What enzyme is deficient in Lesch-Nyhan syndrome?

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT), encoded by the HPRT1 gene on the X chromosome. The enzyme salvages hypoxanthine and guanine by attaching them to PRPP to form IMP and GMP. Classic Lesch-Nyhan syndrome occurs when activity is below about 1.5% of normal; people with 2% or more have milder variant forms with high uric acid but no self-injury.

Why is PRPP increased in Lesch-Nyhan syndrome?

HGPRT normally consumes PRPP in the salvage reactions, so when it is missing, PRPP accumulates while IMP and GMP levels fall. Both changes push glutamine-PRPP amidotransferase, the committed step of de novo purine synthesis, to convert more PRPP to 5-phosphoribosylamine. The extra purines made this way are broken down to uric acid, adding to the uric acid from unsalvaged bases.

Does allopurinol treat the self-injury in Lesch-Nyhan syndrome?

No. Allopurinol inhibits xanthine oxidase, so accumulated hypoxanthine is excreted instead of becoming uric acid, which helps prevent urate stones, kidney damage and gout. It has no effect on the dystonia, intellectual disability or self-injurious behavior, which don't appear to be caused by uric acid. Self-injury is managed with protective restraints, mouth guards or tooth removal, behavioral approaches and sometimes medication.

How is Kelley-Seegmiller syndrome different from Lesch-Nyhan syndrome?

Both are X-linked HGPRT deficiencies, but Kelley-Seegmiller syndrome is the mildest, partial form. Some enzyme activity remains, so patients overproduce uric acid and develop kidney stones and early-onset gout, while neurologic problems, if present, are milder and there is no self-injury. Classic Lesch-Nyhan syndrome, with almost no enzyme activity, adds severe dystonia, intellectual disability and compulsive self-biting.

Can girls get Lesch-Nyhan syndrome?

Very rarely. The disorder is X-linked recessive and almost exclusively affects boys and men. Female carriers usually have no symptoms, partly because the X chromosome carrying the variant is often inactivated in their blood cells, a pattern called skewed X-inactivation. Some carriers develop gout later in life from untreated high uric acid, a detail worth remembering in pedigree questions.

Lesch-Nyhan Syndrome: HGPRT, PRPP, Urate & Self-Injury

Lesch-Nyhan syndrome is an X-linked recessive deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT; gene HPRT1), the salvage enzyme that recycles hypoxanthine and guanine back into IMP and GMP. Without it, those bases are broken down to uric acid and the unused PRPP drives extra de novo purine synthesis, so affected boys overproduce uric acid (orange "sand" in the diaper, urate stones, later gout) while developing dystonia and other severe movement problems, intellectual disability and compulsive self-biting of the lips and fingers. Allopurinol controls the uric acid but does not improve the neurologic or behavioral features.

Mechanism: why a salvage defect raises uric acid

Cells get purines two ways: de novo synthesis, which costs a lot of energy, and salvage, which cheaply reattaches free bases to PRPP (5-phosphoribosyl-1-pyrophosphate). HGPRT runs two salvage reactions:

Hypoxanthine + PRPP → IMP
Guanine + PRPP → GMP

When HGPRT is missing, uric acid climbs from two directions:

Unsalvaged bases are degraded. Hypoxanthine and guanine are both funneled to xanthine, and xanthine oxidase, the last enzyme of purine breakdown, oxidizes hypoxanthine to xanthine and xanthine to uric acid.
De novo synthesis speeds up. With less IMP and GMP and more unused PRPP, glutamine-PRPP amidotransferase, the committed step of de novo purine synthesis, converts more PRPP to 5-phosphoribosylamine. The extra purines are eventually degraded to uric acid too.

HGPRT ↓ → PRPP ↑ and IMP/GMP ↓ → de novo purine synthesis ↑ → uric acid ↑

Both pathways are compared side by side in de novo vs salvage nucleotide synthesis.

The brain disease is a separate problem. People with Lesch-Nyhan syndrome have low dopamine in the brain, possibly because dopamine-producing cells depend on a steady supply of purines, but the exact cause of the neurologic signs is unclear. They do not appear to be caused by uric acid, which is why lowering uric acid doesn't help them.

How much enzyme is left matters. Classic Lesch-Nyhan syndrome occurs with less than 1.5% of normal HGPRT activity; people whose enzyme keeps 2% or more have a milder variant.

How it presents

Age	What you see
Early infancy	Orange, sand-like urate crystals in the diaper, often the first sign; development can look normal for the first few months
From about 3–6 months	Developmental delay, hypotonia and dystonia; infants who could sit typically lose the ability
First years of life	Spasticity, hyperreflexia, choreoathetosis, ballismus and opisthotonus, with dysarthria and dysphagia; most eventually need a wheelchair
Most often 2–3 years (can start once teeth erupt, or later)	Self-injury: biting the lips, cheeks and fingers, head banging, eye poking; sometimes aggression toward others
Infancy onward	Urate kidney stones with hematuria and urinary infections; uric acid nephropathy
Late teens to adulthood, if untreated	Recurrent gouty arthritis and tophi

Intellectual disability is usually moderate, although some patients have normal intelligence, and megaloblastic anemia can occur. Life span is shortened: most affected people don't survive past early adulthood, and kidney failure, respiratory failure and infections such as pneumonia are major complications.

