Information on the following diseases can be found in the Related Disorders section of this report:

• Cerebral Palsy
• Familial Dysautonomia
• Gout
• Megaloblastic Anemia
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The symptoms of Lesch-Nyhan syndrome usually become apparent between the ages of three and six months. Urate crystal formation, due to abnormally increased levels of uric acid in the urine, may lead to the presence of orange colored crystal-like deposits ("orange sand") in the diapers of infants with this disorder. This is frequently the first symptom of Lesch-Nyhan syndrome.

Urate stones may develop in the kidneys of infants with Lesch-Nyhan syndrome as a result of excessive levels of uric acid that is converted into sodium urate crystals. These crystals accumulate in the kidneys causing formation of kidney stones. These stones may cause blood to be present in the urine (hematuria) and increase the risk of urinary tract infections. Urate crystals also accumulate in the joints and other tissues of the body. Children with Lesch-Nyhan syndrome may experience recurring episodes of pain and swelling of the joints, often accompanied by chills and fever. These episodes may become progressively longer each year.

In older children with this disorder, deposits of sodium urate may collect in the tissues around joints, causing urate stones to form. Eventually these stones (calculi) form visible "bulges" that protrude from the joints (tophi). Other destructive joint changes may also occur such as inflammation and breakdown of cartilage. These kidney and joint symptoms, taken together, are commonly known as gout.

Neurological symptoms associated with Lesch-Nyhan syndrome usually begin before the age of 12 months. These may include involuntary writhing movements of the arms and legs (athetosis) and purposeless repetitive movements (chorea) such as flexing of the fingers, raising and lowering of the shoulders, and/or facial grimacing. Infants who had previously been able to sit upright typically lose this ability. Initially, muscles may be weak (hypotonia) and lead to difficulty in holding the head in an upright position. Affected infants may fail to reach developmental milestones such as crawling, sitting or walking (developmental delay). Eventually, most children with Lesch-Nyhan syndrome experience abnormally increased muscle tone (hypertonia) and muscle rigidity (spasticity). Deep tendon reflexes are increased (hyperreflexia), and many children have involuntary contractions of the muscles around the ankles (ankle clonus). Mental retardation may also occur and is typically moderate. However, accurate evaluation of intelligence may be difficult because of poorly articulated speech (dysarthria).

The most striking feature of Lesch-Nyhan syndrome, which has been observed in approximately 85 percent of cases, is self-mutilation. However, this characteristic is quite variable. These behaviors most often begin between the ages of two and three years. However, they can also develop during the first year of life or much later during childhood. Self-injurious behavior may include repeated biting of the lips, fingers, and/or hands, and repetitive banging of the head against hard objects. Some children may scratch their face repeatedly or even dislocate an eye. However, individuals with Lesch-Nyhan syndrome are not insensitive to pain. Additional behavioral abnormalities include aggressiveness, vomiting, and spitting. These self-mutilating behaviors may persist for short periods of time (hours) or they may continue for months and they may lead to the loss of tissue.

Children with Lesch-Nyhan syndrome may have difficulty swallowing (dysphagia) and may be difficult to feed. Vomiting is common and most affected children are underweight for their age. Additional symptoms may include irritability, screaming, uncontrolled aggressiveness, and/or compulsive actions. Some children with Lesch-Nyhan syndrome may also develop a rare anemia known as megaloblastic anemia. (For more information on Megaloblastic Anemia, see the Related Disorders section of this report.)

Another symptom of Lesch-Nyhan syndrome may be a severe muscle spasm that causes the back to arch severely and the head and heels to bend backward (opisthotonos). Affected children may also experience hip dislocation, fractures, abnormal side-to-side curvature of the spine (scoliosis) and/or permanent fixation of several joints in a flexed position (contractures).
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Lesch-Nyhan syndrome is inherited as an X-linked recessive genetic trait. The gene responsible for this disorder is located on the long arm of the X chromosome (Xq27). Symptoms of Lesch-Nyhan syndrome develop due to absence or deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) and the abnormal accumulation of uric acid in the blood.

Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. X-linked recessive disorders are conditions which are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a fifty percent risk of transmitting the carrier condition to their daughters, and a fifty percent risk of transmitting the disease to their sons.

Investigators have determined that Lesch-Nyhan syndrome may be caused by disruption or changes (mutations) of the HPRT gene located on the long arm (q) of the X chromosome (Xq27). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. For example, "chromosome Xq27" refers to band 27 on the long arm of the X chromosome.

