Management of Prader-Willi Syndrome

Chromosome 15 Imprinting Disorders: Genetic Laboratory Methodology and Approaches

“…The chromosome 15 imprinting disorders include Prader-Willi (PWS) and Angelman (AS) syndromes (1)(2)(3)(4)(5)(6) and chromosome 15q duplications. Diagnosis of PWS or AS depends on the parent of origin and whether expression is aberrantly limited to the maternal or the paternal imprinted genes.…”

“…Methylation DNA testing was developed during this time period and an abnormal methylation pattern was seen in PWS and AS. Methylation DNA testing is ∼99% accurate in identifying the diagnosis of PWS, but will not identify the individual PWS molecular class (2). For AS, DNA methylation testing identifies ∼80% of individuals, but again does not distinguish between the molecular classes or detect a mutation in the UBE3A gene causing AS.…”

“…PWS and AS are complex rare neurodevelopmental disorders due to errors in genomic imprinting. PWS is recognized as the most common genetic cause of life-threatening obesity, if left uncontrolled (2,4,6). There are three recognized PWS molecular classes including a paternal 15q11-q13 deletion about 5-6 Mb in size (60% of cases) and maternal disomy 15 (UPD15) in which both chromosome 15s are inherited from the mother (36%) originating from trisomy 15 with loss of the paternal chromosome 15 in early pregnancy leading to two chromosome 15s from the mother (16).…”

“…Most cases of PWS are sporadic with an approximate equity among ethnic groups and sex. The estimated prevalence of PWS is one in 10,000 to one in 30,000 (2). The number of individuals worldwide with PWS is thought to be ∼400,000 with about 20,000 individuals living in the USA (2,17).…”

“…PWS is characterized by infantile hypotonia, a poor suck reflex with feeding difficulties, short stature with small hands and feet, hypogonadism secondary to hormone deficiencies, mild intellectual disability, behavior problems, and hyperphagia often with onset between 6 and 8 years of age that persists into adulthood and results in obesity if environmental controls are not in place. During infancy, characteristic craniofacial features are seen including a narrow bifrontal diameter, strabismus, small upturned nose with a thin upper lip, and down-turned corners of mouth, sticky saliva, and enamel hypoplasia (2,4,6,18). Cognition is generally reduced based on the family background and behavior problems beginning in childhood include selfinjury (skin picking), outbursts, stubbornness, and temper tantrums with psychiatric problems occurring during this time or later in adolescence or young adulthood (2).…”