a general summary...
Introduction
Prader-Willi syndrome (PWS) is a neural developmental disorder that is characterized by infantile hypotonia, feeding difficulties, hypogonadism, mental deficiency, hyperphagia/obesity, learning problems, and behavioral difficulties [2]. The genes are differentially imprinted on maternal and paternal chromosomes, so both copies are needed for normal development. PWS can occur when genes are not expressed on paternal chromosome 15. Deletions account for about 70% of patients; 25% due to maternal uniparental disomy (UPD) and 2 to 5% for abnormalities [2]. In terms of significance, PWS has an incidence of about 1 in 15000 live births [6]. This review will discuss the etiology, diagnosis, and treatment of PWS.
Etiology
The causes of the disease are due to a deletion in paternal chromosome 15q11-q13, maternal UPD 15, or mutations involving the imprinting center [2]. In normal situations, the imprinting center turns on paternal genes on paternal chromosome 15 and turn off maternal genes, vice versa on the maternal chromosome. Deletions can be divided into type I and type II, where type I is the larger deletion and more severe [2; 12]. For individuals with maternal UPD, they would have two chromosomes 15 from mom, and none from dad. Furthermore, defects in imprinting of the PWS domain can also contribute to the absence of important proteins [3]. Without these important proteins, it leads to the outcome of PWS.
One gene, called NIPA1, was reported to make a protein for transporting Magnesium [11]. The NIPA2 gene also makes a similar protein, suggesting transporter function [12]. Together, with the gene CYFIP1, they were thought to have an impact on the nervous system development and/or function.
NDN, MAGEL2, and HBII-52 are examples of paternally expressed genes. NDN, or necdin, was shown to reduce neuronal cell death in cerebellar granule neurons [14]. Unexpression of NDN would likely lead to fewer brain cells. Magel2 transcripts play a role in the circadian output pathway; mutations would affect activities of individuals. HBII-52 regulates alternative splicing of 5-HT22R by binding to a silencing element in exon Vb [16]. These results so far only suggest possible gene functions, but have yet figure out all the pathways leading to PWS.
Diagnosis
The symptoms for PWS are severe hypotonia, feeding difficulties, hypogonadism, small hands and feet, developmental delay, behavior problems, and genital hypoplasia [2]. Children with PWS between 2 to 4 years old tend to have an avid appetite, which resulted in obesity if food intake is not regulated [2]. These behavioral disorders result from the lack of protein production of imprinted genes in the paternal 15 chromosome [6].
source: http://www.nlm.nih.gov/medlineplus/ency/imagepages/17229.htm
Some deletions can be detected by cytogenetic techniques, but most are detected by molecular assays. A variety of cytogenetic and molecular approaches can be used like chromosome G banding, fluorescent in situ hybridization, and a DNA methylation test [6]. Methylation can detect deletions, UPD, and mutations, but cannot tell them apart.
PWS can also be physically measured, since PWS patients have abnormal body and brain structure. Blood pressure, weight and height were measured using a super-view H-101 meter, and body composition by an InBody 3.0 analyzer. In addition, Wechsler Intelligence Scale in Children and Wechsler Adult Intelligence Scale were performed by experienced psychologists on PWS patients; the average IQ score was 52, with a 40-71 range [7]. Another method involving diffusion tensor imaging, based on a high-field MRI system, was used to detect brain developmental abnormalities in PWS patients [8]. PWS individuals had higher trace value and lower fractional anisotropy than normal controls [8].
Treatment
Even though there is no definite cure, two treatments for PWS are discussed as having great impact. One involves the use of growth hormone, a substance that stimulates or controls the growth of an organism. It takes into account that hypothalamic dysfunction in PWS decreases GH secretion. Daily administration of GH doses ≥ 1 mg/m ² can improve growth, body composition, bone mineral density, and physical function in children with PWS. Lower doses are not as effective [10].
The other treatment uses Exendin (Ex)-4, peptide isolated from the venom of the lizard Heloderma Suspectum. Ex-4 is in clinical trial, but its result is promising. It can reduce food intake, weight gain, and fat deposition in obese rats by reducing the level of ghrelin, a hormone that increase appetite. It has the ability to resist enzyme degradation and its effects are long lasting (up to 8 h). Therefore, Ex-4 is hoped to be used as a therapeutic treatment for PWS patients that make high amounts of ghrelin [9].
Conclusion
It is unknown how the genes involved in PWS interact, but the proteins they make definitely play an important role. More research is needed to find the mechanism on how the absence of these proteins leads to PWS. Our hope for the future is to find a definite cure.
For more details, please check out the Scientific Review.
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