Lesch-Nyhan disease is a genetic disorder associated with 3 major clinical elements: overproduction of uric acid, neurologic disability, and behavioral problems.[1] 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 neurologic disability is dominated by dystonia but may include choreoathetosis, ballismus, spasticity, or hyperreflexia.[2] The behavioral problems include intellectual disability and aggressive and impulsive behaviors. Patients with the classic disease also develop persistent and severe self-injurious behavior.
In addition to the classic clinical disease, patients with less severe disease and partial syndromes are increasingly recognized.[3] In these milder variants, self-injury may not occur, cognition may be normal, or dystonia may be mild or even absent. Some may have overproduction of uric acid and its consequences alone. These patients are identified by demonstrating HPRT deficiency or a mutation in the HPRT gene. Collectively, they are referred to as Lesch-Nyhan variants.
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 proven consistently helpful for the neurologic or behavioral difficulties. Motor disability 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.
Hypoxanthine-guanine phosphoribosyl transferase (HPRT) normally plays a key role in the recycling of the purine bases, hypoxanthine and guanine, into the purine nucleotide pools (see the image below).
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Purine metabolic pathways.
In the absence of HPRT, these purine bases cannot be salvaged; instead, they are degraded and excreted as uric acid. In addition to the failure of purine recycling, the synthetic rate for purines is accelerated, presumably to compensate for purines lost by the failure of the salvage process. The failure of recycling together with the increased synthesis of purines is the basis for the overproduction of uric acid.[1]
The increased production of uric acid leads to hyperuricemia. Since uric acid is near its physiologic 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 an inflammatory reaction and gouty arthritis. The kidneys respond to the hyperuricemia by increasing its excretion into the urogenital system, increasing 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 of hematuria and urinary tract infections.
The pathogenesis of the neurologic and behavioral features is incompletely understood.[4] Neurochemical and neuroimaging studies have demonstrated significant abnormalities of dopamine neuron function in the basal ganglia that might account for the abnormal extrapyramidal neurologic signs and many of the behavioral anomalies.[5] Neuropathologic studies suggest a neurodevelopmental defect, with no signs of a degenerative process.[2] However, the mechanism by which HPRT deficiency influences the basal ganglia, and particularly the dopamine systems, remains unknown.
Lesch-Nyhan disease and its variants are caused by mutations in the HPRT gene on the X chromosome.[6] The mutations are heterogeneous, with more than 600 different ones documented, including single base substitutions, deletions, insertions, or substitutions (see the image below).[7, 8]
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The HPRT gene has 9 exons, with the coding region depicted as light gray boxes. Genetic mutations in Lesch-Nyhan disease and its variants are heteroge....
The reported worldwide prevalence of Lesch-Nyhan disease is 1 case per 380,000 population. The disease has been reported in most races, with approximately equal rates for most ethnic groups. Few patients live beyond 40 years.[9]
Lesch-Nyhan disease is an X-linked recessive disorder; therefore, nearly all cases are in males. Only rarely has the disease been reported in females.[9]
With optimal medical care, individuals with Lesch-Nyhan disease typically live into their third or even fourth decade of life. Few patients live beyond 40 years.
Many patients die of aspiration pneumonia or complications from chronic nephrolithiasis and renal failure; however, a significant proportion of patients die suddenly and unexpectedly from unknown causes.[10]
Despite the use of allopurinol to control hyperuricemia, some patients still succumb to the consequences of recurrent nephrolithiasis, such as renal failure or urosepsis. Other patients experience progressive dysphagia and die after aspiration and pneumonia. Sudden, unexpected death also occurs, 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.[10]
Since few reliable treatments are available for Lesch-Nyhan disease, genetic counseling is critical for prevention. Mothers and sisters of patients should be tested to determine if they are carriers.[11, 12]
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.
Most patients with classic Lesch-Nyhan disease present at age 3-12 months with delayed motor development, most commonly hypotonia or failure to reach normal motor milestones. Between ages 6 and 18 months, abnormal involuntary movements indicative of extrapyramidal dysfunction become more prominent; some patients also develop corticospinal signs. Patients may often receive a diagnosis of cerebral palsy. After an initial period of progression that may last until age 3-6 years, motor disability does not continue to progress.[2]
A smaller number of patients present with complications related to the overproduction of uric acid. Sometimes there is 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. A few patients may present with gout.
