Prader-Willi Syndrome and its Linkage to Genetics - Essay Example

Prader-Willi Syndrome and its Linkage to Genetics Table of Contents Contents Page Introduction………………………………………………………….3 2. Phenotypic Features Associated With the Disease………………….4 3. Genetic Features of the Disease……………………………...……...5 4. The Nature of the Defect………………………………….….……..7 5. Cause and Effect Link between the Affected Genes and the Outcome Phenotype…………………………………………………….……..8 6. Diagnosis and Treatment of Prader-Willis Syndrome…….….…….9 7. Conclusion………………………………………………….………10 8. References……………………………………………..….………..12 Prader-Willi Syndrome and its Linkage to Genetics Prader-Willi Syndrome, moreover referred to as PWS, is a genetically linked disorder that afflicts various parts of the human anatomy. The disorder presents as hypotonia during infancy, coupled to delayed physical development, stunted growth, and difficulties in feeding. The carrier begins to develop an unusually high appetite beginning in childhood, which results in hyperphagia or continuous over-eating, as well as overweight and obesity (Cassidy & Driscoll 2009). For individuals carrying the defective genes that cause PWS, especially those afflicted by obesity, a high prevalence of Diabetes Mellitus II exists. The genetic disorder was first characterized by Heinrich Willi and Andrea Prader before research by Guido Fanconi, Andrew Ziegler, and Alexis Labhart provided more information on the disorder. Prader-Willi Syndrome, as a genetic disorder, involves alterations on chromosome 15(q11-13), whereby seven genes on this chromosome are deleted (Goldstone 2009). Alternatively, the 15q chromosome is not expressed because of a partial deletion on the paternally derived chromosomes. This disorder is prevalent in between 1 in 10,000 and 1 in 25,000 of the population. The origin of the defective genes from paternal chromosomes is especially important since the region of the chromosome involved is affected by imprinting from parent origin. This means that only a single gene copy undergoes expression with the other corresponding gene being silenced via imprinting. For those genes that are affected in PWS, the gene that normally undergoes silencing or imprinting is the maternal copy with the expression of the paternal gene copy going ahead (Goldstone 2009). The result of this is that, the carrier only has one working copy of this gene and these PWS carriers possess one silenced copy and one copy that does not work. Prader-Willi Syndrome has a sister syndrome that is known as Angelman Syndrome, which involves maternally-derived genetic material at the same exact genetic location as PWS. While Prader-Willi Syndrome is considered as a rare genetic disorder, it occurs commonly in a majority of genetic clinics, being obesity’s most common genetic cause as identified to date. Prader-Willi Syndrome is prevalent in people of all races, ethnic backgrounds, and gender (Cassidy & Driscoll 2009). Phenotypic Features Associated With the Disease The basis for most of the symptoms presenting in PWS may be due to the brain’s hypothalamic region’s dysfunction (Gelehrter 2008). The hypothalamic region of the fetus is vital during child labor and its deregulation may help to explain the high number of post-mature or pre-mature births for children later diagnosed with PWS. Abnormal release of Luteinizing Hormone is thought to cause the decreased amount of sex hormones that result in testes not descending, small sized gonads, insufficient growth over puberty, and amenorrhea. Hypothalamic deregulation causes deficiency of growth hormone that contributes to reduced energy expenditure due to a deficit in lean body mass and excessive body fat. Disturbance of hypothalamus action also leads to daytime hyper-somnolence and aberrant body temperature control. Hyperphagia and insatiable hunger probably results from a decrease in oxytocin neurons (Gelehrter 2008). The disorder’s clinical phenotype is characterized through atypical faces, weakness of the muscles or hypotonia, ]onset of obesity during childhood, chronic overeating also referred to as hyperphagia late development of key milestones as a child grows up, and hypo-gonadism, which causes the child to have a short stature, pubertal spurts in growth, and conspicuously small feet and hands (Gelehrter 2008). Typical features presented on the face include down-turned mouth corners, a thin upper lip, micrognathia, almond shaped eyes, and a small forehead. The disorder is a multi-phase one characterized