What Is Lesch-Nyhan Syndrome


Lesch-Nyhan Syndrome (LNS) or Lesch-Nyhan Disease (LND) is a rare inherited metabolic disorder characterised by developmental delays, movement issues, and self-injurious tendencies. It is caused by a deficiency of an enzyme that is involved in the synthesis of a biological substance called purines. While this syndrome is relatively rare, it represents a severe form within the spectrum of this enzyme deficiency and can cause significant distress for affected patients. 

The disorder was initially identified and clinically characterised by the American medical student Michael Lesch and his mentor, the paediatrician William Nyhan, at Johns Hopkins School of Medicine. Thus, the disease was named in their honour.

Causes of lesch-nyhan syndrome

LNS is caused by a mutation (alteration) in the HPRT1 gene that provides instructions for making the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme, which is responsible for recycling purines.1 Consequently, the lack of the HPRT enzyme causes the purine to break down but not recycle, which eventually produces a high level of uric acid, a waste product found in the blood. In a normal situation, the uric acid passes through the kidneys, leaving the body in urine. However, in LNS, the body accumulates excessive uric acid, resulting in hyperuricemia (abnormally high levels of uric acid in the blood).

The excessive uric acid clumps into tiny stones or crystals (urate) primarily in the skin, hands, and feet. These clumps cause irritation and potentially lead to a form of arthritis known as gout (accumulation of uric acid in the joints). The tiny stones can also develop in the kidneys or bladder, obstructing the flow of urine and causing discomfort. In severe cases, renal failure can occur, where both kidneys stop functioning.

The LNS is an X-linked recessive disorder caused by a genetic mutation on the X chromosome. Typically, it predominantly affects males who inherit the defective X chromosome from their carrier mothers. However, females can also carry the faulty X chromosome and may occasionally develop the disorder if the healthy X chromosome fails to express itself, allowing the defective X chromosome to present instead.2

Signs and symptoms of lesch-nyhan syndrome


Although hyperuricemia is usually present at birth, it is rarely identified. The only noticeable sign in early life may be orange-coloured crystals in the nappies. However, as the child grows, hyperuricemia leads to:

Neurological features

These signs typically become noticeable by the age of four months. The common early signs include decreased muscle tone (hypotonia) and developmental delays noted when caregivers analyse the child’s red book (child health record). Infants may also have less specific symptoms like repeated vomiting.

As the child approaches his first birthday, new signs appear, such as:

  • Involuntary jerky movements (Dystonia)
  • Delay in achieving milestones like crawling and walking
  • Twitching, writhing (choreoathetosis), and repetitive limb movements (ballismus
  • Slurred or unclear speech (dysarthria)
  • Difficulty in swallowing (dysphagia
  • Involuntary and painful arching of the spine (Opisthotonus
  • Stiffness
  • Unnaturally strong reflexes

Cognitive impairments

These usually present as decreased verbal intelligence due to stiffness and movement difficulties while speaking; otherwise, intelligence is usually normal.3 Most children also have mild or moderate neurocognitive abnormalities with intellectual disability and IQ scores in the range of 55–75. However, severe mental retardation is uncommon. 

Self-injurious behaviour

An overwhelming and uncontrollable tendency towards self-harm is the hallmark of LNS. These behavioural disorders may appear as follows:4

  • Biting of lips, fingers, and cheeks (that usually coincides with tooth eruption)
  • Banging the head
  • Banging the limbs 
  • Poking the eyes 

Moreover, megaloblastic anaemia has been noted in 81 to 92% of LNS patients.5

Management and treatment of lesch-nyhan syndrome

The treatment of LNS is multi-faceted and involves a collaboration between different health and allied professionals, which is known as a multidisciplinary team approach. 


  1. Medications to reduce uric acid levels: These are medications that prevent the formation of uric acid, thus reducing the associated gout, tophi and urinary stones. Since high uric acid levels are present from birth, this medicine is often started early. Examples include Allopurinol and Febuxostat.
  2. Dopamine agonists: These are medications that increase the production and activity of dopamine (a neurotransmitter in the brain). Common examples are Levodopa (L-DOPA) and Carbidopa. However, ongoing research is being conducted to investigate the efficacy of these treatments in patients with LNS, as the use of L-DOPA has been associated with increased dystonia and hyperactivity. Alternatively, treatment with S-adenosyl methionine, in combination with antipsychotics, has helped with dystonia and self-injurious behaviour.6
  3. Muscle relaxants: These medications help reduce stiffness and relax muscles. Baclofen is an example of these medications.

