AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

Michael Lesch and William Nyhan provided the first detailed clinical description of Lesch-Nyhan syndrome in 1964. The enzymatic defect associated with Lesch-Nyhan syndrome, deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), was discovered by Seegmiller and colleagues in 1967. The gene encoding the enzyme was cloned and sequenced by Friedmann and colleagues in 1985.

Lesch-Nyhan syndrome is a genetic disorder associated with 3 major clinical elements. These elements include overproduction of uric acid, neurological disability, and behavioral problems. The overproduction of uric acid is associated with hyperuricemia. If left untreated, it can produce nephrolithiasis with renal failure, gouty arthritis, and solid subcutaneous deposits known as tophi. The neurological disability encompasses a spectrum of extrapyramidal signs, including dystonia, choreoathetosis, and occasionally ballismus. Some patients also develop pyramidal signs, such as spasticity and hyperreflexia. The behavioral problems include cognitive dysfunction and aggressive and impulsive behaviors. Nearly all patients also develop persistent and severe self-injurious behavior.

Treatment of the condition is limited. Allopurinol is useful to control the overproduction of uric acid and reduces the risk of nephrolithiasis and gouty arthritis. Few treatments have proved consistently helpful for the neurological or behavioral difficulties. Spasticity is managed with a combination of baclofen and benzodiazepines, while the behavioral abnormalities are best managed by a combination of behavioral modification techniques and medications.

Pathophysiology

The metabolic basis for the overproduction of uric acid has been studied extensively. HPRT normally plays a key role in the recycling of the purine bases, hypoxanthine and guanine, into the purine nucleotide pools (see Image 1). In the absence of HPRT, these purine bases cannot be salvaged, and instead are degraded and excreted ultimately as uric acid. In addition to the failure of purine recycling, the synthetic rate for purines is accelerated markedly, presumably to compensate for purines lost by the failure of the salvage process. The failure of recycling together with the increased synthesis of purines result in a dramatic overproduction of uric acid.

The increased production of uric acid leads to hyperuricemia. Since uric acid is normally near its physiological limit of solubility in the body, the persistent hyperuricemia increases the risk of uric acid crystal precipitation in the tissues to form tophi. Uric acid crystal deposition in the joints produces a marked inflammatory reaction and gouty arthritis. The kidneys respond to the hyperuricemia by increasing its excretion into the urogenital system. The increased excretion of uric acid increases the risk of forming urate stones in the urinary collecting system. These stones may be passed as a sandy sludge or as larger particles that may obstruct urine flow and increase the risk for hematuria and urinary tract infections.

The pathogenesis of the neurological and behavioral features is incompletely understood. Neurochemical and neuroimaging studies have demonstrated significant abnormalities of dopamine neuron function in the basal ganglia that might account for the abnormal extrapyramidal neurological signs and many of the behavioral anomalies. However, the mechanism by which HPRT deficiency influences the basal ganglia, and particularly the dopamine systems, remains unknown.

Frequency

International

The reported worldwide prevalence is 1 case per 380,000 population.

Mortality/Morbidity

Few patients live beyond 40 years. Despite the use of allopurinol to control hyperuricemia, some patients still succumb to the consequences of persistent nephrolithiasis, such as renal failure or urosepsis. Other patients experience progressive dysphagia and die after aspiration and pneumonia. Sudden unexpected death is common, even on a background of an apparently stable medical condition. The reasons for sudden death remain unknown, though respiratory failure from cervical pathology or laryngospasm are considered leading possibilities.

Race

The disease has been reported for most races, with approximately equal rates for most ethnic groups.

Sex

This is an X-linked recessive disorder; therefore, nearly all cases are in males. Only rarely has it been reported in females.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

• Most patients present at age 3-12 months with delayed motor development, most commonly hypotonia or failure to reach normal motor milestones. Others are identified first by the presence of involuntary movements or increased muscle tone. However, between ages 6 and 18 months, abnormal involuntary movements indicative of extrapyramidal dysfunction become more prominent; a significant proportion of patients also develop corticospinal signs.
• A smaller number of patients present with complications related to the overproduction of uric acid. Sometimes the parents give a history of "orange sand" in the diapers, which is caused by uric acid crystalluria and microhematuria. Other patients may present with renal failure or frank hematuria, resulting from nephrolithiasis.
• Though self-injurious behavior is rarely the presenting feature of the illness, it eventually develops in nearly all cases. The emergence of the behavior often provides the essential clue to the diagnosis in a case with known developmental delay or hyperuricemia.

