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Lesch-Nyhan Syndrome

[HGPRT Deficiency, HPRT Deficiency, Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency, Lesch-Nyhan Disease]

Summary

Disease 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 chidren 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 (HRND) and hyperuricemia alone, sometimes with acute renal failure (HRH).

Diagnosis/testing.  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. Sequence analysis of HPRT1, the only gene known to be associated with Lesch-Nyhan syndrome, is available on a clinical basis.

Management.  Treatment of manifestations: Control of overproduction of uric acid with allopurinol reduces the risk of nephrolithiasis, 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. 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. Testing 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 of gout in later years.

Genetic counseling. Lesch-Nyhan syndrome is inherited in an X-linked manner. The father of an affected male will not have the disease nor be a carrier of the mutant 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 mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation 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 and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

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

Testing

For laboratories offering biochemical testing, see .

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.

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.

  Assay of intact cells from cultured fibroblasts may be necessary to distinguish genetically related 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 had 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 analogue 6-thioguanine, proliferation of peripheral blood T-lymphocytes is confirmatory in most cases; however, this test is available on a research basis only.

• In females.  If the HPRT1 disease-causing mutation 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. This elevated frequency of HPRT-deficient lymphocytes is usually diagnostic by itself; however, at present, this test is only available on a research basis.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

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

Clinical testing

• Sequence analysis and mutation scanning.  Using these two methods, mutations in the HPRT1 gene are detected in the majority of males who display the full Lesch-Nyhan syndrome phenotype [Jinnah et al 2000 , Jinnah et al 2004].

Note: Between 21% [Bertelli et al 2004] and 24% [Jinnah et al 2000] of mutations in HPRT1 are large deletions that cannot be detected in females by sequence analysis; other test methods to detect exonic or whole gene deletions are required, but such testing is available on a research basis only.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Lesch-Nyhan Syndrome Test Method Mutations Detected Mutation Detection Frequency  1,  2 Test Availability Sequence analysis/mutation scanning Sequence variants in HPRT1 A majority of males  3,  4 Clinical

1. Proportion of affected individuals with a mutation(s) as classified by test method 2. Numbers are based on 218 mutations seen in 271 families [Jinnah et al 2004]. 3. Males with the full Lesch-Nyhan syndrome phenotype 4. Between 21% and 24% of mutations are large deletions that cannot be detected in females by sequence analysis.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband.  The gold standard for diagnosis in the proband is HPRT enzyme activity.

Identification of carrier females requires either prior identification of the HPRT1 disease-causing mutation in an affected male or, if an affected male is not available for testing, molecular genetic testing of HPRT1 by sequence analysis or mutation scanning.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Less severe syndromes caused by partial variant HPRT enzyme deficiency are also recognized, although they are much less common than Lesch-Nyhan syndrome.

X-linked hyperuricemia (HRH).   Mutations allowing at least 8% of HPRT enzyme activity are associated with X-linked hyperuricemia, with an increased risk for uric acid crystal deposition in the urinary system and gouty arthritis (previously referred to as Kelley-Seegmiller syndrome). Affected individuals have no neurologic or behavioral abnormalities. Those with HPRT-related hyperuricemia alone may have a normal lifespan if they can avoid renal complications, especially the nephropathy and renal failure that result from deposition of sodium urate in the renal parenchyma [Srivastava et al 2002].

Hyperuricemia with neurologic disability (HRND).   Uric acid overproduction with neurologic disability but without behavioral disturbances has also been reported [Jinnah & Friedman 2001].

• The most severely affected individuals are neurologically indistinguishable from those with classic Lesch-Nyhan syndrome but do not have self-injurious behavior, whereas others may have only minor clumsiness with fine motor skills or slightly indistinct speech patterns and cognitive deficits [Schretlen et al 2001].

• An additional phenotype designated HPRT_Salamanca consists of spasticity and mild intellectual disability [Page et al 1987].

Clinical Description

Natural History

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. Most 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 are rapidly 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 are often not recognized 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. ESRD may be a special risk for variant patients in whom neurologic or behavioral features do not lead to early recognition [Kassimatis et al 2005].

