Eric TanBiochem 118March 8, 1999Prader-Willi Syndrome: Causes and Possible SolutionsPrader-Willi Syndrome is a rare and fascinating disorder in both its causesand its potential solutions. It differs from most genetic diseases in that it iscaused by the absence of a parental set of genes, rather than the absence ordeletion of a particular gene. This causes the syndrome to produce a wide, yethighly specific variety of physiological, behavioral and physical effects as well asdistinct problems for detection and possible genetic therapy.CausesPrader-Willi syndrome is caused by a small interstitial deletion ofchromosome material, specifically on chromosome 15. The syndrome is anexample of genetic imprinting, a process in which genes are expresseddifferently depending on the parent of origin. In a normal individual, thepaternally inherited genes on chromosome 15 are expressed normally, while thematernal genes are present but silent, or not expressed. Prader-Willi resultswhen the active copy of the relevant gene, the paternal copy, is absent. Eitherthe deletion of the paternal copy or the presence of two copies of the maternalgene copies, which is termed uniparental disomy, is the cause. For Prader-Willisyndrome and a related disease, Angelman’s syndrome, an imprinting center hasbeen identified as determining whether the relevant gene or genes causing thesedisorders are expressed. This process occurs in the parental gonad; the genesEric TanBiochem 118March 8, 1999for Prader-Willi syndrome are activated after passing through the paternal gonadbut are silenced through the maternal gonad.Clinical EffectsThe unusual causes of Prader-Willi syndrome produces a great variety ofclinical effects that are found in almost all cases. These effects include alteredbehavioral phenotype, appearance and bodily development. The mostwidespread effect of Prader-Willi is short stature, which is almost always presentby the second half of the second decade. Abnormal pubertal development isalso present, evidenced by. Hyperphagia, or excessive eating is also anothereffect—food-seeking behavior is common, as well as obesity as a result. Facialfeatures include distinctive facial diameter, nasal bridge and mouth. Visual acuitydeficit is also present, as well as high pain threshold, skin picking and highthreshold for vomiting. As can be seen, these are a set of very specific effectsthat, yet, still appear in all individuals diagnosed with Prader-Willi syndrome.These effects stress the unusual effects of paternal deletion, causing changesthat are mostly behavioral and physiological in nature. Despite having beenidentified with a deficiency in gene splicing mechanism, as a result of lack ofgenetic information in forming small nuclear ribonucleproteins, or snRPN’s, thereis no direct lethality associated with the seemingly drastic deletion caused bygenetic imprinting. Study of the causes of Prader-Willi syndrome can not onlyEric TanBiochem 118March 8, 1999directly aid those affected by its effects, but also increase the knowledge ofgenetic influences on human behavior and physical development.DetectionPrader-Willi syndrome is also important in that it is was the firstmicrodeletion syndrome identified by high-resolution chromosome analysis. Infact, high-resolution chromosome analysis remains the first choice for initial testsin detecting deletions in 15q11-q13. However, clinical detection has becomemuch more accurate with the use of fluorescence in situ hybridization (FISH).Current test that search for genetic deletion causal for Prader-Willi syndromenow combines both high-resolution chromosome analysis and FISH. In thecases of uniparental disomy, which occur in approximately %2-%5 of cases, thesimplest way to diagnose UPD is with chromosome-specific microsatellitemarkers. However, these tests are universally expensive and require specialistequipment. The most common test for Prader-Willi syndrome, therefore, consistsof testing for extreme low levels in proteins such as growth hormone that are theresults of the genetic deletions of Prader-Willi syndrome.SolutionsThe current solution, or “cure,” to Prader-Willi syndrome is to address itsmost serious symptom, obesity. Obesity can reach extreme levels and is theEric TanBiochem 118March 8, 1999only serious cause of death as a direct result of Prader-Willi syndrome. As aresult, patients diagnosed with Prader-Willi syndrome are given regular injectionsof growth hormone, now produced by genetically altered E. Colicoli, to combatthis side effect. In regards to genetic therapy, Prader-Willi syndrome presents avariety of problems. Genetic therapy is just being considered today, in light ofnew and hopefully upcoming advances in genetic detection, and targeting, aswell as the completion of the Human Genome Project. However, even if genetictherapy becomes a possibility, there are several prerequisites in order for agenetically caused disease or syndrome to be treated with such methods. It isnecessary to define what product is to be produced from the patient’s cells. Nextis to define the genetic sequence that codes for said product. It can be seenthen, that the disease or syndrome must have an easily alterable geneticsequence that produces a particular protein. Prader-Willi syndrome, however, isthe result of not the deletion of an entire set of genes, but the absence of anentire set of genes from one parent. Thus, inserting a new genetic sequence willbe extremely difficult, as obtaining another copy of such a genetic set can beboth physically (parent may be incapable of donating genetic information) andgenetically impossible. However, some solutions can be created from thepossibilities presented by gene therapy. Although the behavioral effects ofPrader-Willi syndrome are difficult to address through direct genetic alteration,the protein-production elements that are deficient can be addressed. In otherwords, genes that code for production of growth hormone, or, on a more basiclevel, code for proper mRNA splicing or correct snRPN formation, can beEric TanBiochem 118March 8, 1999introduced into a patient with Prader-Willi. Such a procedure, however, rests onthe identification of the genes responsible for such complex procedures, mostprobably via the completion of the Human Genome Project, as well as fullydeveloped genetic therapy procedures. However, the great leaps that medicaltechnology maintains gives hope to those affected by the
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