Physical

• The most salient feature of the general physical examination is growth retardation. Somatic growth is affected more than head circumference; bone age is affected only slightly. Testicular atrophy is common; puberty is delayed or absent.
• Neurologically, cognitive function is impaired, with average intelligence quotient (IQ) values of approximately 60. Basic sensory functions appear largely intact, though motor function is compromised severely. Patients may exhibit a spectrum of extrapyramidal features, including dystonia, choreoathetosis, opisthotonic spasms, and ballismus. A significant proportion also displays pyramidal features, including hyperreflexia and ankle clonus. The severity of the neurological dysfunction precludes normal ambulation, and all patients are wheelchair bound.
• Behavioral problems are also prominent. Frequent attempts toward self-injury may be evident. Partial amputations of the fingers, lips, tongue, or oral mucosa, resulting from self-biting, are common (see Images 2-3). Serious injuries or scarring from repetitive self-abrasion or hitting also may result. In addition to self-injurious behavior, many patients display compulsive behaviors that often are interpreted as signs of aggression. These include hitting, spitting, coprolalia, copropraxia, and manipulative behavior.

Causes

• This is a genetic disorder caused by mutations in the HPRT gene on the X chromosome.
• The mutations are heterogenous, including single base substitutions, deletions, insertion, or substitutions (see Image 4).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

Dystonia
Self-injurious behavior

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• The gross overproduction of uric acid is often evident in routine blood and urine studies.
• • Uric acid levels in the blood typically are elevated, a helpful clue that can be obtained by routine clinical testing; however, hyperuricemia has many different causes, and some patients with Lesch-Nyhan syndrome have serum uric acid levels that repeatedly fall in the normal range. As a result, serum uric acid levels do not provide reliable diagnostic information.
  • Urinary uric acid excretion also is increased typically. A 24-hour urine sample typically demonstrates a marked increase over normative values, particularly if corrected for patient weight. However, 24-hour samples are notoriously difficult to collect. Calculation of the urinary uric acid to creatinine value in a spot urine specimen provides an alternative method, though less information is available concerning normative values. Hyperuricosuria is neither sensitive nor specific enough to provide reliable diagnostic information.
• Definitive diagnosis is obtained most often by measurement of HPRT enzyme activity in blood or tissue. Blood samples often are used, though intact fibroblasts or lymphocytes provide more precise information.
• Diagnosis is confirmed by identifying a molecular genetic mutation in the HPRT gene. Molecular genetic diagnosis provides an ideal tool for carrier detection and prenatal screening of at-risk pregnancies.
• Macrocytic anemia, sometimes profound, is relatively common. Vitamin B-12, folate, and iron results are typically normal.

Imaging Studies

• Neuroimaging studies of the brain, both CT scan and MRI, generally do not reveal any obvious structural malformations or signal changes in the gray or white matter. They may reveal mild loss of brain volume, but this loss is often so small that it escapes notice in most routine imaging studies.
• Neuroimaging studies of the spinal cord, particularly the cervical portions, may reveal early degenerative joint disease that can damage the spinal cord or emerging nerve roots.

Other Tests

• Noninvasive imaging studies of the kidneys and other parts of the urogenital system are warranted because of the marked increase in the risk for kidney stones.
• • Any patient who develops flank pain, hematuria, or recurrent urinary tract infections should be evaluated.
  • Some authorities have recommended yearly investigations in all patients, because asymptomatic stones or sludge may silently compromise renal function.
• Since stones composed of uric acid, oxypurine metabolites, or allopurinol are typically radiolucent, they may be invisible on plain films; however, they are imaged easily by renal ultrasound.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

• The gross overproduction of uric acid must be controlled to prevent the development of urological or articular complications. The control of uric acid requires 2 important components.
• • Allopurinol, which inhibits the metabolism of hypoxanthine and xanthine to uric acid by the enzyme xanthine oxidase, is generally effective in limiting hyperuricemia and its consequences. The dose is titrated with the goal of bringing serum uric acid levels into the normal range.
  • Generous hydration at all times is essential. Hydration should be increased during periods of increased fluid loss, such as a febrile illness or recurrent emesis.
  • Despite the combined use of allopurinol and generous hydration, nephrolithiasis still may occur.
• Several medications are available to mitigate the severity of the neurological features, though no agent has proved consistently efficacious in all cases. Benzodiazepines, such as diazepam or alprazolam, reduce severity and help attenuate anxiety that may indirectly exacerbate the extrapyramidal abnormalities. Antispasticity agents such as baclofen or tizanidine also can be helpful.
• Management of the behavioral problems, and particularly the self-injurious behavior, can be very difficult. In general, behavioral problems are best managed with a combination of behavioral modification techniques and medication. Behavioral extinction methods with positive reinforcement are most beneficial; techniques involving negative reinforcement are not helpful and may even exacerbate the behavior problems. Adjunctive medications, sometimes useful for attenuating problem behaviors, include gabapentin and carbamazepine.

