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Lesch-Nyhan syndrome
This condition is characterised by neurological problems, excessive uric acid production, and a distinctive pattern of self-injurious behaviour. It primarily affects males and is present from early childhood.
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Overview
Lesch-Nyhan syndrome (LNS) is a rare, inherited metabolic disorder. It is caused by a deficiency of an enzyme called hypoxanthine-guanine phosphoribosyltransferase (HPRT), which is crucial for recycling purines - building blocks of DNA and RNA. This enzyme deficiency leads to a build-up of uric acid in the body and also affects brain development and function, resulting in a range of neurological issues [PMID:33679883].
The condition typically manifests in infancy or early childhood and predominantly affects males due to its X-linked inheritance pattern. The key features include neurological dysfunction, intellectual disability, and a notable tendency towards self-injurious behaviour, often involving biting of the lips, tongue, or fingers.
Symptoms & clinical features
The symptoms of Lesch-Nyhan syndrome generally become apparent within the first year of life. Early signs may include developmental delay, especially in motor skills such as sitting up or crawling, and hypotonia (low muscle tone). As the child grows, more distinct neurological features emerge, including dystonia (involuntary muscle contractions) and choreoathetosis (uncontrolled, jerky movements) [PMID:33679883].
A hallmark of LNS is the overproduction of uric acid. This can lead to kidney stones and a form of arthritis called gout, which causes painful inflammation in the joints. The most distinguishing and challenging symptom is often severe self-injurious behaviour, which can begin around age 2-3 years. Individuals may compulsively bite their lips, tongue, or fingers, and these actions are typically not painful to the person due to neurological differences. This behaviour can be difficult to manage and requires careful intervention [PMID:30138977].
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Affected organs
Lesch-Nyhan syndrome primarily affects the central nervous system, leading to its characteristic neurological and behavioural symptoms. The brain's basal ganglia, which are involved in controlling movement, are particularly impacted. This results in the movement disorders observed in affected individuals.
Beyond the brain, the kidneys are also commonly affected due to the excessive production of uric acid. This can lead to the formation of uric acid crystals and stones within the kidneys and urinary tract, potentially causing kidney damage over time. Gout, an inflammatory arthritis, also affects joints due to uric acid build-up.
Risks & severity
Lesch-Nyhan syndrome is a severe condition with a broad spectrum of clinical presentations. While it is uniformly progressive without effective treatment, the specific neurological and metabolic complications can vary in intensity among affected individuals. All individuals with LNS experience profound neurological problems, including movement disorders and cognitive impairment. The self-injurious behaviour is a severe and persistent challenge, often requiring physical restraints or dental intervention to prevent serious harm.
The build-up of uric acid carries risks such as kidney stones and gouty arthritis, which can cause significant pain and kidney damage if not managed. The exact prevalence of LNS is estimated to be approximately 1 in 380,000 live births, making it a very rare condition. Early diagnosis and management are important to mitigate some of the complications, though the neurological symptoms remain challenging to treat.
Genetic causes
Lesch-Nyhan syndrome is caused by pathogenic variants in the HPRT1 gene [PMID:33679883]. This gene provides instructions for making an enzyme called hypoxanthine-guanine phosphoribosyltransferase 1. This enzyme plays a vital role in purine metabolism, specifically in a 'salvage pathway' where it recycles purines - essential components of DNA and RNA - from used molecules.
When there are pathogenic variants in the HPRT1 gene, the HPRT enzyme is either entirely absent or its activity is significantly reduced. This deficiency prevents the proper recycling of purines, leading to an overproduction and build-up of uric acid in the body. The exact mechanism by which HPRT deficiency leads to the neurological symptoms, particularly the self-injurious behaviour, is not fully understood but is thought to involve imbalances in neurotransmitters in the brain [PMID:30138977].
- HPRT1 hypoxanthine phosphoribosyltransferase 1
Inheritance pattern
Lesch-Nyhan syndrome follows an X-linked recessive inheritance pattern. The HPRT1 gene is located on the X chromosome, one of the two sex chromosomes. Males have one X chromosome and one Y chromosome, while females have two X chromosomes.
Because males only have one X chromosome, a pathogenic variant in the HPRT1 gene on their single X chromosome is sufficient to cause the condition. Females, with two X chromosomes, are typically carriers if they inherit one X chromosome with a pathogenic variant and one normal X chromosome. Carrier females usually do not show symptoms because their second, unaffected X chromosome can compensate. However, they have a 50% chance of passing the pathogenic variant to each of their children. If a son inherits the affected X chromosome, he will develop Lesch-Nyhan syndrome. If a daughter inherits the affected X chromosome, she will be a carrier.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
Diagnosis & testing
Diagnosis of Lesch-Nyhan syndrome is often suspected based on the characteristic clinical features, including developmental delay, movement disorders, and especially the presence of self-injurious behaviour, alongside signs of excessive uric acid production. Confirmation involves biochemical testing to measure uric acid levels in blood and urine, and to assess HPRT enzyme activity in cells, typically from red blood cells or fibroblasts.
