What is Lesch-Nyhan Syndrome?
Lesch Nyhan syndrome is a genetic disorder caused by a lack of a particular enzyme, called hypoxanthine-guanine phosphoribosyltransferase (HPRT). This enzyme plays a crucial role in the body’s natural recycling process of certain substances known as purines. Specifically, it transforms two types of purines, guanine and hypoxanthine, into other useful substances. Without this enzyme, levels of guanine and hypoxanthine rise, and they eventually turn into uric acid.
A lack of HPRT can lead to various health issues depending on how severe the deficiency is. Lesch Nyhan syndrome is at the severe end of the scale, with less than 1.5% of the enzyme’s expected activity. It is characterized by high levels of uric acid in the blood (hyperuricemia), delays in mental and physical development, uncontrollable movements, and self-harming behaviors.
There are also less severe versions of this condition. One is called Keeley–Seegmiller syndrome, which involves 8% to 60% of the enzyme’s expected activity and mainly causes symptoms related to high uric acid levels. Another variant involves 1.5 to 2% of the enzyme’s expected activity and causes both high uric acid levels and neurological symptoms like uncontrolled and unwanted movements, muscle stiffness, and intellectual disability.
What Causes Lesch-Nyhan Syndrome?
Lesch Nyhan syndrome is a genetic disorder. It’s linked to the X chromosome and is caused by a mutation (or change) in a gene called HPRT1, which is located on the X chromosome. This condition is usually seen in males as they get this defective X chromosome from their mothers who are carriers of the disease.
Even though only one gene is linked with this disorder, researchers have found more than 600 different mutations in it. Each of these changes can result in varying degrees of the disease, making it more of a range of conditions rather than one single illness.
Women mostly carry the gene but they seldom show symptoms of the disease. This is because they have two X chromosomes – one healthy and one with the mutation. However, in rare cases, they might show symptoms of the disease if the healthy X chromosome is switched off – a process called lionization, allowing the mutated X chromosome to determine the body’s characteristics.
Risk Factors and Frequency for Lesch-Nyhan Syndrome
Lesch Nyhan syndrome is not very common, with estimates showing that it affects between 1 in 235,000 to 1 in 380,000 people. This syndrome is found in all populations without any significant differences. Even though this disorder, linked to the X chromosome, tends to affect males mostly, there are some cases reported in females as well.
- Lesch Nyhan syndrome affects between 1 in 235,000 to 1 in 380,000 individuals.
- This disorder appears evenly across all population groups.
- While it’s typically seen in males due to its relation to the X chromosome, some females have been diagnosed with it too.
Signs and Symptoms of Lesch-Nyhan Syndrome
People who suffer from Lesch-Nyhan syndrome, a disease resulting from a deficiency of the enzyme HPRT, are typically born without noticeable symptoms and experience a normal prenatal growth development cycle. The primary sign present at birth is an increased level of uric acid in the blood (hyperuricemia). A clue to this condition in newborns could be orange-colored crystals in their diapers. Over time, the excess uric acid might lead to the formation of crystals in urine and kidney stones, as well as gout, juvenile arthritis, and urinary stones.
By around four months of age, signs of neurological issues may start to show. Common early indications include muscle weakness (hypotonia), and developmental delays. Infants might also exhibit nonspecific signs like recurring vomiting or difficulties with managing secretions. Additional motor symptoms often emerge between 8 and 12 months of age. One of the most frequent is dystonia, a state of abnormal muscle tone resulting in muscular spasm and abnormal posture. In severe cases, dystonia may prevent individuals from achieving developmental milestones such as crawling or walking. Eventually, this can result in complete independence on a wheelchair and reliance on others for daily activities.
Motor disabilities, like involuntary movements and speech difficulties, can actually skew the cognitive test scores, making it inaccurate to fully determine the intellectual capability of the patient. Despite these challenges, most patients usually maintain good non-verbal intelligence.