Though self-injurious behavior is rarely the presenting feature of the illness, it eventually develops in all cases. The emergence of the behavior often provides the essential clue to the diagnosis in a case with known developmental delay or hyperuricemia. Self-injury does not occur in the Lesch-Nyhan variants. These patients present with signs of motor delay or consequences of overproduction of uric acid.[3]
The most salient feature of the general physical examination in classic cases of Lesch-Nyhan disease is growth retardation. Somatic growth is affected more than head circumference; bone age is affected only slightly. Testicular atrophy is common. Puberty is often delayed or absent. There may be evidence of tissue disfigurement, such as scarring of the lips or hands.
Neurologically, cognitive function is impaired, with average intelligence quotient (IQ) values of approximately 60. Basic sensory functions are intact, though motor function is severely compromised. All patients exhibit severe generalized dystonia. Some also exhibit other features, including choreoathetosis, opisthotonic spasms, and ballismus. Approximately 25% also display hyperreflexia and ankle clonus. The severity of the neurologic dysfunction precludes normal ambulation, and all patients are wheelchair bound.
Behavioral problems are also prominent. Frequent attempts toward self-injury may be evident (see the images below). Partial amputations of the fingers, lips, tongue, or oral mucosa, resulting from self-biting, are common. 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.
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A small portion of the lower lip has been disfigured by persistent self-biting.
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The distal portions of several fingers are shortened by prior uncontrolled self-biting.
In patients with Lesch-Nyhan disease, uric acid levels in the blood and urine are typically, but not always, increased. Definitive diagnosis is generally obtained by measurement of the hypoxanthine-guanine phosphoribosyl transferase (HPRT) enzyme. Confirmation of the diagnosis is most reliably made by identification of the HPRT1 gene.
The gross overproduction of uric acid is often evident in routine blood and urine studies.[1] 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 disease have serum uric acid levels in the normal range. As a result, serum uric acid levels do not provide reliable diagnostic information.
A 24-hour urine sample typically demonstrates a marked increase of uric acid over normative values, particularly if corrected for patient weight. However, 24-hour samples are notoriously difficult to collect. Calculation of the concentration ratio of urinary uric acid to creatinine in a spot urine specimen provides an alternative method, though less information is available concerning normative values. Hyperuricosuria is neither sensitive enough 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 with prognostic implications.
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 levels are typically normal.
Neuroimaging studies of the brain, by CT scan and MRI, generally do not reveal obvious structural malformations or signal changes in patients with Lesch-Nyhan disease.[2] They may reveal mild loss of brain volume, but this loss is often so small that it escapes notice in routine imaging studies. Quantitative MRI measurements reveal significant loss of brain volume in the basal ganglia and frontal cortex, sparing the occipital lobes and cerebellum.[13]
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.
Noninvasive imaging studies of the kidneys and other parts of the urogenital system are warranted because of the marked increase in the risk of 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 ultrasonography.
In Lesch-Nyhan disease, the gross overproduction of uric acid must be controlled to prevent the development of urologic or articular complications. The goal is to maintain uric acid levels in the normal range. A common error is to attempt to suppress uric acid below normal levels, but this approach risks the development of oxypurine stones instead.
The control of uric acid requires 2 important components: (1) inhibiting the metabolism of hypoxanthine and xanthine to uric acid with allopurinol and (2) generous hydration. 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.
In patients with Lesch-Nyhan disease, hospital admissions should be limited to those absolutely necessary for medical interventions, because moving these patients into an unfamiliar environment will exacerbate behavioral problems such as self-injury.
Protective devices such as straps or splints should be applied at all times to prevent self-injury; this includes nighttime sleeping periods and also during transfer for any tests. These devices should be viewed as protective devices (rather than restraints) that are permitted in hospitals for patients with developmental disorders. Most patients and families will request them and may become upset if they are removed.
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. Febuxostat is a newer option for patients who cannot tolerate allopurinol.
Despite the combined use of allopurinol and generous hydration, nephrolithiasis still may occur. Several medications are available to mitigate the severity of the neurologic 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 can also be helpful.
Management of behavioral problems
Management of the behavioral problems, 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 benzodiazepines. Neuroleptics are sometimes used when problems are particularly severe, although long-term use is discouraged because of side effects.
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 Lesch-Nyhan 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 is often required for management of the consequences of the neurologic 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.
Some studies have provided a promising suggestion that deep brain stimulation surgery may be useful for controlling both dystonia and self-injury.[14] 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.
Genetic counseling is essential for informing the family of the risk of additional children with the disorder.
Consultations with neurologists and physiatrists may be necessary for management of associated motor disorders, and consultations with psychiatrists or psychologists are nearly universally required for management of behavioral disorders associated with Lesch-Nyhan disease.
