Etiology and diagnosis of Prader Willi Syndrome

By | May 20, 2012



The etiology and pathology of disease is not well understood until very recent advances in the field of cytogenetics and molecular genetics. These recent advances are now providing some insight of the fairly complicated syndrome. Approximately 70% of the PWS have been shown to have a deletion in chromosome 15, described as 15q11-q13. The remaining 30% have an apparently normal 15th chromosome. Genomic imprinting in parental chromosomes sometimes leads to the deletion of specific region in a patient with a clinical presentation of PWS. Thus the phenotypic characters of the disease on the absence of the sequences from 15th chromosome indicate that the material, which is necessary for the normalcy behavior, is vanished.


Several familial recurrences have been documented:

Gablian and Royer (1968) gave detailed explanation of two cases in same family (a brother and sister) and another case from related parents.

Hall and Smith (1972) reported an instance of affected first cousins.

Jancar (1971) and Evans (1969) reported two brothers one of whom had a normal twin sister.

Brissenden and Levy (1973) and Ikeda, Alaska, Inouye et al. (1973) reported instances of monozygotic twins.

De Fraites, Thurmon, Farhadian (1975) identified one family with five cases of PWS and suggested that the syndrome arose as an autosomal recessive trait.

There have been subsequent reports of siblings with PWS (Bolanos, Lopez, Amor, Vasquez, et al., 1974; Cohen, Hall, Smith, et al., 1973; Endo, Tasaka, Matsuura, et al., 1976).

Lubinsky, Zellweger, Greenswag, et al. (1987) describes a family of four siblings (two female and two male) with PWS and no normal children. These findings were made on physical, clinical and behavioral manifestation. At the time no cytogenetic abnormality and detectable molecular deletion or uniparental diasomy was identified in either the siblings or there parents. Later in 1994 Nicholls described a molecular analysis of two siblings from this family has since confirmed the clinical diagnosis PWS, by showing that both have an imprinting mutation (Nicholls, 1994). Thus both siblings but the parents found with typical methylation at three imprinted loci D1559, D15S63 and SNRPN spanning 1.5 Mb within 15q11-q13. In addition a very small deletion was found in both affected siblings and the father just upstream and overlapping the SNRPN promoter (Saitoh, Rogan & Nicholls). The findings in a USA family are similar to those in another family from Scandinavia (Sutcliffc, 1994; Saitoh, Mutirangura, Kuwano, et al. 1994). The father was a silent carrier of deletion hence almost certainly the methylated sequences were inherited from his mother (explained in later part of essay) however this deletion prevents resetting the imprint in the male germ line, so all his children inheriting the deletion have PWS.


If the PWS is, infect, a sequential pattern of altered growth, development and function stemming from a single localized area of damage in the fetus arising in the central nervous system (Hanson, 1981), it could be predicted that a host of factors, both genetic and environmental, might cause this disorder. A few monogenic cytogenetic problems occurring in a portion of families could explain the low recurrence risk overall, with a few exceptional families presenting with an unusual recurrence patterns. On the other hand, PWS may be regarded as a true malformation syndrome. This implies a more restricted group of casual factors that is affects a single (or few) biochemical or developmental process (es) in a group of tissue leading to a phenotypic consequences of disease. Although a few families with monogenic disorder concealed within the larger population of PWS could explain the observed recurrence patterns, cytogenetic rearrangements afford a more robust explanation. Deletion and the other unbalanced rearrangement of the chromosome may also affect in the same way to more than a single genetic locus and produce variable consequences. Balanced chromosomal rearrangements in a parent (inversion, translocation, etc.) might account for occasional recurrence in a few families (e.g. Gonadal mosaicism). It could be possible that the resulting disease may be of interest for such diverse areas of medical sciences as endocrinology, nutrition, neurophysiology, psychology and morphogenesis. Although the cause of PWS may not be so obvious but he observed abnormality might result in a localized disturbance in development of the brain above the spinal cord, such as the defect in the hypothalamic-pituitary axis (Gorlin, Pinborg & Cohen, 1976; Hanson, 1981). There are some more suggestion regarding the possible causes of PWS as the presence of fat metabolism defect suggested by Afifi and Zellweger (1969) and Tze, Dunn and Rothstein. Schwartz, Brunzell, and Bierman (1979) believed the level of lipoprotein lipase enzyme might be one of the critical mechanism by which the brain regulates the number, size and metabolism of fat cells in the body, and suggested a biochemical explanation for the presence of PWS.


Alteration in the homeostatic mechanism of PWS patient describes the hypothalamus as the dysfunction of brain. Because hypothalamus helps in regulation of growth and sex hormones and both satiety and feeding center are located in the hypothalamus. It could be also responsible for propensity of vomiting in PWS disorder (R.C. Alexander, D.C. Van Dyke and J.W. Hanson, 1995). It is possible that flaws exist in specific type of balances of neurotransmitters regulating cell-cell communication. Other abnormalities seem to reflect problems areas of the brain that are either more confusing or less understood. Sleep, breathing, body temperature, and cognitive functions may represent somewhat more global differences in brain functioning.