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LESCH-NYHAN SYNDROME
Lesch-Nyhan syndrome is a condition that occurs almost exclusively in males. It is characterized by neurological and behavioral abnormalities and the overproduction of uric acid. Uric acid is a waste product of normal chemical processes and is found in blood and urine. Excess uric acid can be released from the blood and build up under the skin and cause gouty arthritis (arthritis caused by an accumulation of uric acid in the joints). Uric acid accumulation can also cause kidney and bladder stones.

The nervous system and behavioral disturbances experienced by people with Lesch-Nyhan syndrome include abnormal involuntary muscle movements, such as tensing of various muscles (dystonia), jerking movements (chorea), and flailing of the limbs (ballismus). People with Lesch-Nyhan syndrome usually cannot walk, require assistance sitting, and generally use a wheelchair. Self-injury (including biting and head banging) is the most common and distinctive behavioral problem in individuals with Lesch-Nyhan syndrome.

METABOLIC PATHWAY-SALVAGE PATHWAY

 * A salvage pathway is a pathway in which nucleotides (purine and pyrimidine) are synthesized from intermediates in the degradative pathway for nucleotides.
 * Salvage pathways are used to recover bases and nucleosides that are formed during degradation of RNA and DNA. This is important in some organs because some tissues cannot undergo de novo synthesis.HPRT metabolism.jpg
 * Phosphoribosyltransferases add activated ribose-5-phosphate (Phosphoribosyl pyrophosphate, PRPP) to bases, creating nucleoside monophosphates. There are two types of phosphoribosyltransferases: adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT). It is an important enzyme in Purine pathway metabolism.[1] It is also involved in Lesch-Nyhan syndrome associated with a deficiency of HGPRT.
 * The salvaged bases and nucleosides can then be converterd back into nucleotides.
 * Defect in the salvage pathway leads to this syndrome.

GENETIC CHANGES AND ENZYMATIC DEFECT:

 * 1) Mutations in the HPRT1 gene cause Lesch-Nyhan syndrome. The HPRT1 gene provides instructions for making an enzyme called hypoxanthine phosphoribosyltransferase 1. This enzyme is responsible for recycling purines, a type of building block of DNA and its chemical cousin RNA. Recycling purines ensures that cells have a plentiful supply of building blocks for the production of DNA and RNA.
 * 2) HPRT1 gene mutations that cause Lesch-Nyhan syndrome result in a severe shortage (deficiency) or complete absence of hypoxanthinephosphoribosyltransferase 1. When this enzyme is lacking, purines are broken down but not recycled, producing abnormally high levels of uric acid.
 * 3) For unknown reasons, a deficiency of hypoxanthine phosphoribosyltransferase 1 is associated with low levels of a chemical messenger in the brain called dopamine. Dopamine transmits messages that help the brain control physical movement and emotional behavior, and its shortage may play a role in the movement problems and other features of this disorder. However, it is unclear how a shortage of hypoxanthine phosphoribosyltransferase 1 causes the neurological and behavioral problems characteristic of Lesch-Nyhan syndrome.
 * 4) Some people with HPRT1 gene mutations produce some functional enzyme. These individuals are said to have Lesch-Nyhan variant. The signs and symptoms of Lesch-Nyhan variant are often milder than those of Lesch-Nyhan syndrome and do not include self-injury.

FREQUENCY
The prevalence of Lesch-Nyhan syndrome is approximately 1 in 380,000 individuals. This condition occurs with a similar frequency in all populations.

INHERITANCE PATTERN
This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

DIAGNOSIS/TESTING
A urinary urate-to-creatinine ratio greater than 2.0, indicating uric acid overproduction (hyperuricemia), is a characteristic for children younger than age ten years who have Lesch-Nyhan syndrome. However, neither hyperuricuria nor hyperuricemia (serum uric acid concentration >8 mg/dL) is sensitive or specific enough for diagnosis. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme activity less than 1.5% of normal in cells from any tissue (e.g., blood, cultured fibroblasts, lymphoblasts) is diagnostic. HPRT1 is the only gene known to be associated with Lesch-Nyhan syndrome.

MANAGEMENT
Treatment of manifestations: Control of overproduction of uric acid with allopurinol reduces the risk for nephrolithiasis, urate nephropathy, gouty arthritis, and tophi but has no effect on behavioral and neurologic symptoms; treatment of renal stones may require lithotripsy or surgery. Baclofen or benzodiazepines for spasticity; physical, behavioral, psychiatric, protective equipment to reduce complications from self-injury and other deleterious behaviors.