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What is the Prader–Willi syndrome? – Part 2

• Prader–Willi syndrome is a rare genetic disorder.
• In this syndrome seven genes (or some subset thereof) on chromosome 15 (q 11–13) are deleted or unexpressed (chromosome 15q partial deletion) on the paternal chromosome.

Neuro-cognitive Symptoms

• Individuals with PWS are at risk of learning and attention difficulties.
• Curfs and Fryns (1992) conducted research into the varying degrees of learning disability found in PWS.
Their results were as follows:
– 5%: IQ above 85 (average to low average intelligence)
– 27%: IQ 70 – 85 (borderline intellectual functioning)
– 39%: IQ 50 – 70 (mild intellectual disability)
– 27%: IQ 35 – 50 (moderate intellectual disability)
– 1%: IQ 20 – 35 (severe intellectual disability)
– <1%: IQ <20 (profound intellectual disability) • Cassidy found that 40% of individuals with PWS have borderline/low average intelligence. • Both studies suggest that most individuals (50–65%) fall within the mild/borderline/low average intelligence range. • Children with PWS show an unusual cognitive profile. • They are often strong in visual organization and perception, including reading and vocabulary, but their spoken language is generally poorer than their comprehension. • A marked skill in completing jigsaw puzzles has been noted although this may be an effect of increased practice. • Auditory information processing and sequential processing are relatively poor. • So are arithmetic and writing skills, visual and auditory short term memory and auditory attention span. • These sometimes improve with age, but deficits in these areas remain throughout adulthood.

Behavioral Symptoms

• Prader–Willi syndrome is frequently associated with an extreme and insatiable appetite.
• This often results in morbid obesity.
• Given that the hypothalamus arcuate nucleus regulates many basic processes.
• This includes appetite.
• In the hypothalamus of PWS patients, nerve cells that produce oxytocin, a hormone thought to contribute to satiety.
• This is found to be abnormal.
• Prader–Willi syndrome patients have high ghrelin levels.
• These levels are thought to directly contribute to the increased appetite, hyperphagia, and obesity seen in this syndrome.
Cassidy states the need for a clear delineation of:
– Behavioral expectations.
– The reinforcement of behavioral limits.
– The establishment of regular routines.
• The main mental health difficulties experienced by people with PWS include compulsive behavior and anxiety

Psychiatric Symptoms (approximately 5–10% of young adults)

• Hallucinations
• Paranoia
• Depression

Endocrine

• There are several aspects of PWS that support the concept of growth hormone deficiency in individuals with PWS.
• Individuals with PWS have short stature.
They are obese with:
– Abnormal body composition
– Have reduced fat free mass (FFM)
– Have reduced LBM
– Total energy expenditure
– Have decreased bone density

Hypogonadism

• PWS is characterized by hypogonadism.
• This is manifested as un-descended testes in males and benign premature adrenarche in females.
• Testes may descend with time or can be managed with surgery or testosterone replacement.
– Adrenarche may be treated with hormone replacement therapy.

Ophthalmologic

• PWS is commonly associated with development of strabismus.
• In one study,[11] over 50% of patients had strabismus, mainly esotropia.

Genetics

• PWS is caused by the deletion of the paternal copies of the imprinted SNRPN and necdin genes along with clusters of snoRNAs. These include:
– SNORD64
– SNORD107
– SNORD108
– Two copies of SNORD109
– 29 copies of SNORD116 (HBII-85)
– 48 copies of SNORD115 (HBII-52)
• Other less common mechanisms include:
– uniparental disomy.
– Sporadic mutations.
– Chromosome translocations.
– Gene deletions.
• Due to imprinting, the maternally inherited copies of these genes are virtually silent.
• Only the paternal copies of the genes are expressed.
• PWS results from the loss of paternal copies of this region.
• Deletion of the same region on the maternal chromosome causes Angelman syndrome (AS).
• PWS and AS represents the first reported instances of imprinting disorders in humans.
• The risk to the sibling of an affected child of having PWS which depends upon the genetic mechanism which caused the disorder.
• The risk to siblings is <1% if the affected child has a gene deletion or uniparental disomy. • Up to 50%, the affected child has a mutation of the imprinting control region. • Up to 25% if a parental chromosomal trans-location is present. • Prenatal testing is possible for any of the known genetic mechanisms. • A micro deletion in one family of the snoRNA HBII-52 has excluded it from playing a major role in the disease. • Studies of human and mouse model systems have shown that deletion of the 29 copies of the C/D box snoRNA SNORD116 (HBII-85) has been shown to be the primary cause of Prader–Willi syndrome.

Prader-Willi Syndrome When a Gene Makes You Smell Like a Fish Psychiatric and Behavioural Disorders in Intellectual and Developmental Disabilities

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