia alone, sometimes with acute renal failure.


A urinary urate-to-creatinine ratio greater than 2.0, indicating uric acid overproduction (hyperuricemia), is a characteristic for children younger than age ten years who have Lesch-Nyhan syndrome. However, neither hyperuricuria nor hyperuricemia (serum uric acid concentration >8 mg/dL) is sensitive or specific enough for diagnosis. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme activity less than 1.5% of normal in cells from any tissue (e.g., blood, cultured fibroblasts, lymphoblasts) is diagnostic. HPRT1 is the only gene known to be associated with Lesch-Nyhan syndrome.


Treatment of manifestations: Control of overproduction of uric acid with allopurinol reduces the risk for nephrolithiasis, urate nephropathy, gouty arthritis, and tophi but has no effect on behavioral and neurologic symptoms; treatment of renal stones may require lithotripsy or surgery. Baclofen or benzodiazepines for spasticity; physical, behavioral, psychiatric, protective equipment to reduce complications from self-injury and other deleterious behaviors.

Prevention of secondary complications: Adjustment of the dose of allopurinol is required to minimize the complication of nephrolithiasis; virtually any reduction of hyperuricemia will prevent urate nephropathy.

Surveillance: Monitoring for early signs of self-injury; medical history, plasma uric acid concentration, urinary oxypurine excretion to monitor for signs of renal stones.

Agents/circumstances to avoid: Probenecid and other uricosuric drugs designed to reduce the serum concentration of uric acid; periods of relative dehydration, which may increase risk for renal stones or urate nephropathy with resulting oliguria/anuria.

Evaluation of relatives at risk: Prenatal testing or testing of at-risk males immediately after birth enables prompt initiation of allopurinol therapy; establishing the carrier status of at-risk female relatives through genetic testing may allow for early treatment that reduces their risk for gout in later years.

Genetic counseling.

Lesch-Nyhan syndrome is inherited in an X-linked manner. The father of an affected male will neither have the disease nor be a carrier of the mutated allele. The risk to sibs of a proband depends on the carrier status of the mother. Carrier females have a 50% chance of transmitting the HPRT1 pathogenic variant in each pregnancy. Sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant are carriers. Thus, with each pregnancy, a carrier female has a 25% chance of having an affected male, a 25% chance of having a carrier female, and a 50% chance of having an unaffected male or female. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.


Clinical Diagnosis

The diagnosis of Lesch-Nyhan syndrome is suspected in males with developmental delay who manifest the characteristic neurologic, cognitive, and behavioral disturbances [Lesch & Nyhan 1964, Nyhan et al 2005].


Lesch-Nyhan syndrome is caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), which catalyzes the conversion of hypoxanthine to inosine monophosphate (inosinic acid, IMP) and guanine to guanine monophosphate (guanylic acid, GMP) in the presence of phosphoribosylpyrophosphate [Seegmiller et al 1967].

The urate-to-creatinine ratio, calculated from the concentration of uric acid and creatinine in the urine, provides a reliable measure of uric acid overproduction. A urate-to-creatinine ratio greater than 2.0 is characteristic for affected males younger than age ten years, but is not considered diagnostic.

Twenty-four-hour urate excretion of more than 20 mg/kg is characteristic but not diagnostic.

Note: Good results with 24-hour samples are difficult to obtain. Bacterial contamination and/or precipitation of urate during collection can influence the result.

Hyperuricemia (serum uric acid concentration >8 mg/dL) is often present but not sensitive or specific enough for diagnostic purposes.

Diagnostic Testing

HPRT enzyme activity

  • In males. HPRT enzyme activity less than 1.5% of normal in cells from any tissue (e.g., blood, cultured fibroblasts, lymphoblasts) establishes the diagnosis of Lesch-Nyhan syndrome.
    The assay that is simplest and most readily available is performed on erythrocytes in anticoagulant or on dried blood spots on filter paper [Nyhan 2008].
    Assay of intact cells from cultured fibroblasts may be necessary to distinguish genetically related HPRT variant disorders from classic Lesch-Nyhan syndrome [Page et al 1981].
  • In females. Measurement of HPRT enzyme activity for carrier detection is technically demanding and not widely used [Puig et al 1998]. Measurement of HPRT enzyme activity on hair bulbs from women at risk has yielded a small number of both false positive and false negative results.