Many affected males have testicular atrophy.

A megaloblastic anemia unresponsive to vitamin supplements is common.

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 symptoms are properly managed, most individuals survive into the second or third decade of life. There is no evidence for disease progression over time.

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 nine-year-old 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 appear to have nonrandom X-chromosome inactivation or skewed inactivation of the X chgromosome 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 the HPRT1 gene.

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 are based on the amount of residual HPRT enzyme activity [Jinnah et al 2000 , Jinnah et al 2004]. Mutations that completely disrupt HPRT enzyme function are associated with Lesch-Nyhan syndrome, whereas mutations that allow some residual HPRT enzyme function may be associated with the less severe phenotypes. Certain missense mutations that have been identified several times independently cause only X-linked hyperuricemia (some cases designated HRH in Jinnah et al 2000). Missense mutations have been analyzed for effects on HPRT enzyme structure [Duan et al 2004].

Nomenclature

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

Individuals with neurologic variants have movement disorder and cognitive deficits but do not self-injure.

Individuals with yperuricemic variants do not self-injure and have minimal or no movement disorderand mild or no cognitive disorder.

HPRT_Salamanca is characterized by spastic gait and mild cognitive deficit.

Prevalence

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

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

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.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

Treatment of Manifestations

Hyperuricemia.  The overproduction of uric acid must be controlled to reduce the risk of nephrolithiasis, gouty arthritis, and tophi. Overproduction of uric acid can be controlled with allopurinol, which blocks the metabolism of hypoxanthine and xanthine into uric acid 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 et al 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 et al 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 by xanthine oxidase.

Surveillance

Monitor patients for early signs of self-injury.

Review medical history for signs or symptoms of silent or active renal stones; monitor plasma uric acid concentration; test for urinary excretion of oxypurines.

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 of 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.

Testing 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 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 cases over longer periods is required to determine its effectiveness.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

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.

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].

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutant allele.
• A woman who has an affected son and one other affected relative in the maternal line is an obligate carrier.
• If a woman has more than one affected son and the disease-causing mutation cannot be detected in her DNA, she has germline mosaicism.
• If a woman is the first in her family with an affected son, Haldane's rule predicts a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germline mutation. Francke et al (1981) reported a higher ratio of carrier mothers.
• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
  • The son has a de novo disease-causing mutation in the HPRT1 gene and his mother is not a carrier.
  • His mother has a de novo disease-causing mutation in the HPRT1 gene, either a) as a "germline mutation" (i.e., occurring at the time of her conception and thus present in every cell of her body); or b) as "germline mosaicism" (i.e., present in a certain percentage of her germ cells only).
  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.
• Some carrier females develop hyperuricemia.

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 mutation in each pregnancy.
  • Sons who inherit the mutation will be affected.
  • Daughters who inherit the mutation 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 disease-causing mutation cannot be detected in the 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 Detection

Carrier testing of at-risk female relatives is available on a clinical basis if the mutation has been identified in the proband [O'Neill 2004].

Related Genetic Counseling Issues

See Testing of Relatives at Risk for information on testing 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 carriers or at risk.

DNA banking.   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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

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

Molecular genetic testing.  Prenatal testing is possible for pregnancies at risk (i.e., pregnancies of women who are carriers or who may have germline mosaicism) if the HPRT1 mutation has been identified in the family. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15-18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation. 46,XX cells can be tested for mutation carrier status as well. When the HPRT1 disease-causing mutation is known in a family, both HPRT enzyme activity and molecular genetic testing are performed to confirm the diagnosis in the fetus.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Normal allelic variants: The gene comprises nine exons over 43 kb of DNA and 657 nucleotides in the coding sequence. No known polymorphisms exist in the coding region of the gene.

Pathologic allelic variants: Pathologic allelic variants are spread nearly randomly throughout the HPRT1 gene. Each family generally has a unique  mutation [Jinnah et al 2000]. Some mutations that have occurred independently in more than one family are known. In the 271 cases studied, 218 pathologic DNA variants (primarily missense and nonsense mutations and small deletions/insertions) have been found [Jinnah et al 2000]. (For more information, see Genomic Databases table .)

