Lesch-Nyhan syndrome

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Lesch-Nyhan Syndrome

 

Definition

Lesch-Nyhan syndrome, which is also known as HPRT deficiency or Kelley-Seegmiller syndrome, is a rare genetic disorder that affects males. Males with this syndrome develop physical handicaps, mental retardation, and kidney problems. It is caused by a total absence of a key enzyme that affects the level of uric acid in the body. Self-injury or self-mutilation is a distinctive feature of this genetic disease.

Description

Lesch-Nyhan syndrome was first described in 1964 by Drs. Michael Lesch and William Nyhan. The enzyme deficiency that causes the disorder was discovered in 1967 by a researcher named Seegmiller. The syndrome is caused by a severe change (mutation) in a gene that encodes an enzyme known as hypoxanthine-guanine phosphoribosyl transferase, or HPRT. This gene was identified and sequenced by Friedmann and colleagues in 1985. HPRT catalyzes a reaction that is necessary to prevent the buildup of uric acid, a nitrogenous waste product that is ordinarily excreted from the body through the kidneys. 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, however, 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.
Lesch-Nyhan syndrome affects approximately one in 380,000 live births. It occurs evenly among races. Almost always, only male children are affected, although a few cases of the disorder in girls have been reported. Women carriers usually do not have any symptoms. Women carriers can occasionally develop inflammation of the joints (gout) as they get older.

Causes and symptoms

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 between families. The HPRT gene is located on the X chromosome. Since the HPRT gene is located on the X chromosome, Lesch-Nyhan syndrome is considered X-liked. 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 to be 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 any 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.
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 the child's symptoms, most commonly involuntary muscle movements or failure to crawl and walk at the usual ages. In some cases the first symptom is related to overproduction of uric acid; the parents notice "orange sand" in the child's diapers. The "sand" is actually crystals of uric acid tinged with blood.
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 confirming the diagnosis and also when the child's 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

There are no known treatments for the neurological defects of Lesch-Nyhan. Allopurinol (Aloprim, Zyloprim), a drug usually prescribed to lower the risk of gout attacks, can lower blood uric acid levels. This medication is a preventive; it does not correct many of the symptoms of Lesch-Nyhan. Other drugs that are given to manage spasticity include baclofen (Lioresal), which is a muscle relaxant, and benzodiazepine tranquilizers.
Some patients with Lesch-Nyhan syndrome have their teeth removed to prevent self-injury. Restraints may be recommended to reduce self-destructive behaviors, although some patients can be managed with a combination of behavioral modification therapy and medications.

Prognosis

With strong supportive care, infants born with Lesch-Nyhan can live into adulthood with symptoms continuing throughout life. Few live beyond 40, however, with death usually resulting either from kidney failure or from aspiration pneumonia. Sudden unexpected death from respiratory failure is common in these patients.
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.

Key terms

Amniocentesis — A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman's abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.
Athetosis — A condition marked by slow, writhing, involuntary muscle movements.
Basal ganglia — A section of the brain responsible for smooth muscular movement.
Chorea — Involuntary, rapid, jerky movements.
Chorionic villus sampling (CVS) — A procedure used for prenatal diagnosis at 10-12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother's vagina or abdominal wall and a sample of cells is collected from around the early embryo. These cells are then tested for chromosome abnormalities or other genetic diseases.
Enzyme — A protein that catalyzes a biochemical reaction or change without changing its own structure or function.
Mutation — A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.
Neurotransmitter — Chemical in the brain that transmits information from one nerve cell to another.
Palsy — Uncontrolable tremors.
Spasticity — Increased mucle tone, or stiffness, which leads to uncontrolled, awkward movements.

Resources

Books

Beers, Mark H., MD, and Robert Berkow, MD., editors. "Cerebral Palsy Syndromes." In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.
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

Jinnah, Hyder, MD, PhD. "Lesch-Nyhan Syndrome." eMedicine January 25, 2002. http://www.emedicine.com/neuro/topic630.htm.
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.
Willers, I. "Germline Mosaicism Complicates Molecular Diagnosis of Lesch-Nyhan Syndrome." Prenatal Diagnosis 24 (September 2004): 737-740.