Proliferation of peripheral blood T-lymphocytes

  • In males. In the presence of the purine analog 6-thioguanine, proliferation of peripheral blood T-lymphocytes (if available) is confirmatory in most cases.
  • In females. If the HPRT1 pathogenic variant is not known in the family, carrier testing for at-risk females may be possible by measuring the frequency of HPRT-deficient lymphocytes by their selective growth in medium containing 6-thioguanine [O'Neill 2004]. The frequency of HPRT-deficient lymphocytes in a carrier female is approximately 0.5-5.0 x 10-2, whereas that of a non-carrier female is approximately 1-20 x 10-6. If available, this elevated frequency of HPRT-deficient lymphocytes is usually diagnostic by itself.

Molecular Genetic Testing

Gene. HPRT1 is the only gene known to be associated with Lesch-Nyhan syndrome.

Table 1.

Summary of Molecular Genetic Testing Used in Lesch-Nyhan Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant Detectable by Method
Affected MalesCarrier Females
HPRT1Sequence analysis 2 / scanning for pathogenic variants>90%-95% 3, 4~80% 5
Deletion/duplication analysis 6See footnote 7.21%-24% 8

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.


Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Deletion/duplication testing can be used to confirm a putative exon/whole-gene deletion in males after failure to amplify by PCR in the sequence analysis.


Large deletions in HPRT1 cannot be detected in females by sequence analysis; deletion/duplication test methods to detect exon or whole-gene deletions are required [Jinnah et al 2000, Bertelli et al 2004].

Testing Strategy

To confirm/establish the diagnosis in a proband

  • HPRT enzyme assay. One strategy for the diagnosis of Lesch-Nyhan syndrome is performance of an HPRT enzyme assay, which is most readily accomplished using erythrocyte hemolysates.
  • Molecular genetic testing. An alternative strategy to HPRT enzyme assay is molecular genetic testing of HPRT1.
    Note: (1) Failure to detect a pathogenic variant in HPRT1 does not exclude the diagnosis of Lesch-Nyhan syndrome. (2) Detection of a pathogenic variant in HPRT1 is of particular utility to family members with respect to carrier testing and prenatal diagnosis.

Clinical Characteristics

Clinical Description

Lesch-Nyhan syndrome is characterized by neurologic dysfunction, cognitive and behavioral disturbances, and uric acid overproduction.

Neurologic dysfunction. Individuals with Lesch-Nyhan syndrome typically have a normal prenatal and perinatal course. The most common presenting feature is developmental delay during the first year of life, with hypotonia and delayed motor skills usually evident by age three to six months. Children with Lesch-Nyhan syndrome fail to reach normal milestones such as sitting, crawling, and walking.

Within the first few years of life, abnormal involuntary movements indicative of extrapyramidal involvement emerge. The characteristic feature is severe action dystonia [Jinnah et al 2006]. Affected children develop dystonia, choreoathetosis, opisthotonos, and sometimes ballismus. They also develop signs of pyramidal involvement including spasticity, hyperreflexia, and extensor plantar reflexes. The neurologic picture closely resembles athetoid cerebral palsy. Many affected children are initially diagnosed as having cerebral palsy.

The motor disability is so severe that virtually all children with the classic Lesch-Nyhan syndrome never walk and are confined to a wheelchair.

Cognitive and behavioral disturbances. Most affected individuals are cognitively impaired, a feature that is difficult to assess because of the behavioral disturbances, motor deficits, and attentional problems [Schretlen et al 2001, Schretlen et al 2005].