Self-injury is not insensitivity to pain. Patients feel the pain of their injuries but have a compulsion to hurt themselves, and many ask to be restrained.

Lesch-Nyhan vs other purine enzyme defects

Disorder	Enzyme and inheritance	What builds up	Clinical picture
Lesch-Nyhan syndrome	HGPRT, less than 1.5% activity; X-linked recessive	Uric acid, with high PRPP	Hyperuricemia plus dystonia, intellectual disability and self-injury
Partial HGPRT deficiency (Kelley-Seegmiller syndrome, Lesch-Nyhan variant)	HGPRT, residual activity; X-linked recessive	Uric acid	Uric acid stones and early-onset gout; neurologic problems possible, no self-injury
Adenine phosphoribosyltransferase (APRT) deficiency	APRT; autosomal recessive	2,8-Dihydroxyadenine	Kidney stones and kidney damage; serum uric acid normal
Adenosine deaminase (ADA) deficiency	ADA; autosomal recessive	Deoxyadenosine, toxic to immature lymphocytes	Severe combined immunodeficiency in about 80%

ADA deficiency sits in the same purine pathways but is an immune disease; see adenosine deaminase deficiency and SCID.

Genetics

X-linked recessive, so it almost exclusively affects boys; an affected father cannot pass it to his sons. Prevalence is roughly 1 in 235,000 to 380,000.
Carrier mothers are usually unaffected, partly because the X chromosome carrying the variant is often inactivated in their blood cells (skewed X-inactivation). Some carriers develop gout later in life.
Pedigree patterns for this group are in the X-linked disorders flowchart.

Diagnosis

Suspect it in a boy with dystonia, intellectual disability and self-injury, especially with orange diaper crystals or early urate stones.
Uric acid: serum uric acid is usually high and urinary uric acid excretion is increased.
Confirm with absent HGPRT enzyme activity or HPRT1 molecular testing. Prenatal diagnosis is possible once the family's variant is known.

Treatment

Uric acid: a low-purine diet and allopurinol, a xanthine oxidase inhibitor. Allopurinol stops accumulated hypoxanthine from becoming uric acid; hypoxanthine is highly soluble and is excreted. This protects the kidneys and joints but has no effect on the neurologic or behavioral symptoms. Stones that form anyway may need lithotripsy; stone types are compared in nephrolithiasis types, including uric acid stones.
Self-injury: protective measures (restraints at the elbows, hips and chest; mouth guards or removal of teeth), behavioral approaches and sometimes medication.
Movement disorder: baclofen or benzodiazepines have been used for spasticity, but no treatment reliably improves the neurologic disease; care is supportive.

Exam traps

PRPP goes up, not down, and de novo purine synthesis increases: the salvage defect accelerates the de novo pathway.
Allopurinol fixes the urate, not the brain. The neurologic features aren't caused by uric acid.
Self-injury with intact pain sensation is classic Lesch-Nyhan syndrome; the partial form causes hyperuricemia and gout without self-injury.
Boys with carrier mothers: an affected male can't pass it to his sons.
Orange diaper crystals are urate, often the first sign, months before the neurologic picture is obvious.
ADA deficiency is also a purine enzyme defect, but it is autosomal recessive and causes SCID, not hyperuricemia with self-injury.
Megaloblastic anemia can be part of the syndrome, so a macrocytic anemia doesn't argue against it.

Worked example

Vignette. A 2-year-old boy is evaluated for developmental delay. He can't sit without support and has involuntary twisting movements of the limbs, increased tone and brisk reflexes. His parents recall orange, sand-like grains in his diapers as a baby. Over the past few months he has bitten his lower lip and fingertips so badly that they are scarred, and he cries while doing it. Serum uric acid is elevated. Which additional finding is most likely?

A. Increased intracellular PRPP and increased de novo purine synthesis
B. Decreased intracellular PRPP
C. Deoxyadenosine accumulation with very low T, B and NK cells
D. Urinary 2,8-dihydroxyadenine with a normal serum uric acid
E. Resolution of the dystonia after allopurinol

Answer: A. Missing HGPRT leaves PRPP unused, and the excess PRPP, with less IMP and GMP feedback, drives the committed step of de novo purine synthesis, adding to the uric acid made from unsalvaged bases.

Why the others are wrong:

B: PRPP rises, not falls, when an enzyme that consumes it is missing.
C: that is ADA deficiency, an autosomal recessive cause of SCID.
D: that is APRT deficiency, which causes 2,8-dihydroxyadenine stones with a normal uric acid.
E: allopurinol lowers uric acid but doesn't change the neurologic or behavioral features.

Key takeaways

HGPRT (HPRT1) deficiency, X-linked recessive: hypoxanthine and guanine aren't salvaged to IMP and GMP.
Uric acid rises two ways: unsalvaged bases are degraded, and excess PRPP accelerates de novo synthesis.
Presentation: orange diaper crystals, then dystonia and other movement problems, intellectual disability and self-biting from early childhood; urate stones and, later, gout.
Partial deficiency (Kelley-Seegmiller): hyperuricemia, stones and early gout without self-injury.
Diagnosis: high uric acid, then HGPRT activity or HPRT1 testing.
Treatment: allopurinol and a low-purine diet for uric acid; protective and supportive care for the neurologic disease, which allopurinol doesn't improve.