Prader-Willi syndrome
Encyclopedia
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
in which seven genes (or some subset thereof) on chromosome 15 (q 11–13)
Chromosome 15 (human)
right|frame|Human chromosome 15Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 106 million base pairs and represents between 3% and 3.5% of the total DNA in cells.Identifying genes on each chromosome is an...
are deleted or unexpressed (chromosome 15q partial deletion
Chromosome 15q partial deletion
Chromosome 15q partial deletion is an extremely rare human genetic disorder, caused by a chromosomal aberration in which the long arm of one copy of chromosome 15 is deleted, or partially deleted. If the mother's copy of the chromosomal arm is deleted, Angelman syndrome results. If the father's...
) on the paternal chromosome. It was first described in 1956 by Andrea Prader
Andrea Prader
Andrea Prader was a Swiss scientist and physician, pediatric endocrinologist. He was one of the co-discoverers of the Prader-Willi syndrome.-Biography:...
(1919–2001), Heinrich Willi (1900–1971), Alexis Labhart (1916), Andrew Ziegler, and Guido Fanconi
Guido Fanconi
Guido Fanconi was a Swiss pediatrician. He was born in Poschiavo, Canton Grisons in the Italian-speaking region of Switzerland. Fanconi is regarded as one of the founders of modern pediatrics....
of Switzerland
Switzerland
Switzerland name of one of the Swiss cantons. ; ; ; or ), in its full name the Swiss Confederation , is a federal republic consisting of 26 cantons, with Bern as the seat of the federal authorities. The country is situated in Western Europe,Or Central Europe depending on the definition....
. The incidence of PWS is between 1 in 25,000 and 1 in 10,000 live births. The paternal origin of the genetic material that is affected in the syndrome is important because the particular region of chromosome 15 involved is subject to parent of origin imprinting, meaning that for a number of genes in this region only one copy of the gene is expressed while the other is silenced through imprinting. For the genes affected in PWS, it is the paternal copy that is usually expressed, while the maternal copy is silenced. This means that while most people have a single working copy of these genes, people with PWS have no working copy. PWS has the sister syndrome Angelman syndrome
Angelman syndrome
Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor....
in which maternally derived genetic material is affected in the same genetic region.
Clinical features and signs
Holm et al. (1993) describe the following features and signs as pretest indicators of PWS, although not all will be present.In utero
- Reduced fetal movement
- Frequent abnormal fetal position
- Occasional polyhydramniosPolyhydramniosPolyhydramnios is a medical condition describing an excess of amniotic fluid in the amniotic sac. It is seen in 0.2 to 1.6% of pregnancies,,...
(excessive amniotic fluid)
At birth
- Often breechBreech birthA breech birth is the birth of a baby from a breech presentation. In the breech presentation the baby enters the birth canal with the buttocks or feet first as opposed to the normal head first presentation....
or caesarean births - Lethargy
- HypotoniaHypotoniaHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
- Feeding difficulties (due to poor muscle tone affecting sucking reflex)
- Difficulties establishing respiration
- HypogonadismHypogonadismHypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
Infancy:
- Failure to thriveFailure to thriveFailure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
(continued feeding difficulties) - Delayed milestones/intellectual delay
- Excessive sleepingHypersomniaHypersomnia is a disorder characterized by excessive amounts of sleepiness.There are two main categories of hypersomnia: primary hypersomnia and recurrent hypersomnia...
- StrabismusStrabismusStrabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...
('crossed eyes') - ScoliosisScoliosisScoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
(often not detected at birth) - CryptorchidismCryptorchidismCryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
Childhood:
- Speech delaySpeech delaySpeech delay, also known as alalia, refers to a delay in the development or use of the mechanisms that produce speech. Speech, as distinct from language, refers to the actual process of making sounds, using such organs and structures as the lungs, vocal cords, mouth, tongue, teeth, etc...
- Poor physical coordination
- HyperphagiaPolyphagiaPolyphagia means "eating too much". It derives from the Greek words πολύς which means "very much", and φαγῶ , verb for "I eat"....
(over-eating) from age 2 – 8 years. Note change from feeding difficulties in infancy - Excessive weight gain
- Sleep disorders
- ScoliosisScoliosisScoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
Adolescence:
- Delayed puberty
- Short stature
- ObesityObesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
- Extreme flexibility
Adulthood:
- Infertility (males and females)
- HypogonadismHypogonadismHypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
- Sparse pubic hair
- Obesity
- Hypotonia (low muscle tone)
- Learning disabilities/borderline intellectual functioning (but some cases of average intelligence)
- Prone to diabetes mellitusDiabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
- Extreme flexibility
General physical appearance (adults)
- Prominent nasal bridge
- Small hands and feet with tapering of fingers
- Soft skin, which is easily bruised
- Excess fat, especially in the central portion of the body
- High, narrow forehead
- Almond-shaped eyes with thin, down-turned lids
- Light skin and hair relative to other family members
- Lack of complete sexual development
- Frequent skin picking
- StriaeStretch marksStretch marks or striae , as they are called in dermatology, are a form of scarring on the skin with an off-color hue. They are caused by tearing of the dermis, and over time can diminish but not disappear completely....