Almost all affected individuals eventually develop persistent self-injurious behavior, a hallmark of the disease [Schretlen et al 2005]. Self-injury most often involves biting of the fingers, hands, lips, and cheeks [Robey et al 2003]. Other individuals bang their heads or limbs against hard objects. Some children develop self-injurious behavior during the first year of life; most develop it between ages two and three years, and some not until much later.

Other compulsive behaviors may include aggressiveness, vomiting, spitting, and coprolalia.

Overproduction of uric acid. The overproduction of uric acid is present at birth but may not be recognized by routine clinical laboratory testing methods. The serum uric acid concentration is usually (but not always) elevated, as the excess purines may be effectively excreted into the urine.

Overproduction of uric acid may lead to deposition of uric acid crystals, sodium urate, or calculi in the kidneys, ureters, or bladder. Crystals appear as an orange sandy material; calculi may be multiple tiny stones ("gravel") or discrete large stones that are difficult to pass. The stones may cause hematuria and increase the risk for urinary tract infections. Stones may be the presenting feature of the disease, but often go unrecognized for months or years.

Gouty arthritis. Another potential consequence of untreated hyperuricemia is gouty arthritis caused by uric acid crystal deposition in articular cartilage. Gout is uncommon in children with Lesch-Nyhan syndrome and typically develops long after other symptoms present.

Other. Growth and puberty are delayed.

End-stage renal disease (ESRD), which prior to the availability of allopurinol was the rule in this disease, is less common now but still occurs.

Affected males may have testicular atrophy.

A megaloblastic anemia unresponsive to vitamin supplements is common, but often resolves spontaneously.

EEG may show nonspecific changes of slowing or disorganization.

Both CT and MRI may show nonspecific changes of atrophy in the central nervous system with reduced cerebral volume and reduced caudate nucleus volume [Harris et al 1998].

Life expectancy. If management of symptoms is effective, most individuals survive into the second or third decade of life. There may be slow progression of disease in adulthood.

Sudden death is increasingly being recognized [Neychev & Jinnah 2006]. Respiratory abnormalities have been implicated. Sudden death appears to be more common in older individuals, often with no discernable cause even on autopsy. Report of atlantoaxial subluxation in an affected child age nine years tends to confirm suspicion that some sudden deaths have resulted from forcible opisthotonos [Hou 2006].

Lesch-Nyhan syndrome in females. The seven reported females with Lesch-Nyhan syndrome have had nonrandom X-chromosome inactivation or skewed inactivation of the X chromosome with the normal HPRT1 allele [De Gregorio et al 2000, Jinnah et al 2000]. Twinning may have led to discordant phenotypes of skewed X-chromosome inactivation in two monozygotic sisters [De Gregorio et al 2005]. In one girl [Rinat et al 2006], there was nonrandom inactivation of one X chromosome, whereas the expression of the other X chromosome was blocked by a de novo X-autosome translocation with a break point in the locus of HPRT1.

Although female carriers are generally asymptomatic, they may have increased uric acid excretion [Puig et al 1998] and some may develop symptoms of hyperuricemia in later years.

Genotype-Phenotype Correlations

Observed genotype-phenotype correlations reflect 544 pathogenic variants in HPRT [Fu et al 2014]. The amount of residual HPRT enzyme activity is important for the phenotype [Jinnah et al 2000, Jinnah et al 2004]. Pathogenic variants that completely disrupt HPRT enzyme function are associated with Lesch-Nyhan syndrome, whereas pathogenic variants that allow some residual HPRT enzyme function may be associated with the less severe phenotypes (see Genetically Related Disorders). Most individuals with the same pathogenic variant have the same phenotype, but there are a few exceptions in which the identical variant has occurred with discordant clinical features, but all were variant phenotypes [Fu et al 2014]. Certain pathogenic missense variants that have been identified several times independently cause only X-linked hyperuricemia.

Pathogenic missense variants have been analyzed for effects on HPRT enzyme structure [Duan et al 2004].


Lesch-Nyhan syndrome is characterized by movement disorder, cognitive deficits, and self-injurious behavior.


The prevalence of Lesch-Nyhan syndrome is approximately 1:380,000.