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 pathologic allelic variants result in nonfunctional or very low-function HPRT enzymatic activity.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Literature Cited

• Bertelli M, Randi D, Micheli V, Gallo S, Andrighetto G, Parmigiani P, Jacomelli G, Carella M, Lievore C, Pandolfo M (2004) Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in Italian Lesch-Nyhan patients: identification of nine novel mutations. J Inherit Metab Dis 27:767-73 [Medline]
  
  
• De Gregorio L, Jinnah HA, Harris JC, Nyhan WL, Schretlen DJ, Trombley LM, O'Neill JP (2005) Lesch-Nyhan disease in a female with a clinically normal monozygotic twin. Mol Genet Metab 85:70-7 [Medline]
  
  
• De Gregorio L, Nyhan WL, Serafin E, Chamoles NA (2000) An unexpected affected female patient in a classical Lesch-Nyhan family. Mol Genet Metab 69:263-8 [Medline]
  
  
• Duan J, Nilsson L, Lambert B (2004) Structural and functional analysis of mutations at the human hypoxanthine phosphoribosyl transferase (HPRT1) locus. Hum Mutat 23:599-611 [Medline]
  
  
• Francke U, Winter RM, Lin D, Bakay B, Seegmiller JE, Nyhan WL (1981) Use of carrier detection tests to estimate male to female ratio of mutation rates in Lesch-Nyhan disease. In: Hook EB, Porter IH (eds) Population Aspects of Human Mutation. Academic, New York, p 117
  
  
• Harris JC (2007) Lesch Nyhan Syndrome. In: Gilman S (ed) MedLink Neurology. MedLink Corporation, San Diego. www.medlink.com
  
  
• Harris JC, Lee RR, Jinnah HA, Wong DF, Yaster M, Bryan RN (1998) Craniocerebral magnetic resonance imaging measurement and findings in Lesch-Nyhan syndrome. Arch Neurol 55:547-53 [Medline]
  
  
• Hou JW (2006) Atlantoaxial subluxation with recurrent consciousness disturbance in a boy with Lesch-Nyhan syndrome. Acta Paediatr 95:1500-4 [Medline]
  
  
• 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 463:309-26 [Medline]
  
  
• Jinnah HA, Harris JC, Nyhan WL, O'Neill JP (2004) The spectrum of mutations causing HPRT deficiency: an update. Nucleosides Nucleotides Nucleic Acids 23:1153-60 [Medline]
  
  
• Jinnah HA, Visser JE, Harris JC, Verdu A, Larovere L, Ceballos-Picot I, Gonzalez-Alegre P, Neychev V, Torres RJ, Dulac O, Desguerre I, Schretlen DJ, Robey KL, Barabas G, Bloem BR, Nyhan W, De Kremer R, Eddey GE, Puig JG, Reich SG (2006) Delineation of the motor disorder of Lesch-Nyhan disease. Brain 129:1201-17 [Medline]
  
  
• Jinnah JA, Friedman T (2001) Lesch Nyhan disease and its variants. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds)The Metabolic Basis of Inherited Disease, 8 ed. McGraw-Hill, New York
  
  
• Kassimatis TI, Simmonds HA, Goudas PC, Marinaki AM, Fairbanks LD, Diamandopoulos AA (2005) HPRT deficiency as the cause of ESRD in a 24-year-old patient: a very rare presentation of the disorder. J Nephrol 18:447-51 [Medline]
  
  
• Lee JH, Berkowitz RJ, Choi B (2002) Oral self-mutilation in the Lesch-Nyhan syndrome. ASDC J Dent Child 69:66-9 [Medline]
  
  
• LESCH M and NYHAN WL (1964) A FAMILIAL DISORDER OF URIC ACID METABOLISM AND CENTRAL NERVOUS SYSTEM FUNCTION. Am J Med 36:561-70 [Medline]
  
  
• Neychev VK and Jinnah HA (2006) Sudden death in Lesch-Nyhan disease. Dev Med Child Neurol 48:923-6 [Medline]
  
