Prader-Willi Flashcards
Chromosome and region affected?
15q11-q13
Whats the first typical cytogenetic test for PW?
FISH
Contrary to what one might have assumed, early in life what are the feeding habits of PW?
Usually severed feeding problems in early life, may necessitate NG tube
Common male finding in PW?
Undescended testicles
PW presentation in newborn period
Hypotonia (floppy) dysmorphic features (almond eyes) undescended testicles severe feeding problems Lighter pigmentation
PW diagnosis can be made with?
FISH or Microarray -
PW has an early course of __________ and ______________ which reverses during preschool age when children develop____________ and ____________
failure to thrive
feeding difficulties
hyperphagia
weight gain
Are PW developmentally delayed?
Mild-moderate developmental delay leading to intellectual disabilities as adults
Do PW patients have ophthalmologic problems?
Yes, ophthalmologic problems are common - especially strabismus and nystagmus
How are many PW children treated (medically)?
With GH
How does GH help PW?
may help control obesity and improve short stature
What is one of the classic key findings in bambinos with PW, if you drape them with one hand?
They are profoundly floppy :)
hypotonia
Which gene is deleted/silenced in PW?
SNRPN on chromosome 15
Small nuclear ribonucleoprotein polypeptide N
In PW are we missing genetic information from the maternal or the paternal allele 15q11-q13?
Paternal allele
Since region 15q11-q13 is imprinted, what becomes critical for normal phenotype?
That information from both maternal and paternal alleles are present for a person to be normal
3 ways PWS can arise from 15q11-13 error?
- Deletion of paternal allele
- Uniparental disomy (2 copies present from one parent) of the maternal allele
- Imprinting error causing “virtual” maternal UPD
So, we know that PWS results from a deletion (or absence of fx) of the paternal 15q11-13 allele… What happens if we have a deletion of 15q11-13 maternal allele?
A completely different disorder known as Angelman syndrome
In addition to Angelman syndrome and PW syndrome, what are 2 additional problems associated with chromosome 15q?
Maternally inherited 15q interstitial duplication
Isodicentric isochromosome 15q(IDIC15)
How do we test for PWS vs Angelman?
Methylation testing…
If a deletion is present, a FISH test or a microarray can be done to confirm the diagnosis
Prader Willi Syndrome
Common Medical Issues
Systems (4)
Eyes
Orthopedics
Respiratory
Developmentally
PWS
Eyes?
Strabismus (unaligned)
Nystagmus (involuntary eye)
PWS
Orthopedics
Scoliosis is common
PWS
Respiratory
Obstructive sleep apnea may develop
PWS
Sleep apnea is a contraindication to the use of what?
Growth Hormone
PWS
Developmental
Mild-moderate cognitive disabilities are usually found, and behavioral issues are common
Other Disorders Associated with Chromosome 15q
Abnormalities of 15q (3)
Marker chromosomes - inverted duplication
Interstitial duplications
Deletions (Angelman)
Disorders Associated with Chromosome 15q
Autism?
Linkage disequilibrium between patients with Autism and polymorphisms in the GABA-a-b3 locus on chromosome 15q have been reported
*gamma-aminobutryic acid type A is an important NT in the CNS
15q11-q13 chromosome anomalies
Maternally derived proximal 15q11-q13 chromosome abomalies are one of the most frequently reported cytogenetic abnormalities in patients with_____
autism
maybe related to GABA-a receptor genes?
Supernumerary marker chromosome (15q)
Inverted duplicated isodicentric 15q (IDIC15) associated phenotype?
Autism
NOT dysmorphic
often hypotonic
seizures common
The autism associated with 15q is of maternal or paternal derivation?
maternal
What are supernumerary marker chromosomes?
The karyotype
of a person with an sSMC shows that in addition to the 46 chromosomes, there
is a 47th extra chromosome, known as a marker chromosome: 47,XX,+mar (for
a female) or 47,XY,+mar (for a male). An sSMC can be derived from any of the
24 different chromosomes – that is, chromosomes 1 to 22, an X or
a Y chromosome.
Interstitial duplication
A piece of a chromosome
can be copied, resulting
in a duplication or partial
Trisomy
15q interstitial duplication
phenotype
maternal phenotype manifested
father no phenotype
Autism NOT dysmorphic seizures hypotonia in infancy similar to IDIC 15
How would you test for an interstitial duplication of 15q?
Karyotype may be the best way - you could also see on a micro-array but wouldn’t know where extra copy was located
Methylation testing would demonstrate maternal inheritance
Angelman Syndrome
Etiology?
15q deletion in PWS/AS region from maternal allele
Angelman detection?
FISH
Uniparental disomy or imprinting errors are detected via methylation studies
Errors in imprinting may be increasind due to what?
Advanced reproductive technologies
Angelman phenotype
mildly dysmorphic facies-evolve with age hypotonia in infancy-progressing to spasticity in older patients Intellectual Disability Seizures Autism
4 potential ways to get Angelman
- Deletion in maternal region
- Mutation in maternal region
- Paternal uniparental disomy
- Pseudo unitparental disomy due to methylation error
Chromosome abnormalities associated with chromosome 15…
To summarize, the following syndromes/conditions are caused by abnormalities on chr15: (4)
Prader Willi (paternal deletion)
Angelman syndrome (maternal deletion)
IDIC 15 (associated with autism, hypotonia, seizures, ID)
Maternally inherited interstitial duplication (assoicted with autism/hypotonia/seizures/ID)
Mutations on chromosome 11 are commonly associated with what disorders that vary depending on which imprinting error occurs?
Beckweth-Widermann vs.
Russel Silver
Beckweth-Wiedermann syndrome
Due to imprinting error on chromosome 11
Basically overgrowth Macroglasmia macrosomia hypoglycemia omphalocele
Russel silver syndrome
Due to imprinting error on chromosome 11 (opp of Beckwith Wiedermann)
Dwarfism
There are growth factors in the area of chromosome 11 associated with which two disorders, explaining why over vs. underexpression may manifest in said disorders
What other important gene fnx is found in this region
Beckwith-Wiedermann - overgrowth
Russel Silver (Dwarf)
Tumor suppressor
Imprinting on chromosome ___ can be associated with cystic fibrosis
7
From most to least common imprinting genetic disorders
3 main chromosomes
15
11
7
