6th February 2024

Lesch-Nyhan Syndrome

Lesch-Nyhan disease is a rare inborn error of purine metabolism characterised by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) encoded on the long arm of the X chromosome at Xq26-q27. It is extremely rare, with an estimated prevalence of between  1 case per 235,000 and 1 case per 380,000 live births, and usually affects male patients due to its X-linked mode of inheritance. Most mutations are expected to occur de novo because male patients with classic Lesch-Nyhan disease do not reproduce.

Hypoxanthine-guanine phosphoribosyltransferase  (HPRT) is a critical enzyme mediating the recycling of purines (hypoxanthine and guanine) into their respective nucleotide pools. In its absence, this does not happen; instead, they are degraded to uric acid. This combination of reduced purine salvage with accompanying de novo purine synthesis results in marked overproduction of uric acid. Typically, renal clearance limits serum uric acid levels. However, levels remain high despite this, resulting in an increased risk of urate crystal deposition in the joints, kidneys and subcutaneous tissues. Untreated, this can lead to many complications, including the development of gouty arthritis, nephrolithiasis, and subcutaneous tophi.

Image Source: Wikimedia Commons (2018). Purine Salvage Pathway, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Purine_Salvage_Pathway.svg (Accessed: 4 January 2024).

Clinical features

This includes:

• Self-injurious behaviour
  • This is the most striking feature of Lesch-Nyhan disease. It typically starts between the ages of 2 and 5, frequently with finger and lip biting, although progression with subsequent loss of tissue in fingers, lips, tongue and oral mucosa is typical.
• Cognitive impairment
  • This is usually seen as a failure to reach motor milestones such as crawling, sitting or walking, with below-average levels of intelligence, mainly involving attention and mental flexibility.
• Hyperkinetic features
  • Involuntary movements are common, often presenting later in the disease course. These include generalised action dystonia, plus additional extraneous movements in the face, neck and limbs, giving twisted postures that limit voluntary movement.
• Features of hyperuricaemia
  • The presence of orange ‘sand’ crystals in the nappy is not uncommon and may be the earliest manifestation of the disorder, so clinicians should screen it. These form secondary to uric acid crystal formation in the urinary tract and subsequent microhaematuria.
  • Hyperuricaemia can also result in nephrolithiasis, gouty arthritis and subcutaneous tophi, particularly in the ears.
• The neuro-behavioural features of LND, including hyperkinetic motor disorder, attentional deficits and abnormal behaviour, are proposed to be secondary to decreased dopamine content in the brain’s basal ganglia and extensive grey and white matter abnormalities. However, the mechanism of this and its relation to HPRT deficiency remains unclear. 

Diagnosis

Lesch Nyhan disease is usually diagnosed early in life, typically before the age of 4 years old. It should be suspected in a patient with delayed development paired with a hyperkinetic disorder or, more typically, self-injurious behaviour, particularly in high uric acid levels.

Formal diagnosis involves confirmation of clinical suspicion with hypoxanthine-guanine phosphoribosyltransferase (HPRT) molecular gene analysis, usually also with analysis of HPRT enzyme activity. The absence of HPRT enzyme in cells from any tissue can confirm the diagnosis.

Most patients will have elevated serum and urine uric acid levels secondary to HPRT deficiency; therefore, these investigations typically form part of the work-up to diagnosis. As already described, they lack sufficient sensitivity and specificity for definitive diagnosis, which relies on genetic testing.

Brain imaging, such as CT or MRI scanning, is not essential for diagnosing Lesch-Nyhan disease. However, it can help exclude other conditions. Typically, these scans report no obvious structural malformations or signal changes in these patients.

Differentials include – cerebral palsy, diseases with developmental delay, and diseases with dystonia at a young age.

Management

Currently, there is no curative treatment for Lesch-Nyhan disease; therefore, supportive management and lifelong monitoring to prevent complications remain the mainstay. This often requires the coordinated efforts of many different specialities, including paediatricians and physical therapists.

