Lesch-Nyhan syndrome screening

Lesch-Nyhan syndrome Microchapters
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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

Lesch–Nyhan syndrome is first suspected when self-inflicted injury behavior develops. When an affected individual has fully developed the three clinical elements of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances, diagnosis of LNS is easily made. It is, however, difficult to confirm diagnosis in early stages of disease progression, when treatment can potentially delay the development of above mentioned complications.

Screening

• Genetic consultation
• Antenatal diagnosis
• 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 HGPRT 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.