What are the other Names for this Condition? (Also known as/Symptoms)

• Choreoathetosis Self-Mutilation Syndrome
• Juvenile Gout, Choreoathetosis, Mental Retardation Syndrome
• Total Hypoxanthine-Guanine Phosphoribosyl Transferase Deficiency

What is Lesch-Nyhan Syndrome? (Definition/Background Information)

• Lesch-Nyhan Syndrome (LNS) is a rare genetic condition characterized by high uric acid levels in the affected individuals. Barring some rare instances, the disease singularly affects males
• Lesch-Nyhan Syndrome is a genetic disorder, and therefore, a positive family history of LNS and being a male, are the risk factors for being diagnosed with the disorder
• Mutations in the HPRT1 gene are responsible for the disorder. The gene codes for an enzyme called hypoxanthine phosphoribosyltransferase 1. This enzyme catalyzes the recycling of purine nucleotides (building blocks for DNA and RNA). The gene mutation leads to enzyme deficiency and impaired recycling of purines, which results in the accumulation of uric acid in the body
• The condition is inherited in an X-linked manner. In this type of inheritance, the genetic mutation is carried on the X chromosome, leading to the manifestation of disease symptoms only in males, since only males carry an X chromosome
• In the affected individuals, the HPRT1 gene mutation also causes deficiency in the neurotransmitter dopamine. Thus, the symptoms observed in those with Lesch-Nyhan Syndrome reflect excess uric acid accumulation as well as dopamine deficiency
• The signs and symptoms of Lesch-Nyhan Syndrome include formation of kidney and bladder stones, joint pain, movement disorders, reduced muscle tone, muscle weakness, actions of self-injury (such as biting oneself and banging one’s head on hard surfaces), vomiting, inability to reach developmental milestones, and decreased intellectual ability
• The diagnosis of Lesch-Nyhan Syndrome requires information from a physical examination, family medical history, assessment of symptoms, blood and urine test to check for uric acid, blood or tissue testing for hypoxanthine phosphoribosyltransferase 1 enzyme activity, and genetic testing for HPRT1 mutation
• Formation of kidney and bladder stones, severely hampered movements, gout, and impaired intellectual ability are some potential complications that could arise in individuals with Lesch-Nyhan Syndrome
• Treatment for the condition is often geared toward addressing individual symptoms. Hence, excess uric acid is controlled by medication. Kidney and bladder stones may be removed using stone dissolving procedures, such that smaller stones are able to pass through urine. Behavioral changes may be addressed with medication and physiotherapy may be required to help individuals with movement disorders
• Since Lesch-Nyhan Syndrome is a genetic condition, currently there are no guidelines or methods available to prevent the condition from developing. Genetic testing of prospective parents and genetic counselling may help them understand LNS better
• The prognosis of Lesch-Nyhan Syndrome is guarded; few affected individuals are able to reach the age of 40 years. Many of them succumb to the disorder between the ages of 20 and 30 years

Who gets Lesch-Nyhan Syndrome? (Age and Sex Distribution)

• Lesch-Nyhan Syndrome is a rare disorder observed almost exclusively in males. The occurrence of LNS in women is very rare
• The onset of the disorder can occur 6 months after the baby is born; typically, newborn children with LNS appear normal
• The condition is reported to occur in individuals across several racial and ethnic backgrounds; the prevalence of Lesch-Nyhan Syndrome is 1:380,000

What are the Risk Factors for Lesch-Nyhan Syndrome? (Predisposing Factors)

The following are the risk factors for Lesch-Nyhan Syndrome:

• A family history of LNS
• Being a male

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Lesch-Nyhan Syndrome? (Etiology)

Lesch-Nyhan Syndrome is caused by mutations in the HPRT1 gene. This gene codes for the enzyme hypoxanthine phosphoribosyltransferase 1. LNS is inherited in an X-linked recessive manner.

• Under normal circumstances, the enzyme catalyzes recycling of purines (adenine and guanine)
  • The pathway of purine recycling is also called the purine salvage pathway, and it consumes less energy than a de-novo synthesis
  • The purines, along with pyrimidines, form the building blocks for DNA and RNA
  • Thus, the availability of purines ensures ongoing synthesis of the nucleic acids
• When the HPRT1 gene is mutated, the resultant enzyme is dysfunctional
  • A severe deficiency of the enzyme leads to an impaired salvage pathway, which allows build-up of abnormal levels of uric acid in the body. This leads to some of the symptoms observed with the disorder
  • The deficiency of the enzyme also down-regulates the neurotransmitter dopamine in the brain. The exact cause of this phenomenon is unknown
  • Since dopamine is an important chemical messenger for movement and emotion, individuals with LNS also exhibit neurological and behavioral signs and symptoms
• In some individuals, the HPRT1 mutation occurs in such a way that there exists some functional enzyme activity despite the mutation. This mutation is called ‘LNS variant’. In such cases, the symptoms are not very severe

X-linked recessive: X-linked recessive conditions are traits or disorders that occur when two copies of an abnormal gene are inherited on a sex chromosome (X or Y chromosome). All X-linked recessive traits are fully evident in males, because they have only one copy of the X chromosome. This means that there is no normal gene present to mask the effects of the mutant copy. All males who are affected will pass the mutated gene onto their female offspring, because they must inherit one copy of the X chromosome from each parent. This means that they will be unaffected carriers. Females are rarely affected by X-linked recessive disorders because they have two copies of the X chromosome. In the rare case that they inherit two mutated copies of the gene, they will inherit the condition.

