Deepu Nair

Lesch-Nyhan Syndrome

What is the Lesch-Nyhan Syndrome?

“Lesch-Nyhan syndrome (LNS) is a rare (only 1 in 380,000 people have it), inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT).” – NINDS (NIH)

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What is the Lesch-Nyhan syndrome

It is often characterized by the overproduction of Uric Acid in the body.

Uric acid is created as the final product of purine metabolism.

Uric acid may be found in human blood or urine.

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What is the Lesch-Nyhan syndrome

Neurological disability and behavioral problems are also characteristic of the Lesch-Nyhan syndrome.

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What are the symptoms?Overproduction of

uric acid may cause gouty arthritis, kidney stones and bladder stones. It also results in sandy diapers (uric acid crystals).

Basillimus (violent flinging movement of limbs)

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What are the symptomsMay have difficulty

walking, may need assistance. A good number of Lesch-Nyhan afflicted are wheel chair bound.

Moderate mental retardation

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What are the symptomsAggressive and

impulsive behaviors (including self-injurious behavior, behavior that may injure others, profane language, and sexually charged language)

Spasticity, dystonia (involuntary spasms and muscle contraction)

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What are the symptomsSpeech impairmentBlood in urine,

painful urinationPain and swelling in

the joints

Difficulty swallowing and eating

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What are the symptomsVomitingImpaired kidney

function

Irritability

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Interesting facts

Unlike a lot of genetically inherited disorders, the Lesch-Nyhan syndrome occurs in all ethnicities with about the same frequency.

Historical backgroundThe Lesch-Nyhan

syndrome was discovered by Michael Lesch and William “Bill” Nyhan when they met two brothers afflicted by hyperuricemia.

They published their findings in 1964 about the brothers aged 4 and 8.

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Historical background

In 1967 (three years after discovery), the cause of the Lesch-Nyhan syndrome was identified by Edwin Seegmiller and William Kelley.

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Chromosome involvedThe Lesch-Nyhan

syndrome is found on the X-chromosome.

Thus it is found in the larger of the two chromosomes on the 23rd pair of chromosomes.

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Gene involvedMutations in the

HPRT1 (hypoxanthine phosphoribosyltransferase 1) gene causes the Lesch-Nyhan syndrome.

More than 200 mutations in the X-chromosome can cause the Lesch-Nyhan syndrome.

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Locus of GeneThe cytogenic

location of the HPRT1 gene is Xq26.1 (long arm of the X-chromosome at position 26.1).

It is located on base pairs 133, 421, 922 to 133, 462,361 on the X-chromosome.

How do people inherit the Lesch-Nyhan syndrome

The Lesch-Nyhan Syndrome is inherited genetically by an X chromosome linked recessive pattern.

Thus, the Lesch-Nyhan syndrome is more common in males than in females

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DiagnosisThe Lesch-Nyhan

syndrome can easily be diagnosed through many ways. It can be diagnosed either genetically, through observing sand-like crystals in the child’s diapers, or through observing high levels of uric acid in the blood.

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PrognosisThe prognosis for

people affected by the Lesch-Nyhan syndrome isn’t very positive.

Most people affected by the Lesch-Nyhan syndrome die within the first one or two decades due to renal failure.

Cure?Currently the Lesch-

Nyhan syndrome doesn’t have a cure for adults.

The Lesch-Nyhan syndrome can be cured in vitro though.

Though the syndrome itself can’t be cured, there is a treatment for the Lesch-Nyhan syndrome.

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TreatmentSince there is no

cure to the Lesch-Nyhan syndrome, the treatment of the condition is purely symptomatic.

Allopurinol may be used to control gouty arthritis . Allopurinol also lowers the level of uric acid in the body.

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TreatmentIn order to treat the

kidney or bladder stones, lithotripsy (a non-invasive form of treatment that uses high intensity acoustic pulses) may be used.