Allopurinol is vital in all patients to reduce serum uric acid levels and decrease the risk of complications associated with hyperuricaemia. It does this by inhibiting the conversion of xanthine and hypoxanthine to uric acid, and dosage should be tailored to the patient’s serum uric acid concentrations and renal function. It has no impact on the neurological features of the disease.

Treatment for patients who develop nephrolithiasis varies from increasing fluid intake and urine alkalinisation with potassium citrate for smaller stones to lithotripsy or surgery required for larger stones. Regular ultrasound (these stones are radiolucent) is recommended to detect subclinical nephrolithiasis.

Although patients show extrapyramidal features secondary to dopamine deficiency, the role of dopamine replacement therapy is inconsistent and of little value in reducing the burden of these features.

Muscle relaxants, including baclofen and dantrolene, can be helpful in patients who exhibit spasticity.

The most challenging aspect of management remains the difficulty in controlling behavioural abnormalities. No pharmacological treatment has been successful at consistently reducing self-injurious behaviour, and likewise, these behaviours do not respond to psychological treatments either. Furthermore, negative reinforcement has been shown to worsen this behaviour. The most remarkable outcomes have been seen by recognising these behaviours are beyond the patient’s control, positively reinforcing good behaviour, ignoring the bad and providing an environment of active engagement in which the patient feels understood. Despite this, some form of physical restraint remains a mainstay to ensure patient safety.

Patients with Lesch-Nyhan disease require a great deal of support; they do not usually develop the ability to sit unsupported or mobilise and generally need assistance with all activities of daily living. Few with the condition live beyond 40 years, with sudden unexpected death a relatively common phenomenon.

References

• Lesch-Nyhan disease Lesch-Nyhan disease – Symptoms, diagnosis and treatment | BMJ Best Practice US. Available at: https://bestpractice.bmj.com/topics/en-us/1192 (Accessed: 02 October 2023). 
• Lesch Nyhan syndrome – symptoms, causes, treatment: Nord (2023) National Organization for Rare Disorders. Available at: https://rarediseases.org/rare-diseases/lesch-nyhan-syndrome/ (Accessed: 02 October 2023). 
• Lesch-Nyhan syndrome (no date) National Institute of Neurological Disorders and Stroke. Available at: https://www.ninds.nih.gov/health-information/disorders/lesch-nyhan-syndrome (Accessed: 02 October 2023). 
• Symons, F.J. & Travis Thompson (1997). A Review of Self-Injurious Behaviour and Pain in Persons with Developmental Disabilities: Lesch-Nyhan syndrome, Lesch-Nyhan Syndrome – an overview | ScienceDirect Topics. Available at: https://www.sciencedirect.com/topics/psychology/lesch-nyhan-syndrome (Accessed: 02 October 2023). 
• Jimenez, R.T. and Puig, J.G. (2012). Purine Metabolism Disorder, Gout and Other Crystal Arthropathies. Available at: https://www.sciencedirect.com/topics/medicine-and-dentistry/purine-metabolism-disorder (Accessed: 02 October 2023). 
• Gout (2023) NHS choices. Available at: https://www.nhs.uk/conditions/gout/ (Accessed: 02 October 2023). 
• Badlissi, F. (2023). Gout, Gout – Symptoms, diagnosis and treatment | BMJ Best Practice US. Available at: https://bestpractice.bmj.com/topics/en-gb/13 (Accessed: 02 October 2023). 
• Overview: Gout: Diagnosis and management: Guidance (no date) NICE. Available at: https://www.nice.org.uk/guidance/ng219 (Accessed: 02 October 2023). 
• Gout and Diet – UK Gout Society (no date) UK Gout Society. Available at: https://www.ukgoutsociety.org/PDFs/goutsociety-allaboutgoutanddiet-0113.pdf (Accessed: 02 October 2023).