Lesch–Nyhan syndrome

Overview

Lesch–Nyhan syndrome (LNS) is a rare, inherited metabolic disorder that primarily affects males and is characterized by the overproduction of uric acid, severe neurological and behavioral abnormalities, and self-injurious behavior. It is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). The condition was first described in 1964 by medical researchers Drs. Michael Lesch and William Nyhan. Symptoms typically begin in infancy, and the disorder has profound effects on both physical and mental development.

Causes

Lesch–Nyhan syndrome is caused by mutations in the HPRT1 gene, which is located on the X chromosome. This gene provides instructions for producing the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), which is critical for recycling purines—essential components of DNA and RNA. The deficiency or complete absence of this enzyme leads to the accumulation of uric acid in the body and severe neurological dysfunction. LNS is inherited in an X-linked recessive manner, meaning it predominantly affects males, while females are typically carriers with no or mild symptoms.

Symptoms

The clinical features of Lesch–Nyhan syndrome generally appear within the first year of life and become progressively more severe. Common symptoms include:

• Hyperuricemia – high levels of uric acid, leading to:

  • Kidney stones

  • Gouty arthritis

  • Crystal deposition in joints and tissues (tophi)

• Neurological abnormalities – such as:

  • Muscle stiffness (dystonia)

  • Involuntary movements (chorea, athetosis)

  • Delayed motor development

• Self-injurious behavior – including:

  • Biting of lips, fingers, or tongue

  • Head banging or eye gouging

• Cognitive and behavioral issues – such as:

  • Moderate to severe intellectual disability

  • Impulsivity, aggression, or obsessive-compulsive traits

Diagnosis

Diagnosis of Lesch–Nyhan syndrome is based on clinical features, laboratory findings, and genetic testing. Key diagnostic steps include:

• Blood and urine tests – to measure elevated uric acid levels

• Enzyme assay – measuring HPRT activity in cultured cells (e.g., fibroblasts or blood cells)

• Genetic testing – identifying mutations in the HPRT1 gene to confirm the diagnosis

• Imaging studies – such as brain MRI, which may show nonspecific changes or help rule out other conditions

Treatment

There is no cure for Lesch–Nyhan syndrome, and treatment is focused on managing symptoms and preventing complications. A multidisciplinary approach is essential. Management includes:

• Allopurinol – a medication that reduces uric acid production and helps prevent gout and kidney stones

• Hydration and dietary adjustments – to lower uric acid levels and protect kidney function

• Medications for movement disorders – such as benzodiazepines or baclofen to manage dystonia

• Behavioral therapies and restraints – to prevent self-injury; dental extractions may be needed in severe cases

• Supportive therapies – including physical therapy, occupational therapy, and speech therapy

• Psychological support – for both patients and families to manage emotional and behavioral challenges

Prognosis

The prognosis for individuals with Lesch–Nyhan syndrome is generally poor due to the severe neurological and behavioral impairments. Most affected individuals are wheelchair-bound for life and require full-time care. While medications like allopurinol can effectively control uric acid levels, they do not improve neurological or behavioral symptoms. Life expectancy is often reduced, with many individuals living into their second or third decade. However, with supportive care and early intervention, quality of life can be improved, and complications can be managed more effectively.