Carbidopa, diazepam, and phenobarbital, haloperidol may be used to alleviate immediate behavioral issues.

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TreatmentThe spasticity can be

treated by baclofens and benzodiazepines.

In order to avoid self-mutilation restraints are used.

Unfortunately there’s no existing solution for the involuntary motor movements of Lesch-Nyhan patients.

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Potential cures being exploredIn studies conducted

with both “deep brain stimulation treatment “and “S-adenosyl methionine treatment”, a major improvement in the neurobehavioral condition of patients was observed.

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Potential cures being exploredTherapy through

creating Induced pluripotent Stem cells from the somatic cells of the patient and then using them for research.

Gene targeting the concerned gene and rectifying the disorder.

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Resources Used Augoustides-Savvopoulou et al, P. (2009, July). Partial

Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency as the unsuspected cause of renal disease spanning three generations: a cuationary tale. Retrieved July 23, 2009, from Journal of the American Academy of Pediatrics Web site: http://pediatrics.aappublications.org/cgi/reprint/109/1/e17 (Augoustides-Savvopoulou, 2009)

Callahan, G N. (2005, February). First Self. Emerging Infectious Diseases Journal, 11, Retrieved July 13, 2005, from http://www.cdc.gov/ncidod/eid/vol11no02/333.htm (Callahan, 2005)

Glick, Norris (2006, August). Dramatic reduction in self-injury in lesch-nyhan disease following S-adenosylmethionine administration. Retrieved July 23, 2009, from Springer Link Home Web site: http://www.springerlink.com/content/6697j71366636878/fulltext.pdf

Jinnah, H A (2009. April). Lesch-Nyhan disease: from mechanism to model and back again. Retrieved July 23, 2009, from Disease models and mechanisms Web site: http://dmm.biologists.org/content/2/3-4/116.full?maxtoshow=&HITS=&hits=&RESULTFORMAT=&fulltext=lesch-nyhan&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

NIH, (2009, July). HPRT1. Retrieved July 23, 2009, from National Institutes of Health Web site: http://ghr.nlm.nih.gov/gene=hprt1

NIH, (2009, July). Lesch-Nyhan Syndrome. Retrieved July 23, 2009, from National Institutes of Health Web site: http://ghr.nlm.nih.gov/condition=leschnyhansyndrome

NIH, (2009). Lesch-Nyhan Syndrome. Retrieved July 23, 2009, from National Institutes of Health Web site: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.298

NIH, (2007, February). Lesch-Nyhan Syndrome Information page. Retrieved July 23, 2009, from National Institutes of Health Web site: http://www.ninds.nih.gov/disorders/lesch_nyhan/lesch_nyhan.htm

Nyhan, W L. (2000, June). Dopamine Function in Lesch-Nyhan disease. Retrieved July 23, 2009, from PubMed Central Homepage Web site: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1637829&blobtype=pdf

Nyhan, W L (1997). The recognition of Lesch – Nyhan syndrome as an inborn error of purine metabolism. Retrieved July 23, 2009, from Springer Link Home Web site: http://www.springerlink.com/content/h08t61073t623565/fulltext.pdf

Richard, P (2007, August). An error in the code. Retrieved July 23, 2009, from The New Yorker Web site: http://www.newyorker.com/reporting/2007/08/13/070813fa_fact_preston

Seegmiller, JE (1967). Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Retrieved July 23, 2009, from Science Magazine Web site: http://www.sciencemag.org/cgi/reprint/155/3770/1682

Ye et al., L (2009, April). Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases. Retrieved July 23, 2009, from Proceedings of the National Academy of Sciences Web site: http://www.pnas.org/content/106/24/9826.full?maxtoshow=&HITS=&hits=&RESULTFORMAT=1&andorexacttitle=and&fulltext=lesch-nyhan&andorexactfulltext=and&searchid=1&FIRSTINDEX=10&sortspec=relevance&fdate=1/1/2009&resourcetype=HWCIT