by three separate phases. The first is the hypotonic phase that occurs in the neo-natal and early infancy period. It is characterized through hypogenitalism, hypothermia, a weak cry, and gavage feeding necessitated by weak sucking action (Gelehrter 2008). During this period, the child is said to be affectionate, easy going, and friendly. The second phase is the hyperphagic phase, starting between the ages of one year and two. It is characterized by foraging for food, hyperphagia, a voracious appetite, cognitive dysfunction, speech articulation difficulties, psychomotor retardation, disturbed thermo-regulation, decreased pain sensitivity, physical inactivity, and changes in the pattern of eating (Gelehrter 2008). There are also temper tantrums, obsessive compulsion symptoms, anxiety, argumentativeness, impulsivity, mood liability, stubbornness, and auto-mutilation. Phase 3 occurs in adolescence and adulthood and is dominated by secondary obesity health problems. These are osteoporosis, hypercholesterolemia, hypertension, diabetes mellitus, dental problems, and scoliosis (Gelehrter 2008). A small proportion also develops psychotic and depressive episodes. Genetic Features of the Disease Prader-Willis Syndrome results from the deletion of necdin genes and imprinted SNPRN, along with various snoRNAs clusters of SNORD 108, SNORD107, forty eight copies of HBII-52 or SNORD115, twenty nine copies of HBII-85 or SNORD116, and two SNORD109 copies of the paternal copies. These are located on the chromosome 15 in the region of 15q11-13 (Khoury et al 2010). This region is also called the Prader-Willi Syndrome/Angelman Syndrome region, and it could be lost through any of several mechanisms of genetics that, in the majority of the cases, happens via chance mutation. Other mechanisms that are less common include gene deletions, chromosome translocations, sporadic mutations, and uni-parental disomy. Because of the imprinting phenomenon, maternally inherited gene copies are silent with the paternal copies being the ones that undergo expression. Prader-Willis Syndrome results from loss in paternal copies inherent in this region of the chromosome. The two; Prader-Willis Syndrome and Angelman Syndrome are representative of the first reported examples of disorders involving imprinting in humans (Khoury et al 2010). The existing risk to the child for the possession of the Prader-Willis disorder is dependent on genetic mechanisms that lead to this disorder. The risk that faces the child is less than one percent if the child has undergone a uni-parental disomy or gene depletion (Khoury et al 2010). This rises to over fifty percent if the affected individual possesses a mutation of the region, which controls imprinting with up to twenty-five percent chance if there is the presence of parental chromosomal translocation. It is possible to undergo pre-natal testing to discover if any genetic mechanism that would support this disorder exists. Micro-deletions in one family of HBII-52 of snoRNAs lead to its exclusion from playing a vital role in the disorder. Various studies investigating mouse and human models have given evidence to the fact those twenty-nine copies of the C/D box HBII-85 or SNORD116 of snoRNAs are primary causative agents of the Prader-Willis Syndrome (Khoury et al 2010). The Nature of the Defect PWS results from the loss of functionality by genes in a specific region of chromosome 15. Individuals usually inherit a copy of the chromosome from both parents. Some of the genes are active or are turned on only on the paternally inherited copy. Genomic imprinting most likely causes this phenomenon of parent-specific activation of genes (Beales 2009). Approximately 70% of all Prader-Willis Syndrome cases happen when a part of the paternal chromosome 15 undergoes deletion on each of the cells. Individuals with this type of chromosomal alteration are missing specific vital genes on the paternal copy, which have undergone deletion. At the same time, the maternal copy genes are inactive or turned off. In twenty five percent of the cases, an individual suffering from PWS possesses two copies of chromosome 15, which they inherited from their maternal side instead of a copy from each of the parents. This is called uni-parental disomy. In rare cases, PWS can result from a rearrangement of chromosomes, also referred to as translocation, or even by mutation and other defects that cause abnormal deactivation of paternal chromosome 15 (Beales 2009). It seems to be most likely