1. Definition
Lesch-Nyhan syndrome (LNS) is a rare X-linked recessive disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), leading to excessive uric acid production and severe neurological symptoms.
2. Biochemical consequences
2.1 Hyperactive De Novo Purine Synthesis
Loss of the salvage pathway means that hypoxanthine and guanine are not recycled, which results in increased availability of PRPP (phosphoribosyl pyrophosphate), a precursor for purine biosynthesis.
PRPP accumulation leads to the overactivation of de novo purine synthesis, since PRPP is a key activator of the rate-limiting enzyme amidophosphoribosyltransferase (GPAT).
The excessive production of purines results in increased purine breakdown, leading to high levels of uric acid.
2.2 Excess Uric Acid Production
Since purines cannot be salvaged, they undergo irreversible catabolism via the following reactions:
- Hypoxanthine → Xanthine (via xanthine oxidase)
- Xanthine → Uric Acid (via xanthine oxidase)
Uric acid is the final product of purine metabolism in humans, as humans lack the enzyme uricase, which would normally convert uric acid into the more soluble allantoin.
As the production of uric acid exceeds the excretion through the kidneys, the blood level of uric acid rises leading to hyperuricemia. The deposition of monosodium urate crystals can manifest as Gout.
3. Neurological consequences
The loss of HPRT activity is linked to dopamine deficiency in the basal ganglia. This is a brain region responsible for motor control and behavior regulation.
This can lead to:
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- Dystonia, chorea, and spasticity (extrapyramidal motor dysfunction)
- Cognitive impairment and developmental delay
- Pathological self-mutilation behavior (autoaggression)
4. Diagnostics
The diagnosis of LNS happens by an HPRT Enzyme Activity Test. A direct diagnosis is also possible by sequencing the mRNA.
5. Therapy
A treatment of LNS is currently not possible. Just the hyperuricemia and attendant symptoms (e.g. neurological problems) can be treated. Therefore Xanthine Oxidase Inhibitors (Allopurinol, Febuxostat) are given to reduce uric acid production.
Although this means that the purine bases are not recycled, they are not broken down further into uric acid.