Rare diseases often hide in plain sight — behind delayed milestones, feeding difficulties or symptoms that seem minor at first glance. Lesch-Nyhan Syndrome (LNS) is one such condition. What begins as a metabolic imbalance soon reveals deeper neurological consequences, making early diagnosis not just important, but life-changing. Understanding its genetic roots and behavioural manifestations is key to improving outcomes for affected children.
At its core, LNS is caused by a mutation in the HPRT1 gene on the X chromosome. “LNS is caused by mutations in the HPRT1 gene located on the X chromosome,” explains Dr Srikanth Reddy S, senior consultant neurosurgeon at Apollo Hospitals Financial District. “This gene produces an enzyme crucial for recycling purines, the building blocks of DNA. When defective, toxic uric acid accumulates, affecting the brain and joints,” he adds.
The missing enzyme — hypoxanthine-guanine phosphoribosyl transferase (HPRT) — plays a key role in purine recycling. Dr Joy Mounica, consultant neurologist at Renova Hospitals, notes, “Lesch-Nyhan Syndrome is an extremely rare X-linked recessive disorder of purine metabolism due to severe inborn deficiency of the HPRT enzyme, often resulting from mutation of the HPRT1 gene located at q26-27 on the long arm of the X chromosome.”
Because the condition is X-linked recessive, it predominantly affects males. With only one X chromosome, a single defective gene is enough to cause disease. Females typically carry a second, healthy X chromosome and are usually asymptomatic carriers.
Infants with LNS usually appear normal at birth, which contributes to delayed diagnosis. “In early infancy, the signs are often subtle and easy to miss,” says Dr Vittal Kumar Kesireddy, consultant and in-charge, department of paediatrics at CARE Hospitals, Banjara Hills. “Many babies show delayed motor milestones — poor head control, delayed sitting, or unusual stiffness or floppiness,” adds Dr Vittal.
One of the most overlooked red flags is visible but easily dismissed. “An early clue that is frequently overlooked is orange or brick-coloured crystals in the diaper, caused by excess uric acid,” he adds.
Dr Joy Mounica also highlights that “reddish-orange sand-like crystals in diapers, developmental delays, persistent vomiting and floppiness” as early indicators. Self-injurious behaviour typically appears after tooth eruption.
While excess uric acid causes kidney stones and gout, the neurological symptoms define the disorder.
“In LNS, deficiency of the HPRT enzyme disrupts purine recycling and alters brain chemistry,” says Dr Srikanth, adding, “The imbalance particularly affects dopamine pathways in the basal ganglia — the region controlling movement and behaviour.”
Children may develop involuntary movements such as chorea, dystonia and athetosis, along with muscle stiffness and moderate intellectual disability. The most distressing feature is self-injury.
“Self-harm remains the most defining and distressing feature. The behaviour is not psychological but neurological, driven by dopamine dysfunction,” notes Dr Srikanth.
Dr Joy Mounica clarifies that the behaviour is ‘uncontrollable, involuntary and compulsive’, involving biting of lips, fingers or tongue. It differs from psychiatric conditions where self-harm may serve as emotional regulation.
Dr Vittal adds, “The key difference really comes down to control rather than choice. Many children are clearly distressed by their actions and may even look for ways to be helped.”
There is no cure for LNS, so treatment focuses on managing symptoms. “Allopurinol, a xanthine oxidase inhibitor, is helpful mainly for uric acid overproduction symptoms,” says Dr Joy Mounica.
However, Dr Vittal states, “Allopurinol reduces risks like kidney stones and gout, but it doesn’t improve the neurological or behavioural symptoms.”
Medications such as baclofen, diazepam or antipsychotics may help manage movement disorders and behavioural symptoms. Physiotherapy and occupational therapy support mobility and function.
In cases of severe self-injury, temporary protective measures may be necessary. “Physical restraints like elbow restraints, dental guards and lip bumpers are helpful temporarily,” says Dr Joy Mounica.
Still, Dr Vittal emphasises that the goal is “to keep the child safe while preserving dignity and as much independence as possible.”
Early identification significantly improves outcomes. Genetic counselling is equally critical. “Since the condition is X-linked, mothers may be carriers without symptoms. Counselling helps families understand recurrence risk and options for future pregnancies,” says Dr Vittal.
Research into gene therapy and dopamine-targeted treatments is ongoing. “Scientists are exploring CRISPR-based gene editing to correct HPRT1 mutations,” says Dr Srikanth.
For now, awareness remains the biggest gap. Earlier recognition, better access to genetic testing and coordinated multidisciplinary care can significantly change outcomes.