Behavioural therapy

Behavioural symptoms are managed with psychiatric, physical, and medical interventions. Mental stress increases self-harm tendencies; hence, managing stress is crucial during therapy.

Some patients find that physical restraints provide relief during compulsive attacks. However, these interventions must be prescribed and monitored by registered healthcare practitioners and must not be tried at home.

It is very important for all treatments to be managed by trained professionals.

Supportive care 

Physical therapy, occupational therapy, and speech therapy can be very helpful in allowing patients to live as comfortably and independently as possible.


Most patients with LNS have a shorter lifespan and only live until their 30s. Respiratory failure and chest infections like pneumonia are the most common causes of death in these cases. However, currently, there are ongoing studies to develop newer treatment methods such as deep brain stimulation, dopamine replacement therapy, and botulinum toxin injections.7,8


The diagnostic process for LNS is complex and typically begins with an evaluation of the child's presentation of the characteristic signs and symptoms mentioned above. However, it's important to be aware that the diagnosis may be confused with other conditions, including:

For a definitive diagnosis, a healthcare provider will take a detailed history, perform a physical and neurological examination, as well as certain tests, such as:

Additionally, five metabolites are associated with the early diagnosis of LSN, these are:10

  • Excessive increase in AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide)
  • Excessive increase in ZTP (Triphosphate form of AICAR)
  • Excessive increase in Vitamin B3 in the form of niacin or niacinamide
  • Excessive increase in S-AMP (Succinyl-Adenosine Monophosphate)
  • Severe depletion of ATP (Adenosine Triphosphate)

Prenatal screening may be offered to parents who have a family history of LNS and are expecting a male child. The prenatal diagnosis methods involve amniocentesis and chorionic villus sampling (CVS).


How can I prevent lesch-nyhan syndrome?

LNS is an inherited genetic disorder, and unfortunately, there are no known preventive measures for it. However, it can be identified during pregnancy through prenatal screening. It is recommended that individuals with a family history of LNS or a previous child with the condition undergo genetic testing to identify potential carriers. The management of LNS primarily focuses on helping patients cope with their symptoms and facilitating their integration into society, with the goal of enabling them to lead as comfortable a life as possible.

How common is lesch-nyhan syndrome?

The estimated prevalence of LNS ranges from 1 in 235,000 to 1 in 380,000 live births across all populations. The condition is usually seen in males but has occasionally been documented in females.

Who is at risk of lesch-nyhan syndrome?

Parents with a known family history of LNS or already have a child diagnosed with the condition face a higher risk of having another child with LNS. Therefore, genetic testing is conducted to detect any alterations or mutations in the HPRT1 gene. Additionally, in subsequent pregnancies, amniocentesis or chorionic villus sampling may be used to identify a foetus with LNS.

What are the different phenotypic variations observed in lesch-nyhan syndrome?

LNS presents a range of phenotypic variations. The most severe form is classic LNS, which is characterised by self-injurious behaviours and prominent clinical features. Intermediate phenotypes, positioned in the middle of the spectrum, do not exhibit self-injurious behaviours and may have relatively normal cognition and intelligence. However, these patients have some difficulties with muscle control and movement, with some experiencing severe muscle spasms and speech difficulties, while others show only minor clumsiness. The mildest phenotypes show no apparent behavioural or neurological problems but have elevated uric acid levels.

When should I see a doctor?

LNS is usually asymptomatic at birth and during early infancy. Once a child grows older, parents and caregivers must look out for the following signs:

  • Involuntary jerky movements, facial grimacing, and spasms
  • Floppiness 
  • Delayed milestones
  • Orange-coloured crystals in the diapers
  • Head-banging and limb-banging
  • Lip-biting and eye-poking

If your child exhibits any similar behaviours, it is important to contact your healthcare provider for an evaluation to determine the underlying cause.


