Description
Lesch-Nyhan syndrome is a condition that 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 in the joints. When uric acid builds up in the joints, it causes a form of arthritis called gouty arthritis. Uric acid accumulation can also cause kidney and bladder stones.
The first sign of Lesch-Nyhan syndrome is typically an orange color in the baby’s diaper that is caused by uric acid deposits in the urine. Babies with this condition often have normal development during the first few months of life, but they begin to experience developmental delays around 3 to 6 months. Affected babies can develop weak muscle tone (hypotonia) and involuntary muscle tensing (dystonia), which can interfere with crawling and walking.
During the first few years of life, children with Lesch-Nyhan syndrome can develop additional movement problems, such as muscle stiffness (spasticity); exaggerated reflexes (hyperreflexia); uncontrolled, jerking movements of the body (choreoathetosis); flailing of the limbs (ballismus); or episodes of muscle spasms that cause backward arching of the spine (opisthotonus). Over time, the movement problems become so severe that affected individuals require the use of a wheelchair and need help with personal care and other activities of daily living.
The characteristic feature of Lesch-Nyhan syndrome is self-injury. Affected individuals will often bite their lips, fingers, and cheeks. This behavior usually starts as soon as they develop teeth. Other, less common self-injurious behaviors can include eye-poking and banging of the head, arms, or legs. While the injurious behavior is typically self-directed, they may attempt to injure others. Although affected individuals feel the pain of the injuries, they have a compulsion to perform these behaviors.
Most individuals with Lesch-Nyhan syndrome develop a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia) and the remaining red blood cells are larger than normal (megaloblastic
).
People with Lesch-Nyhan syndrome have a reduced life span; most affected individuals do not survive past early adulthood. Major health complications experienced by people with Lesch-Nyhan syndrome can include kidney failure, respiratory failure, and serious infections such as pneumonia.
Frequency
Lesch-Nyhan syndrome almost exclusively affects boys and men. The prevalence of Lesch-Nyhan syndrome is approximately 1 in 235,000 to 380,000 individuals.
Causes
Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the HPRT1 gene cause Lesch-Nyhan syndrome. The HPRT1 gene provides instructions for making an enzyme called hypoxanthine-guanine phosphoribosyltransferase (HGprt). This enzyme recycles purines
, which are building blocks 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. Purines also play an important role in providing energy for cells.
The pathogenic variants in the HPRT1 gene that cause Lesch-Nyhan syndrome can severely reduce the amount of functional HGprt enzymes in cells or prevent cells from making this enzyme at all. Without HGprt, cells cannot recycle purines, so the purines are broken down. During this process, uric acid builds up in the body, resulting in gouty arthritis.
People with Lesch-Nyhan syndrome also have low levels of a chemical messenger in the brain called dopamine
. Dopamine transmits messages that help the brain control physical movement and emotional behavior. It is likely that dopamine-producing cells need purines to function. When the supply of purines is low, dopamine-producing cells do not function well and dopamine levels decrease. This shortage of dopamine may play a role in the movement problems and other features seen in people with Lesch-Nyhan syndrome.
Although researchers understand some of the biological processes behind the development of Lesch-Nyhan syndrome, the exact cause of the neurological signs and symptoms of this condition is unclear.
Some people have pathogenic variants in the HPRT1 gene that allow cells to produce some functional HGprt enzymes. These individuals are said to have Lesch-Nyhan variant or partial HPRT1 deficiency. The signs and symptoms of Lesch-Nyhan variant are often milder than those of Lesch-Nyhan syndrome. People with Lesch-Nyhan variant often have high uric acid levels and may have neurological problems, but they do not injure themselves. Because Lesch-Nyhan syndrome and Lesch-Nyhan variant are caused by pathogenic variants in the same gene, they are sometimes considered to be part of the same disease spectrum.
Inheritance
Lesch-Nyhan syndrome is inherited in an X-linked pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes
in each cell. In males (who have only one X chromosome), a variant in the only copy of the gene in each cell is sufficient to cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
In females (who have two copies of the X chromosome), one altered copy of the gene typically does not cause features of the condition. Females with one HPRT1 gene variant should have about half of normal HGprt activity, but often the protein activity is normal. This is because the X chromosome that contains the variant may be turned off (inactive) in many of their blood cells due to a process called X-inactivation. Early in female embryonic development, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. Usually X-inactivation occurs randomly, such that each X chromosome is active in about half of the body's cells. However, in some cases, X-inactivation is not random, and one X chromosome is active in more than half of cells. When X-inactivation does not occur randomly, it is called skewed X-inactivation.
Females with a pathogenic variant in the HPRT1 gene often have skewed X-inactivation, which inactivates the X chromosome that contains the pathogenic variant in most blood cells.
Other Names for This Condition
- Complete HPRT deficiency
- HPRT deficiency
- HPRT1 deficiency
- HPRT1 disorder
- Hypoxanthine guanine phosphoribosyltransferase deficiency
- Lesch-Nyhan disease
- LND
- LNS
Additional Information & Resources
Genetic Testing Information
Genetic and Rare Diseases Information Center
Patient Support and Advocacy Resources
Clinical Trials
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
References
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