A striking feature of Lesch-Nyhan syndrome is a propensity for self-injurious behavior. Patients are known to engage in self-mutilation by biting their lips, fingers, and cheeks, which leads to noticeable disfigurement. This behavior generally starts when the child’s teeth begin to form. However, it’s important to note that these actions stem from compulsive behavior, and not due to a lack of sense of pain – their sensory perception, including the ability to experience pain, remains intact. Patients have also been reported to exhibit compulsive aggressive behaviors, like head-banging, pinching, and verbal abuse, which can be managed with restraints. They often express regret for their actions once the compulsion subsides.
A majority of patients with Lesch-Nyhan syndrome develop megaloblastic anemia, a condition involving larger than normal red blood cells. If this feature is absent, it’s advisable to investigate for coexisting conditions like iron deficiency, thalassemia, or chronic diseases, which could potentially normalize the blood findings.
Testing for Lesch-Nyhan Syndrome
If a child has developmental delays and high levels of uric acid in their body, it could indicate a medical condition that health professionals should investigate further. High levels of uric acid in the blood (over 8 mg/dL) and in urine could suggest an underlying problem, but these signs are not always reliable for a precise diagnosis.
Brain imaging tests usually do not pinpoint any specific brain abnormalities that can explain these symptoms. Some studies have found that part of the brain, known as the basal ganglia, could be smaller in volume. Scientists are still looking into how the body’s chemical messengers that transmit signals in the brain might be affected in this situation.
More accurate diagnostic tests include the enzymatic assay and molecular testing. The enzymatic assay measures the activity of an enzyme called HPRT in red blood cells, but it can also be performed on other types of cells like lymphocytes and fibroblasts. On the other hand, molecular testing examines the HPRT1 gene to see if there are any significant changes, such as duplications, deletions, or substitutions of its parts. These changes could lead to irregular enzyme levels.
Recently, scientists have identified six biomarkers or substances that when present in unusual amounts in red blood cell extracts, could be key indicators of HPRT deficiency. These include AICAR, ZTP, vitamin B3 (as niacin or niacinamide), S-AMP, and a significant reduction of ATP.
Other tests could include a complete blood count (CBC) to check for a type of anemia called megaloblastic anemia, or an EEG to rule out seizures as a possible cause of inattention.
For families with a history of Lesch Nyhan syndrome, prenatal testing for male infants can be performed. This involves either chorionic villus sampling or amniocentesis to look for signs of the syndrome before birth.
Treatment Options for Lesch-Nyhan Syndrome
Allopurinol is a type of medication used as a primary treatment for hyperuricemia or high uric acid levels in the body. This drug works by blocking an enzyme that converts certain substances to uric acid, thus lowering its production. It’s effective in reducing complications like kidney stones, bladder stones, deposits of uric acid in the body (tophi), and a type of arthritis caused by excessive uric acid (gouty arthritis).
Given that high uric acid levels are present from birth, it’s beneficial to start medication as early as possible to effectively prevent complications. Studies have proven that allopurinol, when used in the long term and at the right doses, shows no negative effects. However, it doesn’t impact cognitive or neurological development. Although rare, allopurinol can sometimes cause allergic reactions or severe skin conditions. In such cases, Febuxostat, another drug that also inhibits the enzyme that contributes to uric acid production, can be used.
Neurological issues in patients with high uric acid levels are challenging to address due to a lack of understanding about the precise causes. Current medical understanding suggests that a reduced number of a specific type of brain cells contributes to these issues, but treatments targeting this theory have not been consistently effective. For instance, the drug L-DOPA could increase certain symptoms, while combining a dietary supplement called S-Adenosyl methionine with antipsychotic medication seemed to help with certain behavior problems. The success of these treatments seems to depend on the patient’s age, and more research is needed. Certain physical symptoms can be managed with drugs like benzodiazepines or baclofen, and physical therapy can help with mobility and posture issues.
