Lesch-Nyhan syndrome laboratory findings: Difference between revisions
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==Overview== | ==Overview== | ||
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. 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. Otherwise, the diagnosis should be alleged when developmental delay is associated with kidney stones ([[nephrolithiasis]]) or blood in the urine ([[hematuria]]), caused by uric acid stones. For the most part, Lesch-Nyhan syndrome is first suspected when self-inflicted injury behavior develops. However, self-injurious behaviors occur in other conditions, including nonspecific [[mental retardation]], [[autism]], [[Rett syndrome]], [[Cornelia de Lange syndrome]], [[Tourette syndrome]], [[familial dysautonomia]], [[choreoacanthocytosis]], [[sensory neuropathy]] including hereditary sensory neuropathy type 1, and several psychiatric conditions. Of these, only individuals with Lesch-Nyhan syndrome, de Lange syndrome, and familial dysautonomia recurrently display loss of tissue as a consequence. Biting the fingers and lips is a definitive feature of Lesch-Nyhan syndrome; in other syndromes associated with self-injury, the behaviors usually consist of head banging and nonspecific self-mutilation, but not biting of the cheeks, lips and fingers. Lesch-Nyhan syndrome ought to be clearly considered only when self-injurious behavior takes place in conjunction with hyperuricemia and neurological dysfunction. | |||
===Diagnostic approach=== | ===Diagnostic approach=== | ||
Revision as of 03:57, 15 August 2012
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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, 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. Otherwise, the diagnosis should be alleged when developmental delay is associated with kidney stones (nephrolithiasis) or blood in the urine (hematuria), caused by uric acid stones. For the most part, Lesch-Nyhan syndrome is first suspected when self-inflicted injury behavior develops. However, self-injurious behaviors occur in other conditions, including nonspecific mental retardation, autism, Rett syndrome, Cornelia de Lange syndrome, Tourette syndrome, familial dysautonomia, choreoacanthocytosis, sensory neuropathy including hereditary sensory neuropathy type 1, and several psychiatric conditions. Of these, only individuals with Lesch-Nyhan syndrome, de Lange syndrome, and familial dysautonomia recurrently display loss of tissue as a consequence. Biting the fingers and lips is a definitive feature of Lesch-Nyhan syndrome; in other syndromes associated with self-injury, the behaviors usually consist of head banging and nonspecific self-mutilation, but not biting of the cheeks, lips and fingers. Lesch-Nyhan syndrome ought to be clearly considered only when self-injurious behavior takes place in conjunction with hyperuricemia and neurological dysfunction.
Diagnostic approach
The urate to creatinine (breakdown product of creatine phosphate in muscle) concentration ratio in urine is elevated. This is a good indicator of acid overproduction. For children under ten years of age with Lesch-Nyhan syndrome, a urate to creatinine ratio above two is typically found. Twenty-four-hour urate excretion of more than 20 mg/kg is also typical but is not diagnostic. Hyperuricemia (serum uric acid concentration of >8 mg/dL) is often present but not reliable enough for diagnosis. Activity of the HPRT 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.
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 HPRT1 mutation testing, it is appropriate to grow her lymphocytes in 6-thioguanine (a purine analogue), which allows only HPRT-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 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. 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 HPRT1 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.