Prader-Willi Vignette

Question 1

Understand the chromosomal 15 abnormalities associated with Prader-Willi Syndrome

Answer 1

• Most patients (70%) have a deletion on the long arm of chromosome 15 (at 15q11-q13) on the paternally inherited homolog
• In approximately 25% of cases Prader-Willi can also be caused by maternal uniparental disomy,
• imprinting errors on the paternal chromosome

Question 2

Understand how to test for abnormalities associated with Prader-Willi Syndrome (PWS)

Answer 2

FISH can detect deletions and methylation testing is used to detect the other possible abnormalities.

Question 3

Understand the role of imprinting in disorders involving chromosome 15 (PWS)

Answer 3

Imprinting inactivates genes via methylation based on the sex from which the chromosome is derived. Normally, on chromosome 15, the PWS gene is imprinted on the maternal copy and the AS gene is imprinted on the paternally derived copy. Thus, if the paternal copy is mutant, the maternal copy cannot rescue function because the PWS gene is imprinted. Since only the paternal allele is expressed, there is no functioning gene product when it is mutant.

Question 4

Understand the role of imprinting in disorders involving chromosome 15 (Angelman Syndrome)

Answer 4

Only the mother’s AS gene is expressed, while the father’s is inactivated. If the maternal copy is mutant, disease results because there is no functional gene product

Question 5

Understand the physical features (Phenotype) seen in a patient with Prader-Willi Syndrome

Answer 5

At birth, these children suffer from hypotonia, making them seem “floppy”. They are short in stature and obese. They often have dysmorphic features including almond shaped eyes, triangular mouth, small hands and feet and hypopigmentation of the hair, eyes and skin (i.e. they tend to be pale and blonde).

Question 6

Understand the medical problems seen in patients with PWS (at birth)

Answer 6

in addition to hypotonia, these children suffer from feeding difficulties, hypogonadism and undescended testicles.

Question 7

Understand the medical problems seen in patients with PWS (developing)

Answer 7

• delayed or incomplete pubertal development and infertility
• delayed motor development and while the hypotonia improves, it may persist into adulthood. -greater risk of scoliosis and osteoporosis
• often have strabismus (lazy eye) and/or nystagmus (aberrant eye movement)

Question 8

Understand the medical problems seen in patients with PWS (between ages 1-6)

Answer 8

the feeding difficulties resolve and they suffer from hyperphagia, giving rise to obesity. The obesity is a major cause of morbidity due largely to cardiopulmonary diseases and Type II diabetes mellitus.

Question 9

Understand the developmental phenotype of a patient with PWS

Answer 9

There is mild to moderate developmental delay leading to intellectual disability as adults (IQ 60-80) with severe learning disabilities.

Question 10

Understand the behavioral phenotype of a patient with PWS

Answer 10

• eat excessively and indiscriminately –> food-seeking behaviors such as hoarding, foraging and stealing
• temper tantrums, obsessive-compulsive disorders and poor adaptation to changes in routine
• These problems persist in adulthood and 5-10% also develop psychoses

Question 11

a deletion on the long arm of chromosome 15 (at 15q11-q13) on the paternally inherited homolog causes

Answer 11

the loss of the SNORD116 snoRNA that is likely involved in mRNA processing)

Question 12

maternal uniparental disomy

Answer 12

• both the chromosome 15s in the child are maternally derived (from a non-disjunction event)
• Since the maternal PWS gene is imprinted, it is not transcribed and produced no gene product

Question 13

-imprinting errors on the paternal chromosome can lead to

Answer 13

disease if the chromosome is imprinted like the maternal chromosome. This results in the cell seeing two maternal homologs due to imprinting patterns.