Hyperuricemia (serum uric acid concentration of >8 mg/dL) is often present but not reliable enough for diagnosis. Activity of the HGPRT enzyme in cells from any type of tissue (e.g., blood, cultured fibroblasts, or lymphoblasts) that is less than 1.5% of normal enzyme activity confirms the diagnosis of Lesch–Nyhan syndrome. Molecular genetic studies of the HPRT gene mutations may confirm diagnosis, and are particularly helpful for subsequent carrier testing in at-risk females such as close family relatives on the female side. Testing
The use of biochemical testing for the detection of carriers is technically demanding and not often used. Biochemical analyses that have been performed on hair bulbs from at risk women have had a small number of both false positive and false negative outcomes. If only a suspected carrier female is available for mutation testing, it may be appropriate to grow her lymphocytes in 6-thioguanine (a purine analogue), which allows only HGPRT-deficient cells to survive. A mutant frequency of 0.5–5.0 × 10−2 is found in carrier females, while a non-carrier female has a frequency of 1–20 × 10−6. This frequency is usually diagnostic by itself.Molecular genetic testing is the most effective method of testing, as HPRT1 is the only gene known to be associated with LNS. Individuals who display the full Lesch–Nyhan phenotype all have mutations in the HPRT1 gene. Sequence analysis of mRNA is available clinically and can be utilized in order to detect HPRT1 mutations in males affected with Lesch–Nyhan syndrome.
However, if a male with a less severe phenotype reproduces, all of his daughters are carriers, and none of his sons will be affected. Pathophysiology
As in other X-linked diseases, males are affected because they only have one copy of the X chromosome. In Lesch–Nyhan syndrome, the defective gene is that for hypoxanthine-guanine phosphoribosyltransferase (HGPRT), a participant in the recycling of purine nucleotides. Female carriers have a second X chromosome, which contains a "normal" copy of HPRT, preventing the disease from developing, though they may have increased risk of hyperuricemia.A large number of mutations of HPRT are known. Mutations that only mildly decrease the enzymes function do not normally cause the severe form of LNS, but do produce a milder form of the disease which still features purine overproduction accompanied by susceptibility to gout and uric acid nephrolithiasis.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 and incorporated as necessary. Normally, the nucleotides are synthetized 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".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.