Lesch-Nyhan Syndrome (LNS)

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

2. 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)

3. 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 Symptoms of LNS All of the following are a result of an overproduction of Uric Acid

4. 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

5. 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

6. 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

7. 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.

8. 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

9. 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.

10. X-Linked Recessive Inheritance

11. Bibliography • http://www.guidinghands.org/faqs/cerebralpalsy.htm • http://www.emedicine.com/neuro/topic630.htm • http://www.ninds.nih.gov/disorders/lesch_nyhan/lesch_nyhan.htm • http://depts.washington.edu/genetics/courses/genet371b-aut00/public_html/problems/371B_practice_key_02.html