It appears to occur in all populations that have been studied, and with relatively equal frequency.

Differential Diagnosis

When fully developed with the three clinical elements of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances, the diagnosis of Lesch-Nyhan syndrome is made readily. The main diagnostic difficulties arise during early stages when all the features are not yet apparent, or in individuals who have partial deficiency of HPRT enzyme activity.

The index of suspicion is raised when developmental delay is associated with hyperuricemia. Alternatively, the diagnosis should be suspected when developmental delay is associated with nephrolithiasis or hematuria caused by uric acid stones.

Lesch-Nyhan syndrome is often first suspected when self-injurious behavior develops. However, self-injurious behaviors occur in other conditions, including nonspecific intellectual disability, autism, Rett syndrome, Cornelia de Lange syndrome, Tourette syndrome, familial dysautonomia, choreoacanthocytosis, sensory neuropathy including hereditary sensory neuropathy type 1, and several psychiatric conditions. Of these, only individuals with Lesch-Nyhan syndrome, Cornelia de Lange syndrome, and familial dysautonomia regularly display loss of tissue as a result of the behavior. Finger and lip biting is so characteristic of Lesch-Nyhan syndrome that it is referred to as a behavioral phenotype; in other syndromes associated with self-injury, the topography of behaviors is different, with head banging and/or nonspecific self-biting but not biting of the fingers and lips that results in tissue damage. Lesch-Nyhan syndrome should be strongly considered only when self-injurious behavior occurs in association with the full clinical picture of hyperuricemia and neurologic dysfunction.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Lesch-Nyhan syndrome, the following evaluations are recommended:

  • Complete blood count to evaluate for megaloblastic anemia
  • Chemistry screen for uric acid concentration
  • Neurologic examination
  • Developmental/behavioral assessments
  • Evaluation for renal calculi, usually by ultrasound examination of the abdomen
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Hyperuricemia. The overproduction of uric acid must be controlled to reduce the risk for nephrolithiasis, urate nephropathy, gouty arthritis, and tophi. Overproduction of uric acid can be controlled with allopurinol, which blocks the metabolism of hypoxanthine and xanthine into uric acid catalyzed by xanthine oxidase. The dose of allopurinol is adjusted to maintain the uric acid within normal limits.

Note: Control of serum concentration of uric acid from birth using allopurinol has no effect on behavioral and neurologic symptoms.

Allopurinol therapy results in the accumulation of hypoxanthine and xanthine; xanthine may also form stones. Therefore, care must be taken to avoid periods of relative dehydration that could concentrate the purine metabolites in the urinary system. Stones that develop in allopurinol-treated patients are usually composed of xanthine. A uric acid stone is an index of too little allopurinol. Hypoxanthine is soluble. Therefore, oxypurine analysis is useful in adjusting doses to maximize hypoxanthine. The allopurinol metabolite oxypurinol is also insoluble, and oxypurinol crystalluria has been observed with dehydration. Its concentration can also be monitored by oxypurine analysis of the urine.

Renal stones that form despite allopurinol may require lithotripsy or surgery.

Neurologic dysfunction. Spasticity can be managed by the administration of baclofen or benzodiazepines.

Neurobehavioral symptoms. Currently, no uniformly effective intervention for managing the neurobehavioral aspects of the disease exists. Self-injurious and other deleterious behaviors are best managed by a combination of physical, behavioral [Olson & Houlihan 2000], psychiatric [Harris 2007], and medical interventions.

Because stress increases self-injury, behavioral management through aversive techniques (which reduce self-injury in other conditions) actually increases self-injury in individuals with Lesch-Nyhan syndrome. Virtually all affected individuals require physical restraints to prevent self-injury and are restrained more than 75% of the time, often at their own request and sometimes with restraints that would appear to be ineffective as they do not physically prevent biting. Families report that affected individuals are at ease when restrained.

