What is Lesch Nyhan syndrome
Lesch-Nyhan syndrome is a rare, inherited disorder characterized by neurological and behavioral abnormalities and the overproduction of uric acid in the body, caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Lesch Nyhan syndrome is caused by changes (mutations) in the HPRT1 gene and is inherited in an X-linked recessive, the gene is carried by the mother and passed on to her son. Lesch-Nyhan syndrome is present at birth almost exclusively in baby boys. Rarely, 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. The lack of hypoxanthine-guanine phosphoribosyltransferase (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 Lesch-Nyhan syndrome is self-mutilating behaviors – characterized by lip and finger biting and head banging – that begin in the second year of life. 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 moderate cognitive disability, gout-like swelling in the joints and severe kidney problems such as kidney stones and bladder stones. People with Lesch Nyhan syndrome usually cannot walk, require assistance sitting, and generally use a wheelchair 1. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington’s disease. Because a lack of hypoxanthine-guanine phosphoribosyltransferase (HPRT) causes the body to poorly utilize vitamin B12, some boys may develop a rare disorder called megaloblastic anemia.
The prevalence of Lesch-Nyhan syndrome is approximately 1 in 380,000 individuals. Lesch Nyhan syndrome occurs with a similar frequency in all populations.
Treatment for Lesch Nyhan syndrome is symptomatic and supportive. Gout can be treated with allopurinol to control excessive amounts of uric acid. Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. There is no standard treatment for the neurological symptoms of Lesch Nyhan syndrome. Some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol. Affected people often do not survive past the first or second decade of life due to renal failure 2.
Lesch Nyhan syndrome cause
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.
HPRT1 gene mutations that cause Lesch-Nyhan syndrome result in a severe shortage (deficiency) or complete absence of hypoxanthine phosphoribosyltransferase 1. When this enzyme is lacking, purines are broken down but not recycled, producing abnormally high levels of uric acid. 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.
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.
Lesch Nyhan syndrome inheritance pattern
Lesch Nyhan syndrome 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.
Females that have an abnormal gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the abnormal gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the abnormal gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.
Resources for locating a genetics professional in your community are available online:
- The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
- The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
- The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
- The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.
Figure 1. Lesch Nyhan syndrome X-linked recessive inheritance pattern
How can a carrier of Lesch Nyhan syndrome prevent having an affected child?
With advanced planning and appropriate testing, it may be possible for a carrier to prevent having a child with Lesch Nyhan syndrome. Depending on each person’s individual situation and choices, this may be accomplished either during a pregnancy, or before a pregnancy begins.
To find out whether a fetus is affected during a pregnancy, prenatal testing can be performed either by molecular genetic testing or biochemical genetic testing. Molecular genetic testing may be done if the specific mutation in the HPRT1 gene has been identified in the family. The usual procedure is to first determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (at about 10 to 12 weeks gestation), or by amniocentesis (usually performed at about 15 to 18 weeks gestation). If the fetus is known to be male, DNA from fetal cells can then be tested for the mutation in the family. If the specific mutation in the HPRT1 gene in the family is not known, biochemical genetic testing is preferred. This testing also requires either chorionic villus sampling or amniocentesis, but involves measuring HPRT enzyme activity in the cells obtained during the procedure. If Lesch Nyhan syndrome is confirmed in the fetus by either method of testing, pregnancy options including pregnancy termination may be discussed with a health care provider.
As an alternative to prenatal diagnosis during the pregnancy, preimplantation genetic diagnosis (PGD) before a pregnancy may be available if the mutation in the family is known. Preimplantation genetic diagnosis is done after in vitro fertilization (IVF) to diagnose a genetic condition in an embryo before it is introduced into the uterus. When having preimplantation genetic diagnosis, only embryos known to be unaffected are introduced into the uterus for a possible pregnancy.
People interested in genetic testing, prenatal diagnosis, and/or preimplantation genetic diagnosis should speak with a genetics professional.
Resources for locating a genetics professional in your community are available online:
- The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
- The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
- The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
- The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.
Lesch Nyhan syndrome symptoms
Lesch Nyhan syndrome 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). It is not until the late teens or adulthood that untreated patients with Lesch-Nyhan syndrome experience recurring episodes of pain and swelling of the joints, just like those of adults with gout. These episodes may become progressively more frequent once they begin. Uric acid accumulation can also cause kidney and bladder stones. These stones may cause blood to appear in the urine (hematuria) and increase the risk of urinary tract infections.
The symptoms of Lesch-Nyhan syndrome may become apparent as early as six months of age. Earlier urate crystal formation, resulting from abnormally increased levels of uric acid in the urine, leads to the presence of orange colored deposits (“orange sand”) in the diapers of infants with this disorder. This may be the first manifestation of Lesch-Nyhan syndrome, but it is seldom recognized in early infancy.
Neurological symptoms associated with Lesch-Nyhan syndrome usually begin before the age of 12 months. 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) such as flexing of the fingers, raising and lowering of the shoulders, and/or facial grimacing, and flailing of the limbs (ballismus).
Infants who had previously been able to sit upright typically lose this ability. Initially, muscles may be soft (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). 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.
Intellectual disability may also occur and is typically moderate. However, accurate evaluation of intelligence may be difficult because of poorly articulated speech (dysarthria). Some patients have normal intelligence.