What are the Signs and Symptoms of Lesch-Nyhan Syndrome?

The symptoms of Lesch-Nyhan Syndrome can be broadly categorized into 3 major categories:

• Symptoms associated with uric acid accumulation, which include:
  • Sodium urate crystals in the urine of newborns, resulting in diapers with “orange sand” appearance
  • Formation of stones in the kidney and urinary bladder
  • Blood in urine
  • Susceptibility to repeated infections of the urinary tract
  • Pain and swelling of joints
  • Accumulation of sodium urate in cartilage tissue (which can lead to gout). This can lead to bulges called “tophi” in the ears
• Neurological symptoms that include:
  • Repetitive movements, such as grimacing, lifting shoulders, moving fingers, etc., which are collectively referred to as chorea
  • Muscle contractions (dystonia); low muscle tone (hypotonia)
  • Inability to hold the head up, which is observed in infants
  • Inability to sit upright
  • Difficulty in standing and walking
  • Speech problems (dysarthria)
  • Delay in reaching developmental milestones
• Behavioral symptoms
  • Self-injury: Scratching and biting oneself and banging one’s head against hard surfaces
  • Screaming
  • Vomiting
  • Aggressive behavior

Additional signs and symptoms may include:

• Intellectual disability
• Low weight gain

Note: 

• Females, who are carriers of Lesch-Nyhan Syndrome, do not generally develop the above symptoms. However, many develop gout as a result of uric acid build-up over years
• Individuals with HPRT1 variant classification are not known to exhibit self-injury symptoms

How is Lesch-Nyhan Syndrome Diagnosed?

A diagnosis of Lesch-Nyhan Syndrome is established from information gathered from the following factors:

• A thorough physical examination and assessment of symptoms
• An evaluation of the individual’s personal and family medical history
• Blood test to check for uric acid concentration
• Urine test to check for uric acid levels
• Enzyme assay for hypoxanthine-guanine phosphoribosyltransferase in blood or other tissue, such as fibroblasts
• Molecular genetic testing for confirmation of HPRT1 gene mutation
• Differential diagnosis to rule out medical conditions causing symptoms similar to LNS

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Lesch-Nyhan Syndrome?

The following are some potential complications of Lesch-Nyhan Syndrome:

• Muscle spasticity (rigid muscles) and severely-impaired movements may result in confinement of the individual to a wheelchair
• Abnormal bone structure, contractures and dislocations
• Inflammation of the joints
• Megaloblastic anemia, which is the presence of large, abnormal red blood cells
• Developmental delays and intellectual disability
• Serious self-inflicted injury
• Behavioral issues may lead to social issues and isolation

How is Lesch-Nyhan Syndrome Treated?

The treatment of Lesch-Nyhan Syndrome is based on consideration of the affected individual’s symptoms. Also, since the disorder is often manifested in infancy, a team of specialists from various medical fields are often required to work cooperatively to allow the child to lead as normal a life as possible.

The treatment course for Lesch-Nyhan Syndrome may include:

• Medications
  • Allopurinol to control excess urin acid
  • Benzodiazapines and diazepam for muscle spasms, anxiety
  • Sodium valproate, gabapentin, carbamazepine, and other medicines (belonging to the same class) for behavior modulation
• For dissolving or breaking kidney and urinary bladder stones
  • Extracorporeal shock wave lithotripsy (ESWL)
  • Urine alkalinization to dissolve the stones
• Physical supports and assistive aids
  • Mouth guards to prevent self-inflicted injuries; use of suitable restraints for the same
  • Walking aids
  • Devices to help with muscle control and maintaining posture
• Physiotherapy
• Genetic counseling to family members of an affected individual, so that they understand the disorder better

How can Lesch-Nyhan Syndrome be Prevented?

• Currently, there are no specific methods or guidelines to prevent Lesch-Nyhan syndrome, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Lesch-Nyhan syndrome

Regular medical screening at periodic intervals with tests and physical examinations are advised.

What is the Prognosis of Lesch-Nyhan Syndrome? (Outcomes/Resolutions)

• The prognosis of Lesch-Nyhan Syndrome is guarded, since few patients live beyond the age of 40 years. Often, the quality of life is affected; the individuals may be confined to a wheelchair
• A majority of the individuals with LNS die between the ages of 20 and 30 years
• Death can even occur owing to unknown causes. However, most fatalities are reportedly due to aspiration pneumonia or complications from kidney and bladder stones

Additional and Relevant Useful Information for Lesch-Nyhan Syndrome:

Lesch-Nyhan Syndrome has also been described variously as ‘Juvenile Gout, Choreoathetosis, Mental Retardation Syndrome’ and ‘Choreoathetosis Self-Mutilation Syndrome’.