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Polycystic kidney disease
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Polycystic kidneys - this term refers to the presence of multiple liquid-containing
vesicles (cysts) in the kidney tissue. These cysts contain urine and there can be
a very large number of them. There are two types of the disease:
The severe type, which appears
in infancy/early childhood (the infant type).
The milder type, also known
as the adult type, which appears in adulthood, usually at the age of 40 -
50.
These two types are completely different in severity, inheritance pattern, the gene
responsible, and the method of investigating the family from the genetic point of
view, as described below.
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The adult type
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Clinical signs
This is the more common type. It manifests as a large number of small cysts in the
kidney tissue whose volume increases over the years. Their effect on kidney function
usually appears at the age of 40 - 50, and sometimes in late old age. There are
a few cases of earlier onset, even in early childhood. The kidney function diminishes
to the point of renal failure, in which case dialysis and a kidney transplant are
required. This is the most common cause of renal failure in adults today.
The cysts are small at younger ages, so that they may go unnoticed on ultrasound
scans. Sometimes the kidneys are more echogenic, which suggests that cysts may be
present (an increased echo is shown on ultrasound examination as a kidney tissue
mass that is whiter than normal). It is less common to demonstrate cysts or hyperechogenicity
using an ultrasound transducer during pregnancy. Demonstrating them by ultrasound
at a young age, particularly if intrauterine, indicates a more severe manifestation
of the disease and the development of renal failure at a younger age.
Inheritance pattern
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The disease is transmitted by
autosomal dominant inheritance. Usually one of the parents is affected and
there may also be other family members with polycystic kidneys or renal failure.
Sometimes it will only be discovered that other family members are affected after
they have undergone a thorough examination by ultrasound.
Each of the family members who carries an abnormal gene for polycystic kidney has
a 50% risk in every pregnancy of transmitting it to his or her offspring.
It must be taken into account that the absence of demonstrable cysts on ultrasound
in a family member does not rule out the presence of the abnormal gene in that person,
since the disease may only manifest at an older age than that at the time of examination.
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Therefore genetic testing is a tool that contributes significantly to ascertaining
the presence or absence of the abnormal gene in a person who has relatives with
polycystic kidneys. Genetic testing is also important, of course, for diagnosing
the condition in fetuses or in children.
Penetrance
The disease is usually only expressed in the 4th to 5th decade of life. Hence at
the age of 40, not all carriers of the abnormal gene will demonstrate signs of the
disease. However, the disease is expressed in 100% of the carriers of the abnormal
gene by the age of 80.
Associated features that can be demonstrated by imagery
Cysts have a typical appearance on ultrasound examination. In pregnancy, only some
carriers of the abnormal gene demonstrate hyperechogenicity of the kidneys, which
suggests that cysts may be present and these are an indication that signs of the
disease will appear at an earlier age.
What is the risk of recurrence in a subsequent pregnancy?
In cases where the affected individual
is the only one in the family:
If this is the first case in the family, there is a high probability that the disease
in the child/fetus is the result of a new mutation in the gene for the disease -
i.e. the hereditary transmission starts with the child/fetus, and there is a 50%
chance in every pregnancy that he or she will transmit the abnormal gene to his
or her offspring. On the other hand, in these cases, the parents and other family
members who are not offspring of the patient apparently have no increased risk for
having another affected child (approximately 2%).
In cases where there are many affected
individuals in the family (the more usual situation), family members
must be examined by ultrasound.
One of the parents of each affected individual carries the abnormal