The most striking feature of Lesch-Nyhan syndrome, which has been observed in approximately 85 percent of patients, is self-mutilation. 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. However, individuals with Lesch-Nyhan syndrome are not insensitive to pain. Additional behavioral abnormalities include aggressiveness, vomiting, and spitting. Self-mutilating behaviors regularly lead to 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 or screaming. Some children with Lesch-Nyhan syndrome may also develop a rare anemia known as megaloblastic anemia.
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 curvature of the spine (scoliosis) and/or permanent fixation of several joints in a flexed position (contractures).
Female carriers usually do not have symptoms of the disorder, but may develop gout later in life as a result of untreated excess uric acid in the blood (hyperuricemia).
Lesch Nyhan syndrome diagnosis
The diagnosis of Lesch-Nyhan syndrome may be confirmed by a thorough clinical evaluation, including a detailed patient history and specialized blood tests. Children with this disorder have abnormally high concentrations of uric acid in the blood. The absence of the HPRT enzyme in cells from any tissue confirms the diagnosis. Molecular genetic testing for the HPRT1 gene is available to determine the specific disease-causing mutation. Carrier testing for Lesch-Nyhan syndrome is possible using molecular genetic testing.
Prenatal diagnosis and preimplantation genetic diagnosis are possible if the disease-causing HPRT1 gene mutation has been identified in an affected family member. Prenatal diagnosis can also be done by enzyme analysis.
Lesch Nyhan syndrome 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 Lesch-Nyhan syndrome.
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. Baclofen or benzodiazepines have been used to treat spasticity. Diazepam may be useful.
Individuals with Lesch-Nyhan syndrome have been reported to benefit from behavior modification techniques designed to reduce self-mutilating behaviors, but real success is unusual. Children with Lesch-Nyhan syndrome usually 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 teeth. Many affected individuals request restraints themselves. With advancing age, some affected individuals’ self-mutilating behaviors may improve or cease.
In some patients, drugs have been used to treat behavioral abnormalities associated with Lesch-Nyhan syndrome. These include Depakote (sodium valproate), Gabapentin, baclofen, and carbamazepine. Benzodiazepines may be beneficial in treating anxiety symptoms sometimes associated with Lesch-Nyhan syndrome.
Genetic counseling is recommended for families with children who have Lesch-Nyhan syndrome. Other treatment is symptomatic and supportive.
Behavior problems
The behavior problems, including self-injurious behavior, can also be difficult to eliminate. Effective management of this problem requires three ingredients. The most important of these is prevention by physical restraint. All sharp and dangerous objects must be kept out of reach. The wheelchair should have all sharp edges within reach covered safely. Loose arm ties or elbow splints can be very helpful to control finger biting or hitting. Some children must have their teeth removed if they bite themselves.
The second most important ingredient for controlling self-injurious behaviors is behavior therapy. This can be done at home, but in most cases it is done by professionals who have been trained in behavior therapy. The goal is to focus attention on good behaviors while ignoring bad behaviors. Punishing bad behaviors by shouting or spanking does not work, and may even make the bad behaviors worse. It is also helpful to identify the situations that cause problem behaviors, and then try to avoid these situations.
The third ingredient for controlling self-injurious behaviors is medications. Many different medications have been used to control these behaviors, but they do not work all of the time. Several medications may also be useful in the management of self-injurious behaviors, but none has been evaluated in a controlled clinical trial. Promising possibilities include gabapentin, carbamazepine, diazepam, others. These medications can reduce the frequency of self-injurious behavior, but they rarely eliminate it entirely.
Some physicians also like to use risperdal for self-injurious behavior. Unfortunately, risperdal causes sleepiness and can sometimes make the neuromotor problems worse. If it is used, it is important to verify that improvements in self-injury are not being traded for sedation or worsening of neuromotor function.
Splints
Splints are firm supports that prevent certain types of unwanted movements. The most common ones are attached to the arms to prevent bending of the elbow. By preventing elbow bending, finger biting can be stopped because the child can not get his hand to his mouth. Splints can be obtained from many medical supply stores, such as medi-kid.
Wheelchairs
Most children with Lesch-Nyhan disease need a wheelchair to get around. This wheelchair must be specially designed for safety. Images in this section show an example of a wheelchair expecially designed for Lesch-Nyhan patients.
All sharp corners and objects within hand reach must be covered with soft padding, so the child cannot bang or scrape himself. All sharp corners and objects within reach of the feet must be similarly covered.The spokes of the wheels must be covered to prevent the child from inserting his hand when the chair is in motion.
These arm straps prevent flinging movements of the arms and other forms of self-injurious behavior. The shield next to it can be raised to prevent self-injury such as stretching the arms while being pushed through a doorway, or hitting walls or other objects.These arm straps prevent flinging movements of the arms and other forms of self-injurious behavior. The shield next to it can be raised to prevent self-injury such as stretching the arms while being pushed through a doorway, or hitting walls or other objects.
The head rest must be high enough to prevent the child from flinging his head backward and injuring his neck. Side supports for the head may also be required, to prevent him from flinging his head towards the sides.
Straps for the chest may be needed to prevent the child from flinging himself forward out of the wheelchair, or banging his head on things in front of him. Sometimes, arm straps or shields can be used to prevent flinging movements, or other self-injurious behavior such as biting fingers or poking in the eyes. When these straps are adjustable, they can allow a restricted but safe range of movement, preserving functional use of the hands. Straps for the legs might also be helpful to prevent self injury to the legs and feet.
Lesch Nyhan syndrome life expectancy
The prognosis for individuals with Lesch Nyhan syndrome is poor. Death is usually due to renal failure in the first or second decade of life.
References