Genetic testing, specifically sequencing of the HPRT1 gene, is used to confirm the diagnosis and identify the specific pathogenic variant [PMID:33679883]. This can be accessed through the NHS Genomic Medicine Service. A referral to a clinical genetics service is usually made by a paediatrician or other specialist, and the genetic testing would fall under an appropriate R-code (e.g., R287 Metabolic disorders, R288 Intellectual disability and global developmental delay) within the NHS National Genomic Test Directory.
Management & lifestyle
Management of Lesch-Nyhan syndrome focuses on addressing the symptoms and complications, as there is currently no cure for the underlying enzyme deficiency. Treatment for the excessive uric acid involves medications like allopurinol, which helps to reduce uric acid production and prevent complications such as kidney stones and gout. Hydration is also important to help prevent kidney stone formation.
Managing the neurological symptoms, particularly the severe self-injurious behaviour, is a significant challenge. This often requires a multidisciplinary approach involving neurologists, occupational therapists, physiotherapists, and behavioural specialists. Physical restraints, protective padding, and dental interventions may be necessary to prevent serious injury. There is ongoing research into potential new therapies, but current management focuses on supportive care to improve quality of life and prevent complications.
UK care pathway
In the UK, individuals suspected of having Lesch-Nyhan syndrome would typically be referred to specialist paediatric services. If a genetic condition is suspected, onward referral to a clinical genetics service is the standard pathway within the NHS Genomic Medicine Service. Here, genetic counsellors and clinical geneticists can provide information, support, and arrange for genomic testing as per the National Genomic Test Directory (e.g., R287 or R288). This ensures a consistent approach to diagnosis and ongoing care within the NHS.
Frequently asked questions
What is the life expectancy for someone with Lesch-Nyhan syndrome?
Life expectancy for individuals with Lesch-Nyhan syndrome can vary. While medical advances have improved care, the severe neurological complications and potential for serious self-injury mean that many affected individuals do not live into adulthood. Management focuses on supportive care to maximise quality of life.
Can carriers of Lesch-Nyhan syndrome have any symptoms?
Female carriers of Lesch-Nyhan syndrome are typically asymptomatic, meaning they do not show symptoms of the condition themselves. However, they have a 50% chance of passing the pathogenic gene variant to each of their children. Genetic counselling can provide more detailed information for carriers and their families.
Are there different forms or severities of Lesch-Nyhan syndrome?
Yes, there is a spectrum of severity. While classic Lesch-Nyhan syndrome involves profound neurological problems, excessive uric acid, and self-injury, some individuals may have less severe forms, sometimes called HPRT-related hyperuricemia, where they have high uric acid but milder or no neurological symptoms. These are still due to variants in the HPRT1 gene [PMID:30138977].
How is the self-injurious behaviour managed?
Managing self-injurious behaviour is a significant challenge. It often involves a combination of behavioural therapies, occupational therapy, and protective measures like padding or physical restraints to prevent harm. Dental care is also crucial to protect teeth and oral tissues from biting injuries. Medication to help manage some of the neurological symptoms may also be considered.
What support is available for families affected by Lesch-Nyhan syndrome?
Families affected by Lesch-Nyhan syndrome can access support through specialist NHS services, including clinical genetics teams and paediatric neurologists. Patient advocacy groups and rare disease organisations also provide valuable resources, information, and a community for families facing similar challenges.
References
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- Qurie A, Preuss CV, Musa R. Allopurinol. 2023. PMID: 29763117
- Bell S, Kolobova I, Crapper L. Lesch-Nyhan Syndrome: Models, Theories, and Therapies. Molecular syndromology. 2016. PMID: 27920633
- Nyhan WL. The Lesch-Nyhan syndrome. Annual review of medicine. 1973. PMID: 4575865
- Kopin IJ. Neurotransmitters and the Lesch-Nyhan syndrome. The New England journal of medicine. 1981. PMID: 6117013
- Harris JC. Lesch-Nyhan syndrome and its variants: examining the behavioral and neurocognitive phenotype. Current opinion in psychiatry. 2018. PMID: 29227296
- Negi S, Tripathy S, Merchant Y. Lesch-Nyhan Syndrome and Oral Self-injury: A Systematic Review of Case Reports. International journal of clinical pediatric dentistry. 2024. PMID: 39867109
- Zi Y, Zheng SW, Ning L. Establishment and characterization of Lesch-Nyhan syndrome rabbit model. Yi chuan = Hereditas. 2024. PMID: 38763775