An orthopedist may be required for joint complications, as well as a urologist for management of kidney stones.
Most patients can be on 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.
Despite their profound motor handicap, most patients with Lesch-Nyhan disease prefer to remain actively engaged in their environments.
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.
Clinical Context:
Allopurinol controls hyperuricemia by blocking action of xanthine oxidase, which converts xanthine and hypoxanthine into uric acid. The dose is titrated to lower uric acid levels to a normal range.
Clinical Context:
Febuxostat is a potential alternative to allopurinol. Like allopurinol, febuxostat is a xanthine oxidase inhibitor that prevents uric acid production and lowers elevated serum uric acid levels. Unlike allopurinol, it is a thiazolecarboxylic acid derivative, not a purine base analog. Febuxostat physically blocks the channel to the molybdenum-pterin active site of xanthine oxidase and is metabolized by liver oxidation and glucuronidation.
Common adverse events include upper respiratory tract infections, arthralgias, diarrhea, headache, and liver function abnormalities. Atrioventricular block or atrial fibrillation in 5% and cholecystitis in 2% have also been reported.
Clinical Context:
Lorazepam is a sedative-hypnotic of the benzodiazepine class that has a rapid onset of effect and a relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter, it may depress all levels of the central nervous system (CNS), including the limbic system and reticular formations. Lorazepam is suitable for patients who need to be sedated for longer than 24 hours.
Agents from this class may mitigate the severity of the neurologic features of the disease. Benzodiazepines, such as diazepam or alprazolam, reduce severity and help attenuate anxiety that may indirectly exacerbate the extrapyramidal abnormalities. Additionally, adjunctive medications including benzodiazepines and gabapentin are sometimes useful for attenuating problem behaviors.
Clinical Context:
Gabapentin, a membrane stabilizer, is a structural analogue of the inhibitory neurotransmitter GABA, although, paradoxically, it is thought not to exert an effect on GABA receptors. It appears to exert its action via the alpha(2)delta1 and alpha(2)delta2 auxiliary subunits of voltage-gaited calcium channels. Gabapentin is used to manage pain and provide sedation in neuropathic pain.
Agents from this class may mitigate the severity of the neurologic features of the disease. Adjunctive medications, sometimes useful for attenuating problem behaviors, include gabapentin and benzodiazepines.
Clinical Context:
Baclofen may induce the hyperpolarization of afferent terminals and inhibit monosynaptic and polysynaptic reflexes at the spinal level.
Agents from this class may mitigate the severity of the neurologic features of the disease. Muscle relaxants are commonly used to treat muscle pain, but they must be used cautiously because of sedation and because of the addictive potential of some of the medications in this category of drugs.
H A Jinnah, MD, PhD, Professor, Departments of Neurology, Human Genetics, and Pediatrics, Emory University School of Medicine
Disclosure: Nothing to disclose.
Chief Editor
Amy Kao, MD, Attending Neurologist, Children's National Medical Center
Disclosure: Have stock (managed by a financial services company) in healthcare companies including Allergan, Cellectar Biosciences, CVS Health, Danaher Corp, Johnson & Johnson.
Acknowledgements
Robert J Baumann, MD Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine
Robert J Baumann, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, and Child Neurology Society
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Reference Salary Employment
References
Jinnah HA, Friedmann T. Lesch-Nyhan disease and its variants. 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.
NIH US National Library of Medicine. Lesch-Nyhan syndrome. Genetics Home Reference. Available at https://ghr.nlm.nih.gov/condition/lesch-nyhan-syndrome. Accessed: September 25, 2019.
Schretlen DJ, Varvaris M, Ho TE, Vannorsdall TD, Gordon B, Harris JC, et al. Regional Brain Volume Abnormalities in Lesch-Nyhan Disease and its Variants. Lancet Neurology. 2013.
The HPRT gene has 9 exons, with the coding region depicted as light gray boxes. Genetic mutations in Lesch-Nyhan disease and its variants 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).
A small portion of the lower lip has been disfigured by persistent self-biting.
The distal portions of several fingers are shortened by prior uncontrolled self-biting.
Purine metabolic pathways.
A small portion of the lower lip has been disfigured by persistent self-biting.
The distal portions of several fingers are shortened by prior uncontrolled self-biting.
The HPRT gene has 9 exons, with the coding region depicted as light gray boxes. Genetic mutations in Lesch-Nyhan disease and its variants 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).
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