  
• Nyhan WL, Barshop B, Ozand PT (2005) Lesch-Nyhan disease. In: Atlas of Metabolic Diseases. Chapman and Hall, London
  
  
• Nyhan WL, Vuong LU, Broock R (2003) Prenatal diagnosis of Lesch-Nyhan disease. Prenat Diagn 23:807-9 [Medline]
  
  
• O'Neill JP (2004) Mutation carrier testing in Lesch-Nyhan syndrome families: HPRT mutant frequency and mutation analysis with peripheral blood T lymphocytes. Genet Test 8:51-64 [Medline]
  
  
• Olson L and Houlihan D (2000) A review of behavioral treatments used for Lesch-Nyhan syndrome. Behav Modif 24:202-22 [Medline]
  
  
• Page T, Bakay B, Nissinen E, Nyhan WL (1981) Hypoxanthine-guanine phosphoribosyltransferase variants: correlation of clinical phenotype with enzyme activity. J Inherit Metab Dis 4:203-6 [Medline]
  
  
• Page T, Nyhan WL, Morena de Vega V (1987) Syndrome of mild mental retardation, spastic gait, and skeletal malformations in a family with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase. Pediatrics 79:713-7 [Medline]
  
  
• Puig JG, Mateos FA, Torres RJ, Buno AS (1998) Purine metabolism in female heterozygotes for hypoxanthine-guanine phosphoribosyltransferase deficiency. Eur J Clin Invest 28:950-7 [Medline]
  
  
• Rinat C, Zoref-Shani E, Ben-Neriah Z, Bromberg Y, Becker-Cohen R, Feinstein S, Sperling O, Frishberg Y (2006) Molecular, biochemical, and genetic characterization of a female patient with Lesch-Nyhan disease. Mol Genet Metab 87:249-52 [Medline]
  
  
• Robey KL, Reck JF, Giacomini KD, Barabas G, Eddey GE (2003) Modes and patterns of self-mutilation in persons with Lesch-Nyhan disease. Dev Med Child Neurol 45:167-71 [Medline]
  
  
• Schretlen DJ, Harris JC, Park KS, Jinnah HA, del Pozo NO (2001) Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency. J Int Neuropsychol Soc 7:805-12 [Medline]
  
  
• Schretlen DJ, Ward J, Meyer SM, Yun J, Puig JG, Nyhan WL, Jinnah HA, Harris JC (2005) Behavioral aspects of Lesch-Nyhan disease and its variants. Dev Med Child Neurol 47:673-7 [Medline]
  
  
• Seegmiller JE, Rosenbloom FM, Kelley WN (1967) Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 155:1682-4 [Medline]
  
  
• Srivastava T, O'Neill JP, Dasouki M, Simckes AM (2002) Childhood hyperuricemia and acute renal failure resulting from a missense mutation in the HPRT gene. Am J Med Genet 108:219-22 [Medline]
  
  
• Taira T, Kobayashi T, Hori T (2003) Disappearance of self-mutilating behavior in a patient with lesch-nyhan syndrome after bilateral chronic stimulation of the globus pallidus internus. Case report. J Neurosurg 98:414-6 [Medline]
  
  
• Wojcik BE, Jinnah HA, Muller-Sieburg CE, Friedmann T (1999) Bone marrow transplantation does not ameliorate the neurologic symptoms in mice deficient in hypoxanthine guanine phosphoribosyl transferase (HPRT). Metab Brain Dis 14:57-65 [Medline]
  
  

Suggested Readings

• Jinnah HA and Friedmann T (revised 2002) Lesch-Nyhan disease and its variants. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 107. www.ommbid.com
  
  
• Nyhan WL (2005) Inherited hyperuricemic disorders. Contrib Nephrol 147:22-34 [Medline]
  
  
• Nyhan WL (2005) Lesch-Nyhan Disease. J Hist Neurosci 14:1-10 [Medline]
  
  
• Nyhan WL, Olivier WJ, Lesch M (1965) A familial disorder of uric acid metabolism and central nervous system function. J Pediatr 67:257-63
  
  

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