Lesch-Nyhan Syndrome (LNS) By: Amir Sadafi and Bela Mohapatra

What is LNS?  LNS is a genetic disorder first discovered in 1964 by Michael Lesch and William Nyhan.  It is a recessive disease that is linked to the X chromosome  It is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT)

Symptoms of LNS  Urate crystal formations, which look like orange sand, are deposited in diapers of the babies  Kidney stones  Blood in the urine  Dysphagia (difficulty swallowing)  Swelling of the joints  Vomiting  Athetosis (uncontrolled spastic muscle movements of the arms and legs)  Involuntary writhing movements  Chorea (purposeless repetitive movements)  Moderate mental retardation  Irritability All of the following are a result of an overproduction of Uric Acid

Clinical Elements  Overproduction of Uric Acid - associated with hyperuricernia - can produce Nephrolithiasis (kidney stones) with renal failure and solid subcutaneous deposits (tophi)  Neurological disability - includes dystonia (abnormal firmness of tissue or muscle), choreoathetosis (abnormal movement of body), and occasional ballismus (jerky movement of arms or legs) - other signs include spasticity and hyperreflexia  Behavioral Elements - cognative disfunction and aggressive and impulsive behaviors -severe self injurious behavior is common

HPRT’s role in the body  Hypoxanthine-guanine phosphoribosyltransferase is an enzyme that plays a key role in the recycling of the purine bases, hypoxanthine, and guanine into purine nucleotide pools  Without HPRT the purine bases are broken down and excreted as uric acid  Since these purine bases cannot be reused, the production of purine bases is increased  Both of these together cause a significant overproduction of uric acid

Hyperuricemia  Hyperuricemia is an unusually high concentration of uric acid in the blood  Since the blood usually already has a high concentration of uric acid, the increased uric acid solidifies and deposits in the tissues forming tophi  The deposits in the joints cause inflammation and gouty arthritis  The kidneys excrete the extra uric acid, which increases risk of urate stones forming  The stones may pass as a sandy sludge or may obstruct urine flow  This increases the risk for hematuria and urinary tract infections

Statistics  Frequency: -Reported prevalence is 1 per 380,000  Mortality: -Few patients live beyond 40 years. -The drug allopurinol is used to control hyperuricernia. Most patients experience progressive dysphagia (difficulty swallowing) and die after pneumonia. -Also common is sudden unexpected death, even to patients in stable medical condition.  Race: -LNS effects most races with equal frequency.

LNS and Cerebral Palsy  “Cerebral palsy is a group of movement disorders that result from damage to the brain, either before, during or shortly after birth.”  Thus, LNS is often the cause of the damage to the brain that triggers cerebral palsy

Treatment and Prognosis  Treatment: -LNS itself cannot be treated -Only the symptoms of LNS can be treated. -The drug allopurinol may be used to control excessive amounts of uric acid. -Kidney stones can be treated with lithotripsy -There are unfortunately no treatments for the behavioral and neurological effects of LNS  Prognosis: -The prognosis for LNS is poor because there are no treatments for the neurological effects of the syndrome. -The build-up of excessive uric acid in the body causes painful episodes of self-mutilation and may result in severe retardation and death.

X-Linked Recessive Inheritance

Bibliography  alpalsy.htm alpalsy.htm  0.htm 0.htm  _nyhan/lesch_nyhan.htm _nyhan/lesch_nyhan.htm  rses/genet371b- aut00/public_html/problems/371B_practic e_key_02.html rses/genet371b- aut00/public_html/problems/371B_practic e_key_02.html