Total Hypoxanthine-guanine Phosphoribosyl Transferase Deficiency
Disease Details
Family Health Simplified
- Description
- Total hypoxanthine-guanine phosphoribosyltransferase deficiency, also known as Lesch-Nyhan syndrome, is a rare genetic disorder characterized by overproduction of uric acid, neurological dysfunction, and behavioral problems including self-mutilation.
- Type
- Total hypoxanthine-guanine phosphoribosyltransferase deficiency, also known as Lesch-Nyhan syndrome, is an X-linked recessive disorder.
- 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
- Total hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, also known as Lesch-Nyhan syndrome, typically has an onset in infancy. Symptoms such as delayed motor development, hypotonia, and dysarthria usually begin to appear within the first year of life.
- Prevalence
- Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, also known as Lesch-Nyhan syndrome in its severe form, is a rare genetic disorder. The prevalence is estimated to be about 1 in 380,000 live births.
- Epidemiology
- Total hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency, also known as Lesch-Nyhan syndrome, is a rare genetic disorder. It predominantly affects males, with an estimated incidence of 1 in 380,000 live births. This X-linked recessive disorder is characterized by the overproduction of uric acid, leading to severe gout, kidney stones, and neurodevelopmental issues.
- Intractability
- Total hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, also known as Lesch-Nyhan syndrome, is currently considered intractable. There is no cure for the disorder, and treatment primarily focuses on managing symptoms and complications. Patients typically require a multidisciplinary approach to address neurological, renal, and behavioral issues.
- Disease Severity
- Total hypoxanthine-guanine phosphoribosyltransferase deficiency, also known as Lesch-Nyhan syndrome, is a severe genetic disorder. It often presents with debilitating and complex symptoms, including severe gout, kidney problems, neurological deficits, and behavioral issues such as self-mutilating behaviors. The severity of the disease significantly impacts the quality of life and requires comprehensive medical management.
- Healthcare Professionals
- Disease Ontology ID - DOID:1919
- Pathophysiology
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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
- Carrier status of hypoxanthine-guanine phosphoribosyltransferase deficiency is typically identified through genetic testing. Carriers usually do not exhibit symptoms but can pass the mutated gene to offspring.
- Mechanism
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Total hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is also known as Lesch-Nyhan syndrome.
**Mechanism:**
HPRT is an enzyme involved in the purine salvage pathway, specifically in the recycling of hypoxanthine and guanine into their respective nucleotides, IMP and GMP. This enzyme helps to maintain the proper balance of purines within cells.
**Molecular Mechanisms:**
1. **Gene Mutation:** Lesch-Nyhan syndrome is caused by mutations in the HPRT1 gene located on the X chromosome. These mutations lead to either a reduction or a complete loss of the enzyme's activity.
2. **Purine Metabolism Disruption:** Lack of functional HPRT results in the accumulation of hypoxanthine and guanine, which are then converted into uric acid. Elevated levels of uric acid can lead to hyperuricemia and associated complications like gout and kidney stones.
3. **Neurological and Behavioral Manifestations:** The exact mechanisms leading to the neurological and behavioral symptoms of Lesch-Nyhan syndrome are not fully understood, but it is believed that the imbalance in purine metabolism affects dopaminergic pathways in the brain, leading to self-mutilating behaviors, choreoathetosis, and cognitive impairment.
Understanding these molecular mechanisms can provide a basis for diagnosis and potential therapeutic approaches for managing Lesch-Nyhan syndrome. - Treatment
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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
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Total hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, also known as Lesch-Nyhan syndrome, is a rare inherited disorder. Currently, there are no FDA-approved treatments specifically for the condition, but several off-label and experimental approaches have been explored:
1. **Allopurinol**: This medication is frequently used off-label to reduce uric acid levels in patients, helping to manage gouty arthritis and prevent renal complications.
2. **Baclofen and Benzodiazepines**: These medications can be used off-label to manage the severe muscle spasticity and dystonia associated with the disorder.
3. **Deep Brain Stimulation (DBS)**: Although primarily used for other neurological conditions, DBS is being explored experimentally for managing dystonia and self-injurious behaviors in Lesch-Nyhan syndrome.