that Prader-Willis Syndrome’s characteristic features are a result of functional loss for various genes located on chromosome 15. Among the affected genes are those that give instructions that make small nucleolar RNAs or snoRNAs (Beales 2009). These particular molecules conduct various functions that include aiding in the regulation of other RNA molecule types, which have a vibrant role to play in the production of the body’s proteins and among other cellular functions. Studies are suggestive of the fact that loss of snoRNAs group SNORD116 cluster could have a foremost role to play in the resultant symptoms and signs of PWS (Beales 2009). It is, however, unknown how this missing cluster contributes to behavioral problems, intellectual ability, and other physical manifestations of PWS. In some individuals with PWS, the loss of the OCA2 gene is normally associated with unusually fair and light colored hair and skin (Ostrer 2008). The OCA2 gene is found on chromosome 15’s segment that normally undergoes deletion in people suffering from the disorder. However, its loss does not result in other symptoms and signs of PWS. The protein expressed by this gene expresses is vital in the determination of eye, hair, and skin pigmentation. Most cases of PWS are not inherited, especially those that result from deletion of chromosome 15 on the paternal side or by uni-parental disomy from the maternal side. The genetic changes are as a result of indiscriminate events, which occur during the creation of sperm and eggs or even during early development of the embryo. Most people afflicted by this disorder do not have a history of PWs in their family. In rare cases, a genetic alteration responsible for PWs is inheritable. For instance, it can happen that a genetic change that inactivates genes abnormally on the paternal chromosome 15 can be passed to the next generation from the present one (Ostrer 2008). Cause and Effect Link between the Affected Genes and the Outcome Phenotype In Prader-Willis Syndrome, individuals with uni-parental disomy and deletion display subtle differences in most cases (Pasternak 2010). Patients possessing uni-parental disomy normally fulfill the criterion for the classical form of Prader-Willis Syndrome, although the manifestations are generally viewed to have a somewhat milder effect than those with deletions. Additionally, on top of minor differences in physical manifestation, significantly higher IQ levels are observable most individuals possessing maternal uni-parental disomy in comparison to those with paternal deletion (Pasternak 2010). In addition, two atypical individuals with uni-parental disomy were found to express some chromosome 15 alleles, which are normally silent in typical Prader-Willis Syndrome patients. This is suggestive of the fact that milder phenotypes in these individuals may be because of the expression of paternal genes because of relaxed imprinting. The phenotype of Prader-Willis Syndrome cases that have an imprinting defect can be predicted as equivalent to the uni-parental disomy cases. Clinical analysis of seven patients fulfilled PWS’ clinical criteria, although, there was a lack of hypo-pigmentation that has been created to be caused by a deficiency in the P gene, which is non-imprinted in PWS patients with a deletion in chromosome 15q11-q13 (Pasternak 2010). This gene is a Tyrosine transporter gene that is vital in the development of iris, hair, and skin pigmentation. Deficiency of the P protein also results in strabismus as is often observed in patients who suffer from deletion (Pasternak 2010). Diagnosis and Treatment of Prader-Willis Syndrome A physician normally bases suspected diagnosis of PWS in clinical symptoms. The disorder should be suspected in children born with significant floppiness or weakness of the muscle (Goldstein 2010). This diagnosis can further be confirmed by using a blood test. The testing that is most preferred mode is via methylation analysis that detects over 99% of all presented cases including the majority of PWS genetic sub-types such as imprinting mutation, uni-parental disomy, and deletion. A fluorescent in-situ hybridization test also helps to identify the patients suffering from PWS caused by a deletion, but does not identify patients with uni-parental disomy or imprinting error PWS (Goldstein 2010). PWS has no cure and has no manner of prevention (Whittington & Holland 2009). Its treatment is aimed at easing the problems that are associated with the disorder. Depending on the