Uric Acid MoleculeThe interaction of mRNA in a eukaryote cell.The exon portion of a DNA strand encodes a specific portion of a protein. In some organisms exons are situated between introns which are spliced from the strand before it is exported from the nucleus and do not code for protein parts.
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Lesch-Nyhan syndrome

Lesch-Nyhan syndrome (LNS) is a rare, inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). LNS is an X-linked recessive disease: the gene is carried by the mother and passed on to her son. LNS is present at birth in baby boys. Patients have severe mental and physical problems throughout life. The lack of HPRT causes a build-up of uric acid in all body fluids, and leads to symptoms such as severe gout, poor muscle control, and moderate mental retardation, which appear in the first year of life. A striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting, that begin in the second year of life. more...

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Abnormally high uric acid levels can cause sodium urate crystals to form in the joints, kidneys, central nervous system and other tissues of the body, leading to gout-like swelling in the joints and severe kidney problems. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington's disease. The direct cause of the neurological abnormalities remains unknown. Because a lack of HPRT causes the body to poorly utilize vitamin B12, some boys may develop a rare disorder called megaloblastic anemia.

The symptoms caused by the buildup of uric acid (arthritis and renal symptoms) respond well to treatment with drugs such as allopurinol that reduce the levels of uric acid in the blood. The mental deficits and self-mutilating behavior do not respond to treatment. There is no cure, but many patients live to adulthood.

LNS is rare, affecting about one in 380,000 live births. It was first described in 1964 by Dr. Michael Lesch and Dr. William Nyhan.


LNS is characterized by three major hallmarks: neurologic dysfunction, cognitive and behavioral disturbances, as well as uric acid overproduction (hyperuricemia). Some may also be afflicted with anemia (macrocytic). Virtually all patients are male, and male victims suffer delayed growth and puberty, and most develop shrunken testicles or testicular atrophy. Female carriers are at an increased risk for gouty arthritis, but are usually otherwise unaffected.

Overproduction of uric acid

One of the first symptoms of the disease is the presence of sand-like crystals of uric acid in the diapers of the affected infant. Overproduction of uric acid may lead to the development of uric acid crystals or stones in the kidneys, ureters, or bladder. Such crystals deposited in joints later in the disease may produce gout-like arthritis, with swelling and tenderness.

The overproduction of uric acid is present at birth, but may not be recognized by routine clinical laboratory testing methods. The serum uric acid concentration is often normal, as the excess purines are promptly eliminated in the urine. The crystals usually appear as an orange grainy material, or they may coalesce to form either multiple tiny stones, or distinct large stones that are difficult to pass. The stones, or calculi, usually cause hematuria (blood in the urine) and increase the risk of urinary tract infection. Some victims suffer kidney damage due to such kidney stones. Stones may be the presenting feature of the disease, but can go undetected for months or even years.

Nervous system impairment

The periods before and surrounding birth are typically normal in individuals with LNS. The most common presenting features are abnormally decreased muscle tone (hypotonia) and developmental delay, which are evident by three to six months of age. Affected individuals are late in sitting up, while most never crawl or walk. Lack of speech is also a very common trait associated with LNS.

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New avenues for LNS gene transfer - Lesch-Nyhan syndrome
From Science News, 6/20/87 by Karen Hartley

New avenues for LNS gene transfer

Lesch-Nyhan syndrome (LNS) sitshigh on the heap of most likely candidates for the first human gene transfer therapy. A neurologic disorder, LNS is the result of a single mutated gene that codes for a protein known as hypoxanthine phosphoribosyltransferase (HPRT). And restoring just 1 percent of normal HPRT levels may be enough to reduce a patient's LNS symptoms from compulsive self-mutilation to those of but a simple case of gout.

Gene therapy involves inserting a normalgene that will synthesize the needed product in order to correct a genetic or acquired disease. Of the two types of gene therapy, most research is concentrated on somatic-cell transfer, which targets the synthesis of the cell and affects only the patient. The other type, germ-cell transfer, enables the patient to pass the new gene to offspring.

Much of the work toward achievingsomatic-cell transfer in humans with LNS has been done using retroviruses, which are viruses that use RNA and synthesize it into DNA, in a process called reverse transcription. Through this method, an RNA gene coded with HPRT is transcribed into DNA and integrated into the host chromosomal DNA.

But one team of researchers now thinkswhat will be needed to correct LNS is a viral transfer that uses DNA rather than RNA. Led by Thomas D. Palella and William N. Kelley, researchers at the University of Michigan in Ann Arbor suggest that using the herpes simplex virus type 1 (HSV-1) will aid the transfer and expression of HPRT in deficient neuronal cells. Palella presented his findigns last week at the American Rheumatism Association meeting in Washington, D.C.

Part of the reason the team chose thiscarrier virus, or vector, says Palella, is because it will go directly to the central nervous system, whereas retroviruses cannot be directed there. In addition, retroviruses require replicating cells for integration, and cells in the central nervous system do not replicate. HSV-1, which is the type of herpes associated with cold sores, infects a cell by crawling up the cell's axon and harboring in the cell until activated. Because HSV-1 is incurable, researchers would somehow have to rid it of its disease effects before using it in gene transfer therapy.

The group, which has submitted itsfindings to a scientific journal for review, reports success in survival of human HPRT genes cloned in HSV-1 and transferred into rat neuronal cells. To make the recombinant virus, researchers took the thymidine kinase gene from the HSV-1 genome and cloned it with HPRT. The recombinant virus then successfully infected all cells receiving it. After 20 and 30 hours, the infected rat cells showed HPRT activity at levels comparable to those seen in a naturally occurring HPRT cell line.

Because herpes is a disease-causingvirus, rat cells responded by killing 80 percent of the naturally occurring herpes viral vectors infecting them. In contrast, 80 percent of the recombinant viral vectors were still alive in the rat cells after 30 hours, although researchers had done nothing to alter the disease effects of HSV-1. Part of this, Palella says, may be because interrupting the thymidine kinase chain automatically limits the disease effects of the HSV-1 genome.

Palella and his colleagues would likenext to insert HPRT into other viral genes in the HSV-1 genome to see how well the genes express the HPRT. The researchers also are looking into integrating promoters into a gene and then administering certain metals or steriods to help regulate levels of HPRT expression.

Palella emphasizes that his team's reportis preliminary and that there are many hurdles to overcome before HPRT gene transfer in humans can be realized. "In the gene transfer world, we're swimming upstream,' says Palella, "or at least against the current.'

COPYRIGHT 1987 Science Service, Inc.
COPYRIGHT 2004 Gale Group

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