Surgical Care

• The metabolic defect does not preclude safe application of standard anesthetic or surgical procedures when indicated.
• Dental work is perhaps the most commonly required surgical intervention in this disease. Dental extraction may be the only procedure for preventing serious tissue injury, if self-injurious biting cannot be controlled with behavioral and/or medical therapy.
• Orthopedic intervention often is required for management of the consequences of the neurological disorder. Procedures may be required for release of contractures, reduction of subluxed joints, or stabilization of spinal deformity.
• Nephrolithiasis may require surgical intervention for extraction of stones or relief from urogenital obstruction.
• Recent studies have provided a promising suggestion that deep brain stimulation surgery may be useful for controlling both dystonia and self-injury. The procedure is considered experimental, and further studies are needed before the procedure can be broadly recommended because the brain targets seem to differ from those used for other disorders of dystonia or for Parkinson disease.

Diet

• Most patients can eat a normal diet.
• Dysphagia may be a significant problem, particularly with aging. Some patients respond to changes in the consistency of the diet, while others may require gastrostomy feeding.

Activity

Despite their profound motor handicap, most patients prefer to remain actively engaged in their environments.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Uricosuric agents

These agents are used to control hyperuricemia, thereby reducing risk for nephrolithiasis, gouty arthritis, and subcutaneous tophi.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Further Inpatient Care

• Inpatient admissions should be limited to those absolutely necessary for medical interventions, since moving these patients into an unfamiliar environment will exacerbate behavioral problems such as self-injury.
• Restraints should be applied at all times to prevent self-injury; this includes nighttime sleeping periods and also during transfer for any tests. This disease is one of a few rare conditions that are exempted from the usual regulations of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) against continuous and long-term patient restraints.

Deterrence/Prevention

• Since few reliable treatments are available for the condition, genetic counseling is critical for prevention. Mothers and sisters of patients should be tested to determine if they are carriers.
• Prenatal testing should be offered to all pregnant women known to be carriers. Because of the rare potential for gonadal mosaicism, prenatal testing should also be offered to mothers who have previously given birth to an affected individual, even if she does not appear to be a carrier.

Prognosis

• With optimal medical care, affected individuals typically live into their third or even fourth decade of life.
• Many die from aspiration pneumonia or complications from chronic nephrolithiasis and renal failure; however, a significant proportion of patients die suddenly and unexpectedly from unknown causes.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  Purine metabolic pathways.
	View Full Size Image
Media type:  Photo

Media file 2:  A small portion of the lower lip has been disfigured by persistent self-biting.
	View Full Size Image
Media type:  Photo

Media file 3:  The distal portions of several fingers are shortened by prior uncontrolled self-biting.
	View Full Size Image
Media type:  Photo

Media file 4:  The HPRT gene has 9 exons, with the coding region depicted as light gray boxes. Genetic mutations in Lesch-Nyhan syndrome are heterogenous and include point mutations leading to amino acid substitution (yellow circles), point mutations leading to premature stop (red squares), insertions (blue triangles), deletions (white lines), and other more complex changes (not shown).
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

• Alford RL, Redman JB, O''Brien WE, Caskey CT. Lesch-Nyhan syndrome: carrier and prenatal diagnosis. Prenat Diagn. Apr 1995;15(4):329-38. [Medline].
• Duan J, Nilsson L, Lambert B. Structural and functional analysis of mutations at the human hypoxanthine phosphoribosyl transferase (HPRT1) locus. Hum Mutat. Jun 2004;23(6):599-611. [Medline].
• Jinnah HA, Friedmann T. Lesch-Nyhan disease and its variants. In: Scriver CR, Sly WS, Childs B, Beaudet AL, et al, eds. The Molecular and Metabolic Bases of Inherited Disease. 6th ed. New York, NY: McGraw-Hill; 2000:. Chapter 107.
• Jinnah HA, De Gregorio L, Harris JC, et al. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res. Oct 2000;463(3):309-26. [Medline].
• Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain. May 2006;129(Pt 5):1201-17. [Medline].
• Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med. Apr 1964;36:561-70. [Medline].
• Nyhan WL, Vuong LU, Broock R. Prenatal diagnosis of Lesch-Nyhan disease. Prenat Diagn. Oct 2003;23(10):807-9. [Medline].
• Visser JE, Bar PR, Jinnah HA. Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev. Apr 2000;32(2-3):449-75. [Medline].

Article Last Updated: Aug 29, 2006