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.
International Lesch-Nyhan Disease Association. 114 Winchester Way, Shamong, NJ 08088-9398. (215) 677-4206.
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). 55 Kenosia Avenue, P. O. Box 1968, Danbury, CT 06813-1968. (203) 744-0100. Fax: (203) 798-2291. http://www.rarediseases.org.

Other

GeneClinics. http://www.geneclinics.org/profiles/lns/details.html.
Pediatric Database(PEDBASE). 〈http://www.icondata.com/health/pedbase/files/LESCH-NY.HTM〉.

Lesch-Nyhan syndrome

 
a hereditary disorder of purine metabolism transmitted as an X-linked recessive trait with physical and mental retardation, compulsive self-mutilation of fingers and lips by biting, choreoathetosis, spastic cerebral palsy, and impaired renal function.

Lesch-Ny·han syn·drome

(lesh-nī'han), [MIM*300322]
a disorder of purine metabolism due to deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT); characterized by hyperuricemia, uric acid renal stones, mental retardation, spasticity, choreoathetosis, and self-mutilation of fingers and lips by biting; X-linked inheritance, caused by mutation in the HPRT gene on Xq.

Lesch-Nyhan syndrome

[lesh′ nī′han]
Etymology: Michael Lesch, American pediatrician, b. 1939; William L. Nyhan, Jr., American pediatrician, b. 1926
a hereditary disorder of purine metabolism, characterized by mental retardation, self-mutilation of the fingers and lips by biting, impaired renal function, and abnormal physical development. It is transmitted as a recessive, sex-linked trait.

Lesch-Nyhan syndrome

An X-R condition caused by a deficiency of 24 kD hypoxanthine-guanine phosphoribosyl transferase, with accumulation of uric acid crystals in renal pelvis and bladder, pseudo-gouty arthritis, erosive changes of fingertips, compulsive self-mutilation, choreoathetosis, mental retardation Lab ↑ Oxypurines, hypoxanthine, xanthine in CSF due to purine overload

Lesch-Ny·han syn·drome

(LNS) (lesh nī'ăn sin'drōm)
Complete inborn deficiency of enzyme hypoxanthine phosphoribosyltransferase in purine metabolism pathway; causes mental retardation, self-mutilation, choreoathetosis, and hyperuricemia. Invariably fatal in childhood.

Lesch-Nyhan syndrome

A rare X-linked recessive disease of male children in which a severe over-production of uric acid causes gout, CEREBRAL PALSY, mental retardation, CHOREA and compulsive self-mutilating biting. The disease is due to a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase. (Michael Lesch, American cardiologist, b. 1939, and William Leo Nyhan, American paediatrician, b. 1926).

Lesch-Nyhan syndrome

an INBORN ERROR OF METABOLISM characterized by an enzyme deficiency expressed by spasticity, mental deficiency and problems of self-mutilation.

Lesch,

Michael, U.S. pediatrician, 1939–.
Lesch-Nyhan syndrome - a genetic disorder marked by choreoathetosis, mental retardation, and self-mutilation.

Nyhan,

William Leo, U.S. pediatrician, 1926–.
Lesch-Nyhan syndrome - see under Lesch
Sakati-Nyhan syndrome - see under Sakati
Sakati-Nyhan-Tisdale syndrome - Synonym(s): Sakati-Nyhan syndrome

Lesch-Ny·han syn·drome

(lesh nī'ăn sin'drōm) [MIM*300322]
Disorder of purine metabolism characterized by hyperuricemia, uric acid renal stones, mental retardation, spasticity, choreoathetosis, and self-mutilation of fingers and lips by biting.

Lesch-Nyhan syndrome

(lesh-nī´ən),
n.pr a hereditary disorder of purine metabolism, characterized by mental retardation, self-mutilation of the fingers and lips by biting, impaired renal function, and abnormal physical development. It is transmitted as a recessive, sex-linked trait.
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