4. **Experimental Gene Therapy**: Efforts are ongoing to explore gene therapy as a potential treatment, aiming to correct the underlying genetic defect.
5. **Neural Stem Cell Transplantation**: Research is ongoing as an experimental treatment to explore the potential benefits of stem cell transplantation in alleviating neurological symptoms.
The availability and ethical considerations of these treatments typically require careful evaluation and are often provided under compassionate use or within clinical trial settings. - Lifestyle Recommendations
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Total hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, also known as Lesch-Nyhan syndrome, is a rare genetic disorder. Here are some lifestyle recommendations for managing the condition:
1. **Regular Medical Care:** Ongoing monitoring by healthcare professionals is essential for managing symptoms and complications.
2. **Diet:** A low-purine diet may help reduce uric acid levels, although the impact is limited. Avoid foods high in purines like organ meats and certain seafood.
3. **Hydration:** Adequate fluid intake is crucial to help prevent kidney stones and other complications related to high uric acid levels.
4. **Medication Adherence:** Consistent use of prescribed medications, such as allopurinol, is important to control uric acid levels and prevent gout and kidney stones.
5. **Physical Therapy:** Regular physical therapy can help manage muscle spasms and improve mobility.
6. **Protective Measures:** Protective gear and modifications at home can help prevent self-injury, which is common due to self-mutilating behaviors associated with the condition.
7. **Support Systems:** Engaging with support groups and mental health professionals can provide emotional support for both the patient and caregivers. - Medication
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Total hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a rare genetic disorder also known as Lesch-Nyhan syndrome. Unfortunately, there is no cure for this condition, but treatment focuses on managing symptoms and complications.
Medications can include:
- Allopurinol: to reduce uric acid levels and prevent gout and kidney stones.
- Benzodiazepines or Baclofen: to manage muscle spasticity.
- Dopamine agonists or antipsychotic medications: to help control self-injurious behaviors.
Physical therapy and occupational therapy can also be beneficial in managing symptoms and improving the quality of life. Regular follow-up with healthcare providers is essential for monitoring and adjusting treatment as needed. - Repurposable Drugs
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Total hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, also known as Lesch-Nyhan syndrome, is a rare genetic disorder. Currently, there are no specific FDA-approved drugs for Lesch-Nyhan syndrome, but some off-label or repurposed drugs may help manage symptoms:
1. **Allopurinol**: Used to reduce uric acid levels and prevent gout flares associated with the disorder.
2. **Baclofen**: A muscle relaxant to help control muscle spasms.
3. **Diazepam**: An anti-anxiety medication that can also help with muscle spasms.
4. **Carbamazepine**: An anticonvulsant that might help in controlling self-injurious behavior and aggression.
These medications are primarily symptom-managing agents rather than treatments for the root cause of HPRT deficiency. Regular monitoring and a multidisciplinary approach involving neurologists and other specialists are often required. - Metabolites
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Total hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency, also known as Lesch-Nyhan syndrome, results in the accumulation of certain metabolites due to disrupted purine salvage pathways. Key metabolites that accumulate include:
1. Hypoxanthine
2. Guanine
3. Uric acid
These elevated metabolites can lead to symptoms like gout, kidney stones, and neurological disturbances. - Nutraceuticals
- There are no established nutraceuticals specifically for total hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, also known as Lesch-Nyhan syndrome. This genetic disorder primarily requires medical management, including medications to control symptoms and supportive care. Some general nutritional recommendations might help manage symptoms, but it's crucial to consult healthcare providers for individual advice.
- Peptides
- Total hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is better known as Lesch-Nyhan syndrome. This genetic disorder is primarily caused by mutations in the HPRT1 gene located on the X chromosome. It leads to an accumulation of uric acid in all body fluids. Symptoms include severe gout, kidney problems, neurological dysfunction, and behavioral disturbances, such as self-mutilating behaviors. The disorder is inherited in an X-linked recessive manner, meaning it predominantly affects males. There are currently no peptide-based treatments for this condition. Treatment typically focuses on managing symptoms, particularly hyperuricemia, with medications such as allopurinol.