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Lesch-Nyhan Disease

  • Author: H A Jinnah, MD, PhD; Chief Editor: Amy Kao, MD  more...
 
Updated: Dec 14, 2015
 

Background

Michael Lesch and William Nyhan provided the first detailed clinical description of Lesch-Nyhan disease in 1964.[1] The enzymatic defect associated with Lesch-Nyhan disease, deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), was discovered by Seegmiller and colleagues in 1967. The gene encoding the human enzyme was cloned and sequenced by Friedmann and colleagues in 1985.

Lesch-Nyhan disease is a genetic disorder associated with 3 major clinical elements: overproduction of uric acid, neurologic disability, and behavioral problems.[2] 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.[3] The behavioral problems include intellectual disability (mental retardation) 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.[4] 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.

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Pathophysiology

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).

Purine metabolic pathways. 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.[2]

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.[5] 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. Neuropathologic studies suggest a neurodevelopmental defect, with no signs of a degenerative process.[3] However, the mechanism by which HPRT deficiency influences the basal ganglia, and particularly the dopamine systems, remains unknown.

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Etiology

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]

The HPRT gene has 9 exons, with the coding region 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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Epidemiology

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.

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.

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Prognosis

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.[9]

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.[9]

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Patient Education

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.[10, 11]

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.

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Contributor Information and Disclosures
Author

H A Jinnah, MD, PhD Professor, Departments of Neurology, Human Genetics, and Pediatrics, Emory University School of Medicine

H A Jinnah, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, International Parkinson and Movement Disorder Society, Society for Neuroscience

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD Attending Neurologist, Children's National Medical Center

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, Child Neurology Society

Disclosure: Have stock from Cellectar Biosciences; have stock from Varian medical systems; have stock from Express Scripts.

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
  1. Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med. 1964 Apr. 36:561-70. [Medline].

  2. 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.

  3. Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain. 2006 May. 129(Pt 5):1201-17. [Medline].

  4. Jinnah HA, Ceballos-Picot I, Torres RJ, Visser JE, Schretlen DJ, Verdu A, et al. Attenuated variants of Lesch-Nyhan disease. Brain. 2010 Feb 22. [Medline]. [Full Text].

  5. Visser JE, Bar PR, Jinnah HA. Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev. 2000 Apr. 32(2-3):449-75. [Medline].

  6. 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. 2000 Oct. 463(3):309-26. [Medline].

  7. Fu R, Jinnah HA. Genotype-Phenotype Correlations in Lesch-Nyhan Disease: Moving Beyond the Gene. J Biol Chem. 2011 Dec 7. [Medline].

  8. Fu R, Ceballos-Picot I, Torres RJ, Larovere LE, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2013 Aug 22. [Medline].

  9. Neychev VK, Jinnah HA. Sudden death in Lesch-Nyhan disease. Dev Med Child Neurol. 2006 Nov. 48(11):923-6. [Medline].

  10. Alford RL, Redman JB, O'Brien WE, et al. Lesch-Nyhan syndrome: carrier and prenatal diagnosis. Prenat Diagn. 1995 Apr. 15(4):329-38. [Medline].

  11. Nyhan WL, Vuong LU, Broock R. Prenatal diagnosis of Lesch-Nyhan disease. Prenat Diagn. 2003 Oct. 23(10):807-9. [Medline].

  12. 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.

  13. Deon LL, Kalichman MA, Booth CL, Slavin KV, Gaebler-Spira DJ. Pallidal Deep-Brain Stimulation Associated With Complete Remission of Self-injurious Behaviors in a Patient With Lesch-Nyhan Syndrome: A Case Report. J Child Neurol. 2011 Sep 22. [Medline].

 
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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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