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Lesch-nyhan Syndrome

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Description: Lesch-Nyhan syndrome is a rare genetic disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), leading to severe gout, kidney problems, neurological dysfunction, and self-mutilating behaviors.
Type: Lesch-Nyhan syndrome is a genetic disorder primarily affecting males. It is inherited in an X-linked recessive manner.
Signs And Symptoms: LNS is characterized by three major hallmarks: neurologic dysfunction, cognitive and behavioral disturbances including self-mutilation, and uric acid overproduction (hyperuricemia). Damage to the basal ganglia causes affected individuals to adopt a characteristic fencing stance due to the nature of the lesion. Some may also have macrocytic anemia due to the faulty DNA synthesis, most likely due to deficient purine synthesis that leads to a lag of cell division with respect to increases in cell mass. Virtually all patients are male; males experience delayed growth and puberty, and most develop shrunken testicles or testicular atrophy. Female carriers are at an increased risk for gouty arthritis but are usually otherwise unaffected.
Prognosis: The prognosis for individuals with severe LNS is poor. Death is usually due to kidney failure or complications from hypotonia, in the first or second decade of life. Less severe forms have better prognosis.
Onset: Lesch-Nyhan syndrome typically has an onset in infancy, usually becoming apparent within the first few months of life.
Prevalence: The prevalence of Lesch-Nyhan syndrome is estimated to be approximately 1 in 380,000 live births.
Epidemiology: Lesch-Nyhan syndrome is a rare genetic disorder with an estimated incidence of 1 in 380,000 live births. It primarily affects males due to its X-linked recessive inheritance pattern. There is no significant difference in incidence based on geographical location or ethnicity.
Intractability: Yes, Lesch-Nyhan syndrome is considered intractable as there is currently no cure for the condition. Management focuses on addressing symptoms through medications and supportive care.
Disease Severity: Lesch-Nyhan syndrome is a rare genetic disorder that primarily affects males. It is characterized by severe neurological and behavioral abnormalities and the overproduction of uric acid, leading to gout-like symptoms. The disease severity is high, significantly impacting the quality of life. Pediatric patients often display self-mutilating behaviors, such as biting of the lips and fingers. They also experience involuntary muscle movements and cognitive impairments. There is no cure, and management typically focuses on alleviating symptoms and preventing complications.
Healthcare Professionals: Disease Ontology ID - DOID:1919
Pathophysiology: As in other X-linked diseases, males are affected because they only have one copy of the X chromosome. In Lesch–Nyhan syndrome, the defective gene is that for hypoxanthine-guanine phosphoribosyltransferase (HGPRT), a participant in the 'recycling' of purine nucleotides. Female carriers have a second X chromosome, which contains a "normal" copy of HPRT, preventing the disease from developing, though they may have increased risk of hyperuricemia.A large number of mutations of HPRT are known. Mutations that only mildly decrease the enzyme's function do not normally cause the severe form of LNS, but do produce a milder form of the disease which still features purine overproduction accompanied by susceptibility to gout and uric acid nephrolithiasis.Formation of DNA (during cell division) requires nucleotides, molecules that are the building blocks for DNA. The purine bases (adenine and guanine) and pyrimidine bases (thymine and cytosine) are bound to deoxyribose and phosphate and incorporated as necessary. Normally, the nucleotides are synthesized de novo from amino acids and other precursors. A small part, however, is 'recycled' from degraded DNA of broken-down cells. This is termed the "salvage pathway".HGPRT is the "salvage enzyme" for the purines: it channels hypoxanthine and guanine back into DNA synthesis. Failure of this enzyme has two results:
Cell breakdown products cannot be reused, and are therefore degraded. This gives rise to increased uric acid, a purine breakdown product.
The de novo pathway is stimulated due to an excess of PRPP (5-phospho-D-ribosyl-1-pyrophosphate or simply phosphoribosyl-pyrophosphate).It was previously unclear whether the neurological abnormalities in LNS were due to uric acid neurotoxicity or to a relative shortage in "new" purine nucleotides during essential synthesis steps. Genetic mutations affecting the enzymes of the de novo synthesis pathway may possibly contribute to the disease, although these are rare or unknown. Uric acid has been suggested as a possible cause of neurotoxicity but this is unproven.Importantly, evidence suggests that one or more lesions in striatal dopaminergic pathways may be central to the neurological deficits, especially the choreoathetoid dyskinesia and self-mutilation. 6-hydroxydopamine toxicity in rodents may be a useful animal model for the syndrome, although this is not proven.
However, the link between dopamine and purine synthesis is a nucleotide called guanosine triphosphate or 'GTP'. The first step of dopamine synthesis is GTP cyclohydrolase, and significantly a deficiency of this step produces a syndrome that has a neuropathology similar to LNS. Thus a lack of HGPRT may produce a nucleotide deficiency (specifically: GTP deficiency) disorder, resulting in dopamine deficiency.Another animal model for LNS has been proposed to arise from oxidative damage, caused by the hyperuricemia accompanying LNS. This is based on the theory that uric acid is a powerful reducing agent and likely an important human antioxidant, in high concentration in blood. Thus, it has been suggested that free radicals, oxidative stress, and reactive oxygen species may play some role in the neuropathology of LNS.However, some evidence suggests against a role for uric acid in the neuropathology of Lesch–Nyhan syndrome:

Hyperuricemia associated with classic primary gout, which is caused by low uric acid renal clearance rather than uric acid overproduction, is not associated with neuropathology.
Hypouricemia occurs in a number of purine disorders, in particular xanthinuria. Despite having complete absence of blood uric acid, xanthinuria patients do not have any neuropathology, nor any other disease states – other than the kidney stones caused by accumulation of insoluble xanthine in lieu of uric acid.Similarly, uric acid does not penetrate the blood–brain barrier well. However, oxidative stress due to uric acid is now thought to figure in metabolic syndrome, atherosclerosis, and stroke, all syndromes associated with high uric acid levels. Similarly, Superoxide dismutase ( "SOD" ) and SOD-mimetics such as TEMPOL ameliorate the effects of hyperuricemia. Likewise, 6-hydroxydopamine (the putative animal model for Lesch–Nyhan's neuropathy) apparently acts as a neurotoxin by generation of reactive oxygen species. It may be that oxidative stress induced by some other oxypurine such as xanthine causes the disease.
Carrier Status: Lesch-Nyhan syndrome is an X-linked recessive disorder, meaning it is carried on the X chromosome. Females can be carriers if they have one affected X chromosome and one normal X chromosome. Male carriers of an affected X chromosome typically exhibit symptoms because they have only one X chromosome.
Mechanism: Lesch-Nyhan syndrome (LNS) is a rare genetic disorder caused by mutations in the HPRT1 gene, which leads to a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT).

**Mechanism:**
The deficiency in HPRT enzyme disrupts the purine salvage pathway, a critical process in which purines are recycled to form new nucleotides. As a result, this disruption leads to an overproduction of uric acid, causing various complications.

**Molecular Mechanisms:**
1. **Purine Salvage Pathway Disruption:** HPRT enzyme is crucial for recycling purines (hypoxanthine and guanine) into nucleotides. In the absence of HPRT activity, these purines are instead broken down into uric acid.
2. **Hyperuricemia:** Excess uric acid accumulates in the body, leading to conditions like gout, kidney stones, and renal dysfunction.
3. **Neurological and Behavioral Manifestations:** The exact molecular mechanisms linking HPRT deficiency to the neurological and behavioral symptoms (such as self-mutilation and cognitive impairment) are not fully understood. It is hypothesized that the deficiency in purine recycling affects brain function and development, possibly through altered neurotransmitter levels or disrupted neuronal signaling.

