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Case Details

At the age of 11 months, a boy showed signs of delayed motor development and was brought for consultation. His mother had noticed sand like crystals on the diaper of the baby but reported only when asked particularly about it. History revealed that the child had a compulsive urge to bite his lips and fingers. Upon questioning the mother revealed that she had a brother with similar symptoms.

The Lesch Nyhan syndrome was suspected, urinary and serum uric acid levels were estimated. Both were abnormally high for the boy’s age. The diagnosis was confirmed by estimating enzyme levels in skin fibroblasts; the enzyme activity was 50 % of the normal.

Which enzyme is deficient in Lesch Nyhan Syndrome?

What is the basis for Hyperuricemia, hyperuricosuria and self-mutilation in this disorder?

Lesch–Nyhan syndrome (LNS)

Case discussion

Lesch–Nyhan syndrome (LNS), also known as Nyhan’s syndrome and Juvenile gout, is a rare inherited disorder.

Biochemical Defect

LNS is an X-linked recessive disorder, caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT), and produced by mutations in the HGPRT gene. This enzyme is normally present in each cell in the body, but its highest concentration is in the brain, especially in the basal ganglia. The HGPRT gene has been localized to the long arm of the X chromosome (q26-q27). The disorder appears in males; occurrence in females is extremely rare.


Formation of DNA (during cell division) requires nucleotides, molecules that are the building blocks for DNA. The purine bases (adenine and guanine) and Pyrimidine bases (thymine and cytosine) are bound to deoxyribose and phosphate is incorporated as necessary. Normally, the nucleotides are synthesized de novo from amino acids and other precursors. A small part, however, is ‘recycled’ from degraded DNA of broken-down cells. This is termed the “salvage pathway”.(Figure) 

HGPRT is the “salvage enzyme” for the purines: it channels hypoxanthine and guanine back into DNA synthesis. Failure of this enzyme has two results:

  • Cell breakdown products cannot be reused, and are therefore degraded. This gives rise to increased uric acid, a purine breakdown product.
  • The de novo pathway is stimulated due to an excess of PRPP (5-phospho-D-ribosyl-1-pyrophosphate or simply phosphoribosyl-pyrophosphate).

In the absence of HGPRT, these purine bases cannot be salvaged, and instead are degraded and excreted as uric acid. In addition to the failure of purine recycling, the synthetic rate for purines is accelerated, presumably to compensate for purines lost by the failure of the salvage process. The failure of recycling together with the increased synthesis of purines is the basis for the overproduction of uric acid.

Figure-1 showing Salvage pathway.

The increased production of uric acid leads to hyperuricemia. Since uric acid is near its physiological limit of solubility in the body, the persistent hyperuricemia increases the risk of uric acid crystal precipitation in the tissues. Uric acid crystal deposition in the joints produces an inflammatory reaction and gouty arthritis. The kidneys respond to the hyperuricemia by increasing its excretion into the urinary tract, increasing the risk of forming urate stones in the urinary collecting system. These stones may be passed as a sandy sludge or as larger particles that may obstruct urine flow and increase the risk for hematuria and urinary tract infections.


The reported worldwide prevalence is 1 case per 380,000 population.

Clinical Manifestations

LNS is characterized by three major hallmarks: neurological dysfunction, cognitive and behavioral disturbances including self-mutilation, and uric acid overproduction (hyperuricemia). Some may also be afflicted with macrocytic anemia. Virtually all patients are males; males suffer delayed growth and puberty, and most develop shrunken testicles or testicular atrophy. Female carriers are at an increased risk for gouty arthritis, but are usually otherwise unaffected.

1) Overproduction of uric acid

One of the first symptoms of the disease is the presence of sand-like crystals of uric acid in the diapers of the affected infant.

The overproduction of uric acid is present at birth, but may not be recognized by routine clinical laboratory testing methods. The serum uric acid concentration is often normal initially, as the excess purines are promptly eliminated in the urine. But as the disease progresses the hyperuricemia may be observed.

The crystals usually appear as an orange grainy material, or they may coalesce to form either multiple tiny stones or distinct large stones that are difficult to pass. The stones, or calculi, usually cause hematuria (blood in the urine) and increase the risk of urinary tract infection. Some victims suffer kidney damage due to such kidney stones. Stones may be the presenting feature of the disease, but can go undetected for months or even years.

2) Nervous system impairment

The most common presenting features are abnormally decreased muscle tone (hypotonia) and developmental delay, which are evident by three to six months of age. Lack of speech is also a very common trait associated with LNS.

Irritability, loss of motor control, involuntary movements and arching of the spine (opisthotonus) are also there

3) Self-injuring behavior

The age at onset of self-injury may be as early as 1 yr and occasionally as late as the teens. The self-injury begins with biting of the lips and tongue; as the disease progresses, affected individuals frequently develop finger biting and head banging. The self-injury can increase during times of stress. Self-mutilation is a distinguishing characteristic of the disease and is apparent in 85% of affected males.


The gross overproduction of uric acid is often evident in routine blood and urine studies.

1) Uric acid levels in the blood typically are elevated,

2) Urinary uric acid excretion also is increased typically.

3) Definitive diagnosis is obtained most often by measurement of HGPRT enzyme activity in blood or tissue

Diagnosis is confirmed by identifying a molecular genetic mutation in the HGPRT gene. Molecular genetic diagnosis provides an ideal tool for carrier detection and prenatal screening of at-risk pregnancies.

4) Macrocytic anemia, sometimes profound, is relatively common. Vitamin B-12, folate, and iron results are typically normal.

Other Tests

Noninvasive imaging studies of the kidneys and other parts of the urogenital system are warranted because of the marked increase in the risk for kidney stones.


Treatment for LNS is symptomatic. Gout can be treated with Allopurinol to control excessive amounts of uric acid. Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. There is no standard treatment for the neurological symptoms of LNS


The prognosis for individuals with severe LNS is poor. Death is usually due to renal failure or complications from hypotonia, in the first or second decade of life. Less severe forms have better prognosis.

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