- Delayed motor development
Neuro-cognitive
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 Prader Willi Syndrome (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, a figure higher than that found in Curfs and Fryns' study (32%). However, 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 (sometimes affected by hypernasality) is generally poorer than their comprehension. A marked skill in completing jigsaw puzzle
Jigsaw puzzle
A jigsaw puzzle is a tiling puzzle that requires the assembly of numerous small, often oddly shaped, interlocking and tessellating pieces.Each piece usually has a small part of a picture on it; when complete, a jigsaw puzzle produces a complete picture...
s has been noted, although this may be an effect of increased practice.
Auditory information processing and sequential processing are relatively poor, as 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
Prader–Willi syndrome is also frequently associated with an extreme and insatiable appetite, often resulting in morbid obesity. There is currently no consensus as to the cause for this particular symptom, although genetic abnormalities in chromosome 15 disrupt the normal functioning of the hypothalamus. Given that the hypothalamus regulates many basic processes, including appetite, there may well be a link. In the hypothalamus of PWS patients, nerve cells that produce oxytocinOxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
, a hormone thought to contribute to satiety, have been found to be abnormal.
Prader–Willi syndrome patients have high ghrelin
Ghrelin
Ghrelin is a 28 amino acid peptide and hormone that is produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger. Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone...
levels, which 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 behavioural expectations, the reinforcement of behavioural limits and the establishment of regular routines.[21]
The main mental health difficulties experienced by people with PWS include compulsive behaviour (usually manifested in skin-picking) and anxiety. Psychiatric symptoms, for example, hallucinations, paranoia and depression have been described in some cases and affect approximately 5–10% of young adults. Psychiatric and behavioural problems are the most common cause of hospitalization.
Endocrine
There are several aspects of PWS that support the concept of growth hormone deficiency in individuals with PWS. Specifically, individuals with PWS have short stature, are obese with abnormal body composition, have reduced fat free mass (FFM), have reduced LBM and total energy expenditure, and have decreased bone density.PWS is characterized by hypogonadism. This is manifested as undescended testes in males and benign premature adrenarche
Adrenarche
Adrenarche is an early sexual maturation stage in some higher primates that in humans typically occurs at around 6 to 8 years of age. During adrenarche the adrenal cortex secretes increased levels of androgens such as DHEA and DHEAS, but without increased cortisol levels. Adrenarche is the result...
in females. Testes may descend with time or can be managed with surgery or testosterone replacement. Adrenarche may be treated with hormone replacement therapy.
Genetics
Small nuclear ribonucleoprotein polypeptide N
Small nuclear ribonucleoprotein-associated protein N is a protein that in humans is encoded by the SNRPN gene.-Further reading:...
and necdin
NDN (gene)
Necdin is a protein that in humans is encoded by the NDN gene.-Interactions:NDN has been shown to interact with NUCB2, E2F1, IL1A, Low affinity nerve growth factor receptor, P53 and HNRNPU.-Further reading:...
genes along with clusters of snoRNA
SnoRNA
Small nucleolar RNAs are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs...
s: SNORD64
Small Nucleolar RNA SNORD64
SNORD64 is a non-coding RNA molecule which functions in the biogenesis of other small nuclear RNAs . This type of modifiying RNA is located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis...
, SNORD107, SNORD108 and two copies of SNORD109, 29 copies of SNORD116
Small nucleolar RNA SNORD116
SNORD116 is a non-coding RNA molecule which functions in the modification of other small nuclear RNAs . This type of modifiying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis...
(HBII-85) and 48 copies of SNORD115
Small nucleolar RNA SNORD115
SNORD115 is a non-coding RNA molecule known as a small nucleoloar RNA which usually functions in guiding the modification of other non-coding RNAs. This type of modifiying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis...
(HBII-52). These are on chromosome 15
Chromosome 15 (human)
right|frame|Human chromosome 15Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 106 million base pairs and represents between 3% and 3.5% of the total DNA in cells.Identifying genes on each chromosome is an...
located in the region 15q11-13. This so-called PWS/AS region may be lost by one of several genetic mechanisms which, in the majority of instances occurs through chance mutation. Other less common mechanisms include; uniparental disomy
Uniparental disomy
Uniparental disomy occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent.. UPD could involve isodisomy or heterodisomy ....
, sporadic mutations, chromosome translocations, and 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
Angelman syndrome
Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor....
(AS). PWS and AS represent the first reported instances of imprinting disorders in humans.
The risk to the sibling of an affected child of having PWS 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% if the affected child has a mutation of the imprinting control region, and up to 25% if a parental chromosomal translocation is present. Prenatal testing is possible for any of the known genetic mechanisms.
A microdeletion 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
Small nucleolar RNA SNORD116
SNORD116 is a non-coding RNA molecule which functions in the modification of other small nuclear RNAs . This type of modifiying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis...
(HBII-85) has been shown to be the primary cause of Prader–Willi syndrome.