individual’s needs, various methods of treatment can be used. One is the strict supervision of a patient’s diet since there are no current means of curbing appetite. The patient is also advised to use plenty of physical activity to maintain their weight in the normal range. Hormone deficiency is also tackled, by use of Growth Hormone therapy, to combat the child’s short stature. Hormone therapy can also be used to boost inadequate levels of sex hormone and increase muscle mass (Whittington & Holland 2009). Medication can be used to control compulsive and obsessive behavior while kyphosis or scoliosis can be treated using orthopedic therapy. The patient can also be fitted with appropriate prescription glasses. In PWS, specialist care is crucial, especially for children. Health professionals who deal with PWS include behavioural psychologists, opticians, dentists, speech therapists, physiotherapists, dieticians, paediatricians, and general practitioners (Whittington & Holland 2009). Conclusion Prader-Willi syndrome can be defined as a complex genetic condition affecting numerous parts of the body. The condition is characterized by hypotonia or weak muscle tone during infancy, as well as delayed development, poor growth, and feeding difficulties. The disorder afflicts between one in every 10,000 and 1 in 25,000. The maternal copy of the PWS affected gene is normally silenced with the expression of the paternal gene being dominant, which causes a person to have only one working gene. Most of the symptoms that present with PWS have to do with hypothalamic dysfunction. Its clinical phenotype is characterized through atypical facies, muscle hypotonia, child-hood onset obesity, hyperphagia, delayed developmental milestones, and hypo-gonadism, which results in short stature, pubertal growth spurt, and small feet and hands. The disorder results from deletion of necdin genes and imprinted SNPRN and various clusters of SNORD 108. PWS results from the loss of functionality by genes on chromosome 15. In some individuals, OCA2 gene loss can be associated with unusually fair colored skin and hair. Diagnosis of the disorder can be done via clinical testing followed by blood tests. It has no cure and most treatments are meant to treat its symptoms. Future research into the disorder seeks to target oxytocin that is vital in building empathy and social interactions. Oxytocin has been shown to increase trust, decreased disruptive behavior, and sadness (Redei 2008). Other areas that may yield future research include; the use of exenatide that could act as a potential future treatment for obesity and hyperphagia in individuals suffering from Prader-Willis Syndrome. Research could also look into the identification of various substances that could act as substitutes for snoRNAs loss from the critical region of Prader-Willis Syndrome. Future research could also involve investigation of the role played HBII-85 snoRNA clusters in PWS pathogenesis, as well as the effect that using growth hormone replacement therapy could have in PWS persons as far as sexual, behavioral, and physical development is concerned (Redei 2008). References Beales L, Farooqi S, & ORahilly S. 2009. The genetics of obesity syndromes. Oxford : Oxford University Press. 121 p Cassidy SB, & Driscoll, DJ. (2009). Prader-Willi syndrome. Eur J Hum Genet , 3-13. Retrieved from: http://ghr.nlm.nih.gov/condition/prader-willi-syndrome/show/References Gelehrter T, Francis C, David G. 2008. Principles of medical genetics. Baltimore : Williams & Wilkins. 124 p. Retrieved from; www.atlasgeneticsoncology.org/Educ/MicrodeletionID30059ES.html Goldstone AP. (2009). Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab. , 12-20. Retrieved from: http://ghr.nlm.nih.gov/condition/prader-willi-syndrome/show/References Khoury M, Beaty T, Cohen B. 2010. Fundamentals of genetic epidemiology. New York : Oxford University Press. 105 p. Ostrer, H. 2008. Non-mendelian genetics in humans. New York : Oxford University Press. 20 p. Pasternak, J. 2010. An Introduction to Human Molecular Genetics : Mechanisms of Inherited Diseases. Hoboken : John Wiley & Sons; 57 p. Redei, G. 2008. Encyclopedia of genetics, genomics, proteomics, and informatics. New York: Springer. 76 p. Goldstein S, Reynolds C. 2010. Handbook of Neurodevelopmental and Genetic Disorders in Children. New York: Guilford Press. 485 p. Whittington J, Holland T. 2009. Prader-Willi syndrome : development and manifestations. Cambridge: Cambridge University Press. 41 p. Read More