Some studies suggest that individuals with Lesch-Nyhan syndrome may have abnormally low levels of a chemical known as dopamine, or may be unable to properly utilize dopamine. Some neurobehavioral features of Lesch-Nyhan syndrome may be associated with dysfunction of the basal ganglia dopamine systems. The basal ganglia are paired nerve cell clusters within the cerebrum that play a role in controlling movements.
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Lesch-Nyhan syndrome is a rare disorder that affects males. In extremely rare cases, females may be affected by the disorder. However, in most cases, females may be carriers of the disease gene, but do not exhibit any symptoms. According to one estimate, the disorder occurs at the rate of approximately one in 380,000 births in the United States.
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The following disorders may be associated with Lesch-Nyhan syndrome as a secondary characteristic. They are not necessary for a differential diagnosis:

Cerebral palsy is a neurological movement disorder characterized by a lack of muscle control and impaired ability to coordinate movement (ataxia). This disorder is usually a result of injury to the brain during early development in the uterus or at birth. Cerebral palsy is not a progressive disease. An infant with cerebral palsy may experience developmental delays during the first or second year of life. As an affected child grows, additional symptoms may develop including drooling, speech impairment, difficulty maintaining bladder and/or bowel control, convulsive seizures, hand tremors, and/or difficulty coordinating voluntary movement. Spastic cerebral palsy is characterized by involuntary contractions of the muscles in the arms and legs and an awkward "scissor" gait. These muscle movements may be accompanied by facial grimacing and/or abnormal tongue movements. (For more information on this disorder, choose "Cerebral Palsy" as your search term in the Rare Disease Database.)

Familial dysautonomia is a rare genetic disorder of the autonomic nervous system (ANS), which controls vital involuntary body functions. It is characterized by diminished sensitivity to pain, lack of overflow tearing in the eyes, a decrease in the number of knob-like projections that cover the tongue (fungiform papillae), unusual fluctuations of body temperature, and unstable blood pressure. An infant born with familial dysautonomia typically has poor sucking ability, impaired swallowing reflexes, and poor muscle tone (hypotonia). Symptoms of this disorder are apparent at birth (congenital). (For more information on this disorder, choose "Familial Dysautonomia" as your search term in the Rare Disease Database.)

The following disorders may be associated with Lesch-Nyhan syndrome as secondary characteristics. They are not necessary for a differential diagnosis:

Gout is a common metabolic disorder characterized by an inborn error of uric acid (purine) metabolism. Excessive uric acid forms crystals (sodium urate) that are deposited in the kidneys, joints and other areas of the body. The large toe is the most common site for the accumulation of crystals. Symptoms may include acute pain in the toe or other affected area, joint swelling and pain, chills, and/or fever. The symptoms recur with episodes becoming longer in duration each year. If left untreated, destructive changes occur in the joints and kidneys.

Megaloblastic Anemia is a rare blood disorder characterized by the presence of abnormal white blood cells, low white blood cell counts, and abnormally low levels of circulating platelets. The initial symptoms of the disorder may include diarrhea, vomiting, a profound loss of appetite (anorexia), and weight loss. Other symptoms may include an abnormally enlarged liver and/or spleen, weakness, heart palpitations, breathing problems, and/or irritability. (For more information, choose "Megaloblastic Anemia" as your search term in the Rare Disease Database.)
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Diagnosis
The diagnosis of Lesch-Nyhan syndrome may be confirmed by a thorough clinical evaluation, including a detailed patient history and specialized blood tests. The absence of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) from red blood cells confirms the diagnosis of this disorder. Children with this disorder have abnormally high concentrations of uric acid in the blood. Lesch-Nyhan syndrome can be detected prior to birth (prenatally) by an examination of the cells in the amniotic fluid (amniocentesis) or by chorionic villus sampling (CVS). During chorionic villus sampling, a tissue sample is removed from a portion of the placenta and studied.

Females who are carriers for Lesch-Nyhan syndrome may develop gout later during life. Therefore, relatives of individuals with Lesch-Nyhan syndrome should undergo genetic testing to determine whether they are carriers for the disorder.

Treatment
The treatment of Lesch-Nyhan syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

The drug allopurinol is used to control the excessive amounts of uric acid associated with Lesch-Nyhan syndrome and control symptoms associated with excessive amounts of uric acid. However, this treatment has no effect on the neurological or behavioral symptoms associated with this disorder.

When kidney stones are present, they may be treated with extracorporeal shock wave lithotripsy (ESWL). During this procedure, the patient is immersed in water and high energy shock waves are directed to the body in the area of the kidney stone. The stone dissolves into small pieces, and these fragments are passed with the urine.

No sustained treatment or drug therapy has proven uniformly effective for the treatment of the neurological problems associated with Lesch-Nyhan syndrome. Some symptomatic relief has been achieved with the drugs carbidopa/levodopa. The drugs diazepam, phenobarbital, and haloperidol have also achieved some success in managing the symptoms. When haloperidol is not beneficial, then the drug fluphenazine may be prescribed. Baclofen or benzodiazepines have been used to treat spasticity.