Behavioral issues require a mixture of psychological, physical, and medical care. Stress management techniques have proven effective, as stress worsens self-harming behavior. Physical restraints such as arm guards and dental guards can offer temporary solutions. In more extreme cases, like those where other methods are ineffective, dental extraction might be considered. Patients often feel relief being restrained, and some even request it when they experience compulsive urges.
So far, other treatment methods such as bone marrow transplants and blood transfusions have not proven successful. Current research is investigating other potential therapies, including deep brain stimulation, dopamine replacement therapy, and local injections of a drug called botulinum.
What else can Lesch-Nyhan Syndrome be?
When a patient exhibits symptoms such as dystonia (a movement disorder) and slower than normal development, they are often initially diagnosed with a condition known as cerebral palsy.
Often, the first noticeable sign of these issues is a high level of uric acid in the body, which is termed hyperuricemia. However, other conditions linked to enzyme disorders like excessive activity of the enzyme phosphoribosyl pyrophosphate (PRPP) synthetase and a deficiency in the glucose 6-phosphate dehydrogenase (G6PD) enzyme can also lead to increased uric acid paired with excessive production of a compound called purine.
Additionally, habits of self-harm can appear in various conditions such as:
- Rett syndrome
- Autism spectrum disorder
- Tourette syndrome
- Cornelia de Lange syndrome
- Hereditary sensory neuropathy
- Familial dysautonomia
Also, please note the below conditions that may present with the symptoms mentioned above:
- Autism spectrum disorder
- Cerebral palsy
- Cornelia de Lange syndrome
- Familial dysautonomia
- Glucose 6-phosphate dehydrogenase (G6PD) deficiency
- Hereditary sensory neuropathy
- Phosphoribosyl pyrophosphate (PRPP) synthetase hyperactivity
- Rett syndrome
- Tourette syndrome
What to expect with Lesch-Nyhan Syndrome
Individuals with Lesch Nyhan syndrome often have a reduced life expectancy, seldom living beyond their 30s. A significant complication of this condition can be kidney failure. However, with early diagnosis and prompt treatment using a medication called allopurinol, this complication becomes a less common cause of death. The primary causes of death associated with Lesch Nyhan syndrome are respiratory failure and infections, such as pneumonia. It’s worth noting that there have been instances of sudden, unexpected death in some patients as reported in case studies.
Possible Complications When Diagnosed with Lesch-Nyhan Syndrome
: Uric acid stones are formed when there’s too much uric acid in the body. These stones can’t be seen in an x-ray which can cause a delay in recognizing them, potentially resulting in kidney failure. A medication called allopurinol can reduce these levels, but it causes an increase in other substances, called hypoxanthine and xanthine. Xanthine, which doesn’t dissolve easily, can form stones, especially if the person is not properly hydrated.
For good oral health, it is important to know that dental guards and other protective devices in the mouth can make it difficult to maintain oral hygiene. If teeth are removed too early in childhood, this can cause facial deformity as the child grows. On the other hand, leaving decayed teeth untreated can result in tissue damage resulting in more severe cosmetic issues. It’s possible to save the living part of a tooth and protect the surrounding bone with a procedure called ‘vital pulpotomy.’ This process can be a solution to prevent potential facial deformation due to tooth extraction.
- Uric acid stones formation due to excessive uric acid
- Delayed diagnosis due to the invisibility of uric acid stones in x-ray
- Potential kidney failure from uric acid stones
- The risk of xanthine stones due to allopurinol medication
- Difficulties of maintaining oral hygiene with dental guards
- Potential facial deformation due to early extraction of teeth in childhood
- Damage from leaving decayed teeth untreated
- Potential prevention of facial deformation by ‘vital pulpotomy’
Preventing Lesch-Nyhan Syndrome
It’s crucial for both patients and caregivers to understand the responsibility and need to continue with the prescribed medication. They should also be guided on how to control anxiety and the importance of regular check-ups with various health experts. While there’s no absolute cure for the disorder, you can manage symptoms effectively and improve life expectancy through close and regular monitoring and timely treatments provided when needed.
