What is the pathophysiology of Prader-Willi syndrome (PWS)?

Updated: Oct 10, 2018
  • Author: Ann Scheimann, MD, MBA; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Answer

Prader-Willi syndrome is the first human disorder attributed to genomic imprinting. In such disorders, genes are expressed differentially based on the parent of origin. An imprinting center has been identified within 15q11-13; gene expression may be regulated by DNA methylation at cytosine bases. [13] Prader-Willi syndrome results from the loss of imprinted genomic material within the paternal 15q11.2-13 locus. [14] The loss of maternal genomic material at the 15q11.2-13 locus results in Angelman syndrome. [15]

Most cases of Prader-Willi syndrome that involve deletions, unbalanced translocations, and uniparental (maternal) disomy are sporadic. Monozygotic twins are concordantly affected. Approximately 70% of Prader-Willi syndrome cases arise from deletion of band 15q11-13 on chromosome 15. Maternal uniparental disomy caused by chromosomal nondisjunction accounts for 28% of Prader-Willi syndrome cases. [16, 17] Less than 1% of patients have mutations isolated to the imprinting center, which carries a risk of recurrence. [18] Buiting et al have suggested that deletions solely localized to the imprinting center may be due to a failure to erase the maternal imprint during spermatogenesis. [19]

Several genes have been mapped to the 15q11.2-13 region, including the SNRPN gene, P gene (type II oculocutaneous albinism), [20] UBE3A gene (encodes a ubiquitin-protein ligase involved in intracellular protein turnover), and necdin gene (codes for a nuclear protein expressed exclusively in the differentiated mouse brain). [21] Mutations associated with the maternal UBE3A gene result in Angelman syndrome. [19]

A report by Butler et al suggested that individuals with Prader-Willi syndrome have decreased mitochondrial function, with basal respiration, maximal respiratory capacity, and adenosine triphosphate (ATP)–linked respiration in the study differing significantly between Prader-Willi syndrome patients and healthy controls. [22]

The role of ghrelin in the satiety defect found in Prader-Willi syndrome is a subject of active investigation. In 2002, Cummings et al reported significantly elevated ghrelin levels (4.5-fold higher) in individuals with Prader-Willi syndrome. [23] Haqq et al reported improvement in ghrelin levels after octreotide infusion but no significant improvement in postprandial suppression of ghrelin levels. [24] After correction of relative hypoinsulinemia, Goldstone et al reported a residual 1.3-fold to 1.6-fold elevation in fasting ghrelin levels and a 1.2-fold to 1.5-fold elevation in postprandial ghrelin levels in adults with Prader-Willi syndrome. [25]


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