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Lesch-Nyhan syndrome - Metabolic mutilation |
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Written by Lev Prasov
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May 20, 2006 at 11:29 PM |
Lesch-Nyhan syndrome is an X-linked genetic disorder that results from a deficiency in the nucleotide "salvage pathways." This disease leads to multiple neurological deficiencies (most notably, mutilation), as well as gout.
Ever wonder what drives people to self-mutilating behaviors, such as tongue biting, finger chewing, and head banging? Well, in some cases, these behaviors may be due to biology. Problems in neurological development can have profound effects on behavior. Specifically, one mutation in an enzyme involved in nucleotide metabolism can lead to these behavioral abnormalities. This defect in the hypoxanthine-guanine phosphoribosyl transferase (HPRT) enzyme leads to Lesch-Nyhan syndrome, the topic for this week's DOTW.
 Figure I: Structure of uric acid, one of the metabolites of purine nucleotide degradation. ( Image courtesy of Wikipedia)
Lesch-Nyhan syndrome (LNS) is an X-linked genetic disorder that primarily affects boys. Women that carry one copy of the defective HPRT enzyme can have symptoms, but the effects of the deficiency are not nearly as severe, as these women also have one normal copy of the gene. The HPRT enzyme serves a vital role in the nucleotide "salvage pathways." When a cell dies, its DNA is degraded, but "salvage pathways" can be used by other cells rebuild some of these metabolites into nucleotides, so that they can be reused. In Lesch-Nyhan syndrome, one of the steps in the salvage of purine nucleotides (adenosine and guanosine) is disrupted. As breakdown products of these nucleosides can no longer be reused, they tend to build up. During rapid development, cells may not be able to synthesize all of their nucleotides from scratch and thus rely on these salvage pathways. It is not known whether the defects in Lesch-Nyhan syndrome are due to the increases in nucleotide metabolites or the inability of cells to keep up with nucleotide demand.
There are three key symptomatic hallmarks that result from HPRT deficiency: overproduction of uric acid (one endpoint metabolite), neurological deficiency, and self-mutilating behavior. Build up of uric acid can cause a condition known as gout. Uric acid is not very soluble and can form crystals in places that it should not. In patients with gout, crystals of uric acid are often formed in the joints, leading to pain and swelling. Additionally, crystal deposits in the kidneys form kidney stones that may block passage of urine or damage the kidney filtration apparatus. Females with one bad copy of HPRT can experience these symptoms of gout, but they do not suffer from the neurological impairments.
The neurological consequences of Lesch-Nyhan syndrome are devastating. The first neurological signs of LNS are irritability, decreased muscle tone, and some developmental delay. Additionally, children with LNS may experience some involuntary muscle spasms and have overactive reflexes. The most striking issues in LNS patients are the behavioral defects. Patients have the uncontrollable urge to hurt themselves, whether it is by biting their tongues, biting their fingers, or banging their heads against the wall.
Unfortunately, there is no cure for Lesch-Nyhan syndrome. Treatments focus on alleviating the various symptoms of the disease. For the gout aspect, allopurinol can be given to decrease the breakdown of purines into uric acid. Problems with spasticity and involuntary movements can be treated by giving nervous system depressants, such as phenobarbitol or diazepam (valium). No treatments are effective at stopping the self-mutilating behaviors. As cruel as it sounds, it may be necessary to restrain children and even pull out all of their teeth in order to keep them from hurting themselves. The prognosis for patients with LNS is very poor. Gene therapy may be a promising solution in the future, but it is still many years away.
For more information on Lesch-Nyhan syndrome, check out the following resources:
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