Lesch-Nyhan syndrome laboratory findings
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]
Overview
When an affected individual has fully developed the three clinical elements of uric acid overproduction which is neurologic dysfunction, and cognitive and behavioral disturbances, diagnosis of LNS is easily made. Difficulties of diagnosis are abundant in the early stages when the three features are not yet obvious. Suspicion often comes about when the developmental delay of the individual is associated with hyperuricemia.
Laboratory Findings
Blood tests
- Hyperuricemia
- Increase in serum creatinine levels
- Increased uric acid levels
- Megaloblastic anemia:
- Raised MCV
- Macrocytosis
- Vitamin B12, Folate and serum iron levels are normal
- Urate: creatinine ratio is elevated
- good indicator of acid overproduction
- For children under 10 years of age, the ratio is usually more than 2
Urinalysis
- Microhematuria or frank hematuria
- 24 hour urate excretion of more than 20 mg/kg is also typical but is not diagnostic.
Biochemical Testing
- Biochemical analyses, although not routinely 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 HGPRT1 mutation testing, it is 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 x 10-2 is found in carrier females, while a non-carrier female has a frequency of 1-20 x 10-6. This frequency is usually diagnostic by itself.
- Molecular genetic testing is the most effective method of testing, as HGPRT1 is the only gene known to be associated with LNS. *Individuals who display the full Lesch-Nyhan phenotype all have mutations in the HGPRT1 gene. Sequence analysis of mRNA is available clinically and can be utilized in order to detect HGPRT1 mutations in males affected with Lesch-Nyhan syndrome. *Techniques such as RT-PCR, multiplex genomic PCR, and sequence analysis (cDNA and genomic DNA), used for the diagnosis of genetic diseases, are performed on a research basis. If RT-PCR tests result in cDNA showing the absence of an entire exon or exons, then multiplex genomic PCR testing is performed. Multiplex genomic PCR testing amplifies the nine exons of the HGPRT1 gene as eight PCR products.
- If the exon in question is deleted, the corresponding band will be missing from the multiplex PCR. However if the exon is present, the exon is sequenced to identify the mutation, therefore causing exclusion of the exon from cDNA. If no cDNA is created by RT-PCR, then multiplex PCR is performed on the notion that most or all of the gene is obliterated.
Other tests
- Activity of HGPRT enzyme fibroblastss or lymphoblasts that is less than 1.5% of normal enzyme activity confirms the diagnosis of Lesch-Nyhan syndrome.