Lesch-Nyhan syndrome was first described in 1964 by Dr. Michael Lesch and Dr. William Nyhan. The syndrome is caused by a severe change (mutation) in the HPRT gene. This gene is responsible for the production of the enzyme called hypoxanthine-guanine phosphoribosyltransferase (HPRT). HPRT catalyzes a reaction that is necessary to prevent the buildup of uric acid. A severe mutation in the HPRT gene leads to an absence of HPRT enzyme activity which, in turn, leads to markedly elevated uric acid levels in the blood (hyperuricemia). This buildup of uric acid is toxic to the body and is related to the symptoms associated with the disease. Absence of the HPRT enzyme activity is also thought to alter the chemistry of certain parts of the brain, such as the basal ganglia, affecting neurotransmitters (chemicals used for communication between nerve cells), acids, and other chemicals. This change in the nervous system is also related to the symptoms associated with Lesch-Nyhan syndrome.
Males with Lesch-Nyhan syndrome develop neurologic problems during infancy. Infants with Lesch-Nyhan syndrome have weak muscle tone (hypotonia) and are unable to develop normally. Affected males develop uncontrollable writhing movements (athetosis) and muscle stiffness (spasticity) over time. Lack of speech is also a common feature of Lesch-Nyhan syndrome. The most dramatic symptom of Lesch-Nyhan syndrome is the compulsive self-injury seen in 85% of affected males. This self injury involves the biting of their own lips, tongue, and finger tips, as well as head banging. This behavior leads to serious injury and scarring.
Genetic profile
Severe changes (mutations) in the HPRT gene completely halt the activity of the enzyme HPRT. There have been many different severe mutations identified in the HPRT gene. These mutations may be different within
families. Since the HPRT gene is located on the X chromosome, Lesch-Nyhan syndrome is considered an X-linked disorder. This means that it only affects males.
A person's sex is determined by their chromosomes. Males have one X chromosome and one Y chromosome. Females, on the other hand, have two X chromosomes. Males who possess a severe mutation in their HPRT gene will develop Lesch-Nyhan syndrome. Females who possess a severe mutation in their HPRT gene will not; they are considered carriers. This is because females have another X chromosome without the mutation that prevents them from getting this disease. If a woman is a carrier, she has a 50% risk with each pregnancy to pass on her X chromosome with the mutation. Therefore, with every male pregnancy she has a 50% risk to have an affected son, and with every female pregnancy she has a 50% risk to have a daughter who is a carrier.
Demographics
Lesch-Nyhan syndrome affects approximately one in 380,000 live births. It occurs evenly among races. Almost always, only male children are affected. Women carriers usually do not have any symptoms. Women carriers can occasionally develop inflammation of the joints (gout)as they get older.
Signs and symptoms
At birth, males with Lesch-Nyhan syndrome appear completely normal. Development is usually normal for the first few months. Symptoms develop between three to six months of age. Sand-like crystals of uric acid in the diapers may be one of the first symptoms of the disease. The baby may be unusually irritable. Typically, the first sign of nervous system impairment is the inability to lift their head or sit up at an appropriate age. Many patients with Lesch-Nyhan will never learn to walk. By the end of the first year, writhing motions (athetosis), and spasmodic movements of the limbs and facial muscles (chorea) are clear evidence of defective motor development.
The compulsive self-injury associated with Lesch-Nyhan syndrome begins, on average, at three years. The self-injury begins with biting of the lips and tongue. As the disease progresses, affected individuals frequently develop finger biting and head banging. The self-injury can increase during times of stress.
Males with Lesch-Nyhan disease may also develop kidney damage due to kidney stones. Swollen and tender joints (gout) is another common problem.
Diagnosis
The diagnosis of Lesch-Nyhan syndrome is based initially on the distinctive pattern of symptoms. Measuring the amount of uric acid in a person's blood or urine can not definitively diagnose Lesch-Nyhan syndrome. It is diagnosed by measuring the activity of the HPRT enzyme through a blood test. When the activity of the enzyme is very low it is diagnostic of Lesch-Nyhan syndrome. It can also be diagnosed by DNA testing. This is also a blood test. DNA testing checks for changes (mutations) in the HPRT gene. Results from DNA testing are helpful in making the diagnosis and also if the family is interested in prenatal testing for future pregnancies.
Prenatal diagnosis is possible by DNA testing of fetal tissue drawn by amniocentesis or chorionic villus sampling (CVS). Fetuses should be tested if the mother is a carrier of a change (mutation) in her HPRT gene. A woman is at risk of being a carrier if she has a son with Lesch-Nyhan syndrome or someone in her family has
Lesch-Nyhan syndrome. Any woman at risk of being a carrier should have DNA testing through a blood test.
Treatment and management
There are no known treatments for the neurological defects of Lesch-Nyhan. The medication Allopurinol can lower blood uric acid levels. This medication does not correct many of the symptoms. Some patients with Lesch-Nyhan syndrome have their teeth removed to prevent self-injury. Restraints are recommended to reduce self-destructive behaviors.
Prognosis
With strong supportive care, infants born with Lesch-Nyhan can live into adulthood with symptoms continuing throughout life.
At present, there are no preventive measures for Lesch-Nyhan syndrome. However, recent studies have indicated that this genetic disorder may be a good candidate for treatment with gene replacement therapy. Unfortunately, the technology necessary to implement this therapy has not yet been perfected.
BOOKS
Jinnah, H.A., and Theodore Friedmann. "Lesch-Nyhan Disease and Its Variants." The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001.
PERIODICALS
Lesch, M., and W.L. Nyhan. "A Familial Disorder of Uric Acid Metabolism and Central Nervous System Function." American Journal of Medicine 36 (1964): 561–570.
Mak, B.S., et al. "New Mutations of the HPRT Gene in Lesch-Nyhan Syndrome." Pediatric Neurology (October 2000): 332–335.
Visser, J.E., et al. "Lesch-Nyhan Disease and the Basal Ganglia." Brain Research Reviews (November 1999): 450–469.
ORGANIZATIONS
Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. <http://www.geneticalliance.org>.
Lesch-Nyhan Syndrome Registry. New York University School of Medicine, Department of Psychiatry, 550 First Ave., New York, NY 10012. (212) 263-6458.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
