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Angelman syndrome and Prader Willi syndrome
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Types
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These two syndromes are caused by a mutation in the same region of chromosome 15, but differ in clinical presentation, as
described below. The mutation is a deletion of a specific part of this chromosome.
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Clinical signs
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Prader Willi syndrome manifests as a combination of features; in infancy there is
muscle flaccidity and dysphagia (problems with swallowing) that result in inadequate
weight gain at this time. This later changes to polyphagia (overeating) and obesity
that may be severe enough to cause respiratory failure. In addition, patients have
developmental delay of differing degrees of severity. The genitalia are typically
underdeveloped.
Angelman syndrome is marked by a decreased rate of the growth of the head towards
or around the second year of life the head circumference is smaller than that of
their peers and is less than the norm. They have epileptic convulsions, difficulties with balance
while standing or walking, and severe mental retardation. Patients also have repetitive
monotonous movements and a tendency to have unexplained attacks of laughter.
Diagnosis is made by molecular genetic tests. Sometimes the deletion is large enough
for the condition to be diagnosed by a regular
chromosome test.
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Inheritance pattern
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The mutation is the deletion of a specific region of
chromosome 15. In Prader Willi syndrome, the deletion is in the chromosome
15 that was transmitted to the child from his or her father. In Angelman syndrome,
the deletion is in the chromosome 15 that was transmitted to the child from his
or her mother. The parents do not carry the mutation, which arises in two main ways:
- Deletion of a specific part of chromosome 15: A new mutation, which is the deletion
of a specific segment of chromosome 15, arises in the oocyte or sperm cell creating
the fetus. If the segment that is deleted is from the chromosome 15 from the sperm
cell, the result is Prader Willi syndrome. If the segment that is deleted is from
the chromosome 15 from the oocyte, the result is Angelman syndrome. The sex of the
infant is not relevant.
- Uniparental disomy (UPD): In this situation the infant receives two normal, intact
chromosome 15s from one parent, and no chromosome 15 from the other. If the infant
receives two chromosome 15s from the mother and none from the father, the result
is Prader Willi syndrome. Conversely, if both the chromosome 15s come from the father
and there is no maternal chromosome 15, the result is Angelman syndrome. The reason
why this occurs is because in this area of chromosome 15, the testis and the ovary
turn on or turn off different genes (a process called genomic imprinting). In other
words, in this case, in order for there to be functional completeness, the infant
must receive one chromosome 15 that has been treated by the ovary and one that has
been treated by the testis, i.e. there must be both a maternal and a paternal contribution.
- There may be other mutations, possibly involving hereditary transmission of these
syndromes. In these cases there is usually a family history of individuals in previous
generations with one of these syndromes.
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Penetrance
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Full
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Associated features that can be demonstrated in tests performed during pregnancy
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In fetuses with Prader Willi syndrome, an attempt can be made to detect the slightly
smaller genitalia by
ultrasound examination.
There may be fewer than usual fetal movements.
However, these are not diagnostic signs. Failure to demonstrate these signs does
not rule out these syndromes.
In all these cases it is important to refer the couple for genetic counseling, to which they should bring
all data, including the results of other tests performed during the pregnancy such
as alpha-fetoprotein, nuchal translucency, etc.
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What is the risk of recurrence in a subsequent pregnancy?
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As a rule, if there is a single case in the family, the risk is low (less than 1%),
and may be even lower. In the case of UPD, there is no risk of recurrence, either
for the couple who has already had an affected child or for other relatives, and
the patient himself has no theoretical increased risk for having a child with the
same condition. If there is a chromosomal deletion, this is usually a new mutation,
and here the parents have a slight risk of recurrence in future pregnancies. This
can be tested in each subsequent pregnancy. It should be noted that the patients
offspring have a 50% risk of being affected.
The risk for more distant relatives depends on the number of affected individuals
in the family, the degree of relationship between the relatives and the affected
individuals, the results of genetic tests performed on the patient and the parents,
etc. The risk is established within
genetic counseling.
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Molecular genetic information
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The gene for the disease
A number of genes
Location
The long arm of chromosome 15.
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Genetic testing
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Diagnostic testing
A molecular test will determine whether there is a chromosomal deletion in the critical
region of chromosome 15, and also whether the two chromosome 15s come from the same
parent (UPD). This test is carried out in Israel in a number of places, and is aimed
at confirming diagnoses and providing prenatal testing of amniotic fluid or chorionic villus cells.
The test for rare mutations in the genes in cases where there is neither a chromosomal
deletion nor UPD is a complicated and difficult test it is performed only in special
cases as research through genetic institutes.
Carrier testing
This is not practicable unless the family has many affected individuals or a point
mutation (this is rare) that has been found in previous tests conducted on the patient.
Fetal testing
If there is a clinical suspicion and the couple has had an affected child from a
previous pregnancy, it is advisable to undertake prenatal diagnosis. The test is
performed on chorionic villus or amniotic fluid cells, and is intended to identify
the common mutations (chromosomal deletion or UPD).
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