Diagnosis
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, short stature, hyperphagia, obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, behavioral issues (specifically OCD-like behaviors), small hands and feet, hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
, and mild mental retardation. However, with early diagnosis and early treatment (such as with growth hormone therapy), the prognosis for persons with PWS is beginning to change. Like autism, PWS is a spectrum disorder and so symptoms can range from mild to severe, and may change throughout the person's lifetime. Various organ systems are affected.
Traditionally, Prader-Willi Syndrome was diagnosed by clinical presentation. Currently, the syndrome is diagnosed through genetic testing; testing is recommended for newborns with pronounced hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
. Early diagnosis of PWS allows for early intervention as well as the early prescription of growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
. Daily recombinant growth hormone (GH) injections are indicated for children with PWS. GH supports linear growth and increased muscle mass, and may lessen food preoccupation and weight gain.
The mainstay of diagnosis is genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
, specifically DNA-based methylation testing to detect the absence of the paternally contributed Prader–Willi syndrome/Angelman syndrome
Angelman syndrome
Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor....
(PWS/AS) region on chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
15q11-q13. Such testing detects over 97% of patients. Methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially those who are too young to manifest sufficient features to make the diagnosis on clinical grounds or in those individuals who have atypical findings.
Because PWS infants have a higher rate of difficulties at birth (including breech delivery and respiratory delay) birth-related injuries and oxygen deprivation may complicate the genetic handicaps, resulting in atypical PWS.
Differential diagnosis
Prader–Willi syndrome is often misdiagnosed as a variety of other syndromes due to many in the medical community's unfamiliarity with PWS. Sometimes it is misdiagnosed as Down syndromeDown syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
, simply because of the relative frequency of Down syndrome compared to PWS. Also, marked obesity can occur in Down syndrome due to behavioral problems. Adding to the confusion, parents of children who already carry a diagnosis of Prader–Willi syndrome may tell friends, family, and even physicians and nurses that their child has Down syndrome because more people have heard of that condition. It is thought that 75% of those with PWS are undiagnosed.
Treatment
Prader–Willi syndrome has no cure; however, several treatments are in place to lessen the condition's symptoms. During infancy, subjects should undergo therapies to improve muscle tone. Speech and occupational therapy are also indicated. During the school years, children benefit from a highly structured learning environment as well as extra help. The largest problem associated with the syndrome is severe obesity.Prescription of daily recombinant growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
injections are indicated for children with PWS. GH supports linear growth and increased muscle mass, and may lessen food preoccupation and weight gain.
Because of severe obesity, obstructive sleep apnea is a common sequela, and a positive airway pressure machine is often needed.
Society and culture
Prader–Willi syndrome appeared in the UK media in July 2007 when Channel 4Channel 4
Channel 4 is a British public-service television broadcaster which began working on 2 November 1982. Although largely commercially self-funded, it is ultimately publicly owned; originally a subsidiary of the Independent Broadcasting Authority , the station is now owned and operated by the Channel...
aired a program Can't Stop Eating
Can't Stop Eating (documentary)
Can't Stop Eating is a 2006 documentary film that follows the lives of several people with Prader-Willi Syndrome .The film is set in Gretton House, near Kettering in England, which is a government-funded care home deliberately constructed to assist people with PWS.-Plot summary:The film focuses on...
, surrounding the everyday lives of two Prader-Willi patients, Joe and Tamara.
An individual with Prader-Willi Syndrome featured in the episode entitled "Dog Eat Dog" of the television series CSI: Crime Scene Investigation
CSI: Crime Scene Investigation
CSI: Crime Scene Investigation is an American crime drama television series, which premiered on CBS on October 6, 2000. The show was created by Anthony E. Zuiker and produced by Jerry Bruckheimer...
(aired on November 24, 2005).
Another individual with Prader–Willi syndrome, Ethan Starkweather, was on Extreme Makeover: Home Edition
Extreme Makeover: Home Edition
Extreme Makeover: Home Edition is a reality television series providing home renovations for less fortunate families and community schools etc...
originally aired on Mothers Day 2010.
On TLC's
TLC (TV channel)
TLC is an American cable TV specialty channel which initially focused on educational content. Since 1991 TLC has been owned by Discovery Communications, the same company that operates the Discovery Channel, Animal Planet and The Science Channel, as well as other learning-themed networks...
My Deadly Appetite (aired in December 2010), a patient named Will was treated for the condition (as well as others featured).http://tlc.discovery.com/tv-schedules/special.html?paid=2.13700.130858.0.0
In The Judas Strain by James Rollins
James Rollins
* For the American baseball pitcher, see Jim Czajkowski* For the American baseball shortstop, see Jimmy Rollins* For the 19th century American politician from Missouri, see James S. Rollins...
, victims of an unknown plague exhibit an insatiable hunger described as bearing "a striking similarity to Prader-Willi syndrome."
External links
- PWS research short film
- Prader-Willi syndrome explanation Video
- Foundation for Prader-Willi Research
- Foundation for Prader-Willi Research Canada
- Prader-Willi Syndrome Association (USA)
- Prader-Willi Syndrome (UK)
- Prader-Willi Syndrome Association (UK)
- Prader-Willi Syndrome Association (South Africa)
- SPINE Foundation (Argentina)
- (GeneReview on Prader-Willi syndrome)