Individuals with Lesch-Nyhan syndrome may benefit from behavior modification techniques because they may help to reduce self-mutilating behaviors. Children with Lesch-Nyhan syndrome may require physical restraint at the hips, chest, and elbows so they do not injure themselves. Elbow restraints keep the hands free. Biting of fingers and/or lips, which can lead to permanent disfigurement, may be prevented by the use of a mouth guard (oral prosthetic) or the removal of the primary teeth. In some cases, affected individuals may request such restraints themselves. With advancing age, some affected individuals' self-mutilating behaviors may improve or cease.

In some cases, drugs have been used to treat behavioral abnormalities associated with Lesch-Nyhan syndrome. These include Depakote (sodium valproate), Gabapentin, and carbamazepine. Benzodiazepines may be beneficial in treating anxiety symptoms sometimes associated with Lesch-Nyhan syndrome.

Genetic counseling will benefit families with children who have Lesch-Nyhan syndrome. Other treatment is symptomatic and supportive.
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The application of gene therapy for the treatment of Lesch-Nyhan syndrome is being investigated and the gene for hypoxanthine-guanine phosphoribosyltransferase has been cloned. The objective of gene therapy would be to provide the gene that manufactures the missing enzyme to people with Lesch-Nyhan syndrome. However, although animal studies are underway, this technique is not yet ready for human clinical trials.

Scientists at the National Institutes of Health are using Lesch-Nyhan syndrome as a model for the development of gene therapy delivery systems into the central nervous system. In animal studies, normal cell or synthesized viral expression vectors are implanted into the central nervous system. More studies are needed to determine the possible role of gene therapy for the treatment of Lesch-Nyhan syndrome.

For information on other clinical research projects on Lesch-Nyhan syndrome, contact the agencies and physicians listed in the Resources section of this report.

Matheny School and Hospital and the Matheny Institute of Applied Research have established the International Lesch-Nyhan Disease Registry. For more information, contact:

International Lesch-Nyhan Disease Registry
Tel: (908) 234-0618
E-mail: Research@mathenynj.com

NORD does not promote, endorse, or encourage participation in any specific medical research study. This information is presented to further scientific understanding that could lead to the prevention, treatment, and/or cure of rare disorders. NORD recommends that anyone interested in participating in a clinical research program seek the advice or counsel of his or her own personal physician(s).

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:1/18/00; Last Update:308000.

GeneClinics web site:www.geneclinics.org; University of Washington, Seattle.

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Visser JE, et al. Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev. 2000;32:449-75.

Jinnah HA, et al. Calcium channel agonists and dystonia in the mouse. Movement Disorders. 2000;15:542-51.

Olson L, et al. A review of behavioral treatments used for Lesch-Nyhan syndrome. Behav Modif. 2000;24:202-22.

De Gregorio L, et al. An unexpected affected female patient in a classical Lesch-Nyhan family. Mol Genet Metab. 2000;69:263-68.

Sponseller PD, et al. Orthopedic problems in Lesch-Nyhan syndrome. J Pediatr Orthop. 1999;19:596-602.

Matthews WS, et al. Cognitive functioning in Lesch-Nyhan syndrome: a 4-year follow-up study. Dev Med Child Neurol. 1999;41:260-62.

Nyhan WL, et al. New approaches to understanding Lesch-Nyhan disease. N Engl J Med. 1996;334:1602-04.

Ernst M, et al. Presynaptic dopaminergic deficits in Lesch-Nyhan disease. N Engl J Med. 1996;334:1568-72.

Jenkins EA, et al. Lesch-Nyhan syndrome presenting with renal insufficiency in infancy and transient neonatal hypothyroidism. Br J Rheumatol. 1994;33:392-96.

Sugahara T, et al. Lesch-Nyhan syndrome: successful prevention of lower lip ulceration caused by self-mutilation by use of mouth guard. Int J Oral Maxillofac Surg. 1994;23:37-38.

Anderson LT, et al. Cognitive abilities of patients with Lesch-Nyhan disease. J Autism Dev Disord. 1992;22:189-203.

Anderson LT, et al. Self-injury in Lesch-Nyhan disease. J Autism Dev Disord. 1994;24:67-81.

Evans J, et al. Lesch-Nyhan syndrome and the lower lip guard. Oral Surg Oral Med Oral Pathol. 1993;76:437-40.

Hatanaka T, et al. Lesch-Nyhan syndrome with delayed onset of self-mutilation: hyperactivity of interneurons at the brainstem and blink reflex. Acta Neurol Scand. 1990;81:184-87.