Sixty percent of individuals have their teeth extracted to avoid self-injury through biting. Families have found this to be an effective management technique. More conservative than tooth extraction are vital pulpotomy and coronal resection, which maintain the root portion of the tooth in the bone, an approach that may preserve alveolar bone [Lee et al 2002].

Behavioral extinction methods may be useful in a controlled setting for reducing self-injury, but seldom transfer well to the home setting [Harris 2007].

Prevention of Primary Manifestations

The overproduction of uric acid can be controlled with allopurinol, which blocks the metabolism of hypoxanthine and xanthine into uric acid.

Prevention of Secondary Complications

Adjustment of the dose of allopurinol is required to minimize the complication of nephrolithiasis. Virtually any reduction of hyperuricemia will prevent urate nephropathy.


Appropriate surveillance includes the following:

  • Monitor plasma uric acid concentration and urinary excretion of oxypurines.
  • Review medical history for signs or symptoms of silent or active renal stones.
  • Monitor affected individuals for early signs of self-injury.

Agents/Circumstances to Avoid

Probenecid and other uricosuric drugs designed to reduce the serum concentration of uric acid are contraindicated because they augment the delivery of uric acid into the urinary system and raise the risk for acute anuria from deposition of uric acid crystals in the renal collecting system.

Periods of relative dehydration are to be avoided because they could concentrate the purine metabolites in the urinary system and increase the risk for renal stones or urate nephropathy with resulting oliguria/anuria.

Evaluation of Relatives at Risk

Prenatal testing or testing of males at risk for Lesch-Nyhan syndrome immediately after birth enables prompt initiation of allopurinol therapy.

Some carrier females develop gout in later years; thus, establishing carrier status of female relatives through genetic testing may be valuable to their clinical management.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Elimination of self-injury and partial improvement of dystonia after deep brain stimulation in the globus pallidus was reported in a single patient [Taira et al 2003]. Of the small number of other individuals who have received this treatment, only one was successful; at least one died as a result of the procedure [Author, personal observation]. Deep brain stimulation must be considered experimental at present; evaluation of more affected individuals over longer periods is required to determine its effectiveness.

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.


Recent studies suggesting that gabapentin and carbamazepine may help attenuate self-injury and other behavioral disturbances have not been confirmed in a long-term study. Treatment with S-adenosylmethionine has led to mixed results [Dolcetta et al 2013]. Treatment with intravenous AICAR was without effect on the behavior [Page et al 1995].

No medication has been consistently effective in controlling the extrapyramidal motor features of the disease. The following have been unsuccessful in reducing neurologic or behavioral symptoms:

  • Partial exchange transfusion in two individuals
  • Bone marrow transplantation (BMT). BMT in a mouse model of HPRT deficiency has had no effect on the neurologic manifestations [Wojcik et al 1999]. Bone marrow transplantation was also ineffective in humans [Nyhan et al 1986].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Lesch-Nyhan syndrome is inherited in an X-linked recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to sibs of a proband depends on the carrier status of the mother.
  • A female who is a carrier has a 50% chance of transmitting the HPRT1 pathogenic variant in each pregnancy.
    • Sons who inherit the pathogenic variant will be affected.
    • Daughters who inherit the pathogenic variant are carriers.
    • Thus, with each pregnancy, a female who is a carrier has a 25% chance of having an affected male, a 25% chance of having a carrier female, and a 50% chance of having a normal male or female.
  • If the pathogenic variant cannot be detected in the leukocyte DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males with Lesch-Nyhan syndrome do not reproduce. If a male with a less severe phenotype reproduces, all of his daughters are obligate carriers and none of his sons is affected.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier (Heterozygote) Detection

Carrier testing of at-risk female relatives is possible if the HPRT1 pathogenic variant has been identified in the proband [O'Neill 2004].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Prenatal testing is possible for at-risk pregnancies [Nyhan et al 2003].

Molecular genetic testing. Once the HPRT1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for Lesch-Nyhan syndrome are possible.

