Prader-Willi and Angelman Syndromes: Mechanisms and Management

Abstract

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Methylation is the first line for molecular diagnostic testing; MS-MLPA is the most sensitive test. The molecular subtype of PWS/AS provides more accurate recurrence risk information for parents and for the individual affected with the condition. Management should include a multidisciplinary team by various medical subspecialists and therapists. Developmental and behavioral management of PWS and AS in infancy and early childhood includes early intervention services and individualized education programs for school-aged children. Here, we compare and discuss the mechanisms, pathophysiology, clinical features, and management of the two imprinting disorders, PWS and AS.

Keywords: chromosome 15; developmental delay; hyperphagia; imprinting disorders; obesity; uniparental disomy.

Figure 1

Diagram of maternal (MAT; top) and paternal (PAT; bottom) regions of human chromosome 15q11-q13. Clear boxes represent actively expressed genes; grey boxes represent those whose expression has been silenced through genomic imprinting (maternal allele) or through expression of the antisense transcript (paternal UBE3A).

Figure 2

(A) Algorithm for genetic testing in an infant with hypotonia and/or developmental delays, and suspected clinical diagnosis of PWS/AS. (B) Recommended follow-up parental testing, based on molecular etiology of proband, to establish recurrence risk [Targeted testing to assess for maternal UBE3A variant; karyotype or FISH to assess for translocation/cytogenetic abnormality in mother or father].