  • Lesch-Nyhan Syndrome (LNS) is a genetic disorder characterised by developmental delays, movement difficulties, and self-injurious tendencies
  • Clinical features appear during infancy and increase in severity as the child grows. Initial symptoms, such as muscle stiffness, speech and swallowing difficulty, and abnormal movements, can be misdiagnosed with other movement disorders. However, self-injurious behaviours, like head-banging, biting, and self-harm, are the hallmark of LNS
  • Treatment approaches encompass a combination of medications, behavioural therapy, and supportive care
  • Unfortunately, the prognosis for this condition remains poor, with most patients rarely surviving beyond their thirties. However, ongoing research and studies continue to explore new medications and therapies for LNS


  1. Nanagiri A, Shabbir N. Lesch-nyhan syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Nov 6]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK556079/
  2. Doucet BP, Jegatheesan D, Burke J. Late diagnosis of Lesch-Nyhan disease variant. Case Reports [Internet]. 2013 Dec 10 [cited 2023 Nov 6];2013:bcr2013201997. Available from: https://casereports.bmj.com/content/2013/bcr-2013-201997
  3. Torres RJ, Puig JG. Hypoxanthine-guanine phosophoribosyltransferase (Hprt) deficiency: Lesch-Nyhan syndrome. Orphanet J Rare Dis [Internet]. 2007 Dec 8 [cited 2023 Nov 6];2:48. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234399/
  4. Schretlen DJ, Harris JC, Park KS, Jinnah HA, del Pozo NO. Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency. J Int Neuropsychol Soc [Internet]. 2001 Nov [cited 2023 Nov 6];7(7):805–12. Available from: https://pubmed.ncbi.nlm.nih.gov/11771623/
  5. Cakmakli HF, Torres RJ, Menendez A, Yalcin-Cakmakli G, Porter CC, Puig JG, et al. Macrocytic anemia in lesch-nyhan disease and its variants. Genet Med [Internet]. 2019 Feb [cited 2023 Nov 6];21(2):353–60. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281870/
  6. Momosaki K, Kido J, Matsumoto S, Taniguchi A, Akiyama T, Sawada T, et al. The effect of s-adenosylmethionine treatment on neurobehavioral phenotypes in lesch-nyhan disease: a case report. Case Rep Neurol [Internet]. 2019 Sep 19 [cited 2023 Nov 6];11(3):256–64. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787411/
  7. Ferrazzoli D, Carter A, Ustun FS, Palamara G, Ortelli P, Maestri R, et al. Dopamine replacement therapy, learning and reward prediction in parkinson’s disease: implications for rehabilitation. Front Behav Neurosci [Internet]. 2016 Jun 14 [cited 2023 Nov 6];10:121. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906006/
  8. Garcia-Romero M del M, Torres RJ, Garcia-Puig J, Pascual-Pascual SI. Safety and efficacy of botulinum toxin in the treatment of self-biting behavior in lesch-nyhan disease. Pediatric Neurology [Internet]. 2022 Feb 1 [cited 2023 Nov 6];127:6–10. Available from: https://www.sciencedirect.com/science/article/pii/S0887899421002459
  9. de Brouwer AP, Christodoulou J. Phosphoribosylpyrophosphate synthetase superactivity. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2023 Nov 6]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1973/
  10. Ceballos-Picot I, Le Dantec A, Brassier A, Jaïs JP, Ledroit M, Cahu J, et al. New biomarkers for early diagnosis of Lesch-Nyhan disease revealed by metabolic analysis on a large cohort of patients. Orphanet J Rare Dis [Internet]. 2015 Jan 23 [cited 2023 Nov 6];10:7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320826/ 
This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Aparajita Balsavar

Bachelor of Medicine, Bachelor of Surgery - MBBS, Medicine, Rajiv Gandhi University of Health Sciences

Aparajita is a Junior Doctor with a keen interest in clinical research, clinical governance and academic writing and has experience working in public health awareness. She is a GMC Registered doctor and is looking forward to working in Child and Adolescent mental health, developmental disabilities and inborn genetic disorders, while simultaneously continuing to work in mentoring future doctors.

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