Biochemical genetic testing. Assay of HPRT enzyme activity in cultured amniocytes or chorionic villus cells is the preferred method for prenatal testing if the HPRT1 pathogenic variant has not been identified in the family. No false positive or false negative diagnoses have been encountered in prenatal testing but it is possible that maternal cells could contaminate and overgrow the culture.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Lesch-Nyhan Disease International Study Group
  • Lesch-Nyhan Syndrome Children's Research Foundation
    210 South Green Bay Road
    Lake Forest IL 60045
    Phone: 847-234-3154
    Fax: 847-234-3136
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Lesch-Nyhan Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
HPRT1Xq26​.2-q26.3Hypoxanthine-guanine phosphoribosyltransferaseHPRT1 databaseHPRT1HPRT1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Lesch-Nyhan Syndrome (View All in OMIM)


Gene structure. The gene comprises nine exons over 43 kb of DNA and 657 nucleotides in the coding sequence. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. No known benign variants exist in the coding region of the gene.

Pathogenic variants. Pathogenic variants are spread nearly randomly throughout HPRT1. Each family generally has a unique pathogenic variant [Jinnah et al 2000]. Some pathogenic variants that have occurred independently in more than one family are known. In the 271 cases studied, 218 pathogenic DNA variants (primarily missense and nonsense variants and small deletions/insertions) have been found [Jinnah et al 2000]. (For more information, see Table A.)

Normal gene product. The HPRT enzyme (hypoxanthine-guanine phosphoribosyltransferase) catalyzes the conversion of hypoxanthine to IMP and guanine to GMP in the presence of phosphoribosylpyrophosphate. Thus, it recycles purines from DNA and RNA that are otherwise degraded. HPRT accounts for 0.05% of the total soluble protein in brain.

Abnormal gene product. The pathogenic variants result in nonfunctional or very low-function HPRT enzymatic activity.


Literature Cited

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  • De Gregorio L, Jinnah HA, Harris JC, Nyhan WL, Schretlen DJ, Trombley LM, O'Neill JP. Lesch-Nyhan disease in a female with a clinically normal monozygotic twin. Mol Genet Metab. 2005;85:70–7. [PubMed: 15862283]
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Chapter Notes

Author Notes

Professor O'Neill is a molecular biologist who has studied HPRT1 variants for 20 years. Since 1990, he has applied these methods to inherited HPRT1 variants in order to define the variants involved in Lesch-Nyhan syndrome and related diseases. In particular, he applies these molecular methods to determine the carrier status of females in these families.

Dr Jinnah is a neurologist with more than ten years of experience in research and clinical management in Lesch-Nyhan syndrome. He has an NIH-funded laboratory program devoted to developing a better understanding of the abnormalities in brain function that lead to the neurobehavioral aspects of the disease.

Dr Harris is a developmental neuropsychiatrist who specializes in the treatment of psychiatric and behavioral problems in Lesch-Nyhan syndrome. His research focuses on neuroimaging studies in individuals with Lesch-Nyhan syndrome.

Dr Nyhan has devoted more than 55 years to research and patient care in genetic diseases of metabolism. He and Michael Lesch, MD, first described the Lesch-Nyhan syndrome in 1964. Clinical investigation of this disease and other disorders of purine metabolism are under study in an NIH-funded Clinical and Translational Research Institute at the UCSD Medical Center.

Author History

James C Harris, MD (2000-present)
Hyder A Jinnah, MD, PhD (2000-present)
Janice A Nicklas, PhD; University of Vermont (2000-2007)
William L Nyhan, MD, PhD (2000-present)
J Patrick O'Neill, PhD (2000-present)

Revision History

  • 15 May 2014 (me) Comprehensive update posted live
  • 10 June 2010 (me) Comprehensive update posted live
  • 27 January 2009 (cd) Revision: deletion/duplication analysis available clinically
  • 27 November 2007 (me) Comprehensive update posted live
  • 8 February 2005 (me) Comprehensive update posted live
  • 6 February 2003 (me) Comprehensive update posted live
  • 25 September 2000 (me) Review posted live
  • 20 March 2000 (jn) Original submission
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