In summary, Lesch-Nyhan syndrome results from HPRT1 gene mutations, causing HPRT enzyme deficiency, impaired purine recycling, excessive uric acid production, and complex neurological manifestations.
Treatment: Treatment for LNS is symptomatic. 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 LNS. Some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol.It is essential that the overproduction of uric acid be controlled in order to reduce the risk of nephropathy, nephrolithiasis, and gouty arthritis. The drug allopurinol is utilized to stop the conversion of oxypurines into uric acid, and prevent the development of subsequent arthritic tophi (produced after having chronic gout), kidney stones, and nephropathy, the resulting kidney disease. Allopurinol is taken orally, at a typical dose of 3–20 mg/kg per day. The dose is then adjusted to bring the uric acid level down into the normal range (<3 mg/dL). Most affected individuals can be treated with allopurinol all through life.No medication is effective in controlling the extrapyramidal motor features of the disease. Spasticity, however, can be reduced by the administration of baclofen or benzodiazepines.There has previously been no effective method of treatment for the neurobehavioral aspects of the disease. Even children treated from birth with allopurinol develop behavioral and neurologic problems, despite never having had high serum concentrations of uric acid. Self-injurious and other behaviors are best managed by a combination of medical, physical, and behavioral interventions. The self-mutilation is often reduced by using restraints. Sixty percent of individuals have their teeth extracted in order to avoid self-injury, which families have found to be an effective management technique. Because stress increases self-injury, behavioral management through aversive techniques (which would normally reduce self-injury) actually increases self-injury in individuals with LNS. Nearly all affected individuals need restraints to prevent self-injury, and are restrained more than 75% of the time. This is often at their own request, and occasionally involves restraints that would appear to be ineffective, as they do not physically prevent biting. Families report that affected individuals are more at ease when restrained.The Matheny Medical and Educational Center [2] in Peapack, NJ, has six Lesch–Nyhan syndrome patients, believed to be the largest concentration of LNS cases in one location, and is recognized as the leading source of information on care issues.
Treatment for LNS patients, according to Gary E. Eddey, MD, medical director, should include: 1) Judicious use of protective devices; 2) Utilization of a behavioral technique commonly referred to as 'selective ignoring' with redirection of activities; and 3) Occasional use of medications.An article in the August 13, 2007 issue of The New Yorker magazine, written by Richard Preston, discusses "deep-brain stimulation" as a possible treatment. It has been performed on a few patients with Lesch–Nyhan syndrome by Dr. Takaomi Taira in Tokyo and by a group in France led by Dr. Philippe Coubes. Some patients experienced a decrease in spastic self-injurious symptoms. The technique was developed for treating people with Parkinson's disease, according to Preston, over 20 years ago. The treatment involves invasive surgery to place wires that carry a continuous electric current into a specific region of the brain.An encouraging advance in the treatment of the neurobehavioural aspects of LNS was the publication in the October, 2006 issue of Journal of Inherited Metabolic Disease of an experimental therapy giving oral S-adenosyl-methionine (SAMe).
This drug is a nucleotide precursor that provides a readily absorbed purine, which is known to be transported across the blood–brain barrier. Administration of SAMe to adult LNS patients was shown to provide improvement in neurobehavioural and other neurological attributes. The drug is available without prescription and has been widely used for depression, but its use for treating LNS should be undertaken only under strict medical supervision, as side effects are known.
Compassionate Use Treatment: Lesch-Nyhan syndrome is a rare genetic disorder that primarily affects males and is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Currently, there are no cures for the disease, but several treatments are under investigation.

### Compassionate Use Treatments
Compassionate use allows for the use of investigational drugs outside of clinical trials. In the context of Lesch-Nyhan syndrome:
- **Allopurinol**: Though it doesn’t address neurological aspects, allopurinol is commonly used to control uric acid levels and prevent gout.
- **Baclofen**: Known primarily for treating spasticity, baclofen could be utilized for managing muscle spasticity associated with Lesch-Nyhan.

### Off-Label or Experimental Treatments
Several off-label or experimental treatments are being explored:
- **Deep Brain Stimulation (DBS)**: A surgical approach that targets specific brain areas to alleviate dystonia and involuntary movements.
- **Adeno-Associated Virus (AAV) Gene Therapy**: Investigated to replace or repair the defective HPRT gene.
- **L-Dopa**: Used off-label to manage movement disorders, though its efficacy in Lesch-Nyhan is variable.
- **Dantrolene**: Occasionally used to manage severe muscle spasticity.

Treatment approaches for Lesch-Nyhan syndrome are continually evolving, with ongoing research aimed at better managing the symptoms and improving the quality of life for patients.
Lifestyle Recommendations: Lesch-Nyhan syndrome (LNS) is a rare genetic disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Here are some lifestyle recommendations for managing the condition:

1. **Medical Management**: Regular follow-ups with healthcare providers, including neurologists, geneticists, and other specialists, are crucial.

2. **Medication**: Administer prescribed medications to control symptoms such as uric acid levels and to manage neurological symptoms.

3. **Dietary Adjustments**: A low-purine diet may help to manage uric acid levels. Ensure adequate hydration to prevent kidney stones.

4. **Physical Therapy**: Engage in physical therapy to maintain mobility, strength, and to manage spasticity.

5. **Occupational Therapy**: Utilize adaptive devices and strategies to assist with daily activities.

6. **Behavioral Support**: Implement behavioral therapy to manage self-injurious behaviors and other psychological issues.

7. **Safety Measures**: Use protective devices like mouth guards to prevent injury from self-harming behaviors.

8. **Nutritional Support**: Monitor nutrition closely to ensure adequate calorie and nutrient intake, as feeding difficulties may occur.

9. **Support Networks**: Engage with support groups and counseling services for emotional and psychological support for both patients and caregivers.

These recommendations aim to improve quality of life and manage the symptoms associated with Lesch-Nyhan syndrome.
Medication: There is currently no cure for Lesch-Nyhan syndrome. However, medications can help manage some of its symptoms. Allopurinol is commonly used to reduce uric acid levels and prevent gout and kidney stones. Benzodiazepines, baclofen, or gabapentin may help manage self-injurious behaviors and muscle spasms. Each treatment plan is tailored to the individual's needs.
Repurposable Drugs: Lesch-Nyhan syndrome is a rare genetic disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). This deficiency leads to an overproduction of uric acid and a range of neurological and behavioral abnormalities. Currently, there is no cure for Lesch-Nyhan syndrome, and treatment focuses on managing symptoms. While there are no widely recognized repurposable drugs specifically for Lesch-Nyhan syndrome, some medications used to manage individual symptoms include:

1. **Allopurinol**: This is commonly used to reduce uric acid levels and prevent gout and kidney stones.
2. **Baclofen or Diazepam**: These muscle relaxants may be used to help manage spasticity.
3. **Medications for Behavioral Issues**: Antipsychotics or antidepressants may sometimes be prescribed to manage self-injurious behaviors, though their efficacy varies.

Research is ongoing to identify potential repurposable drugs, but as of now, these medications primarily address symptom management rather than the underlying genetic cause.
Metabolites: In Lesch-Nyhan syndrome, the key metabolites involved include uric acid and hypoxanthine. Lesch-Nyhan syndrome is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), leading to the overproduction of uric acid, which can result in gout, kidney stones, and neurological symptoms.
Nutraceuticals: Nutraceuticals are not specifically used to treat Lesch-Nyhan syndrome. This condition is a rare genetic disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Management primarily focuses on symptom control, including medications to manage uric acid levels and behavioral interventions for self-injurious behaviors. Nutraceuticals have not been established as an effective treatment for the core symptoms of Lesch-Nyhan syndrome.
Peptides: Lesch-Nyhan syndrome is primarily a disorder of purine metabolism due to a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Peptides don't play a central role in its pathophysiology, which is more related to dysfunctional nucleotide recycling. HPRT deficiency leads to excessive uric acid production and severe neurological manifestations. While peptides are involved in many bodily functions, they are not the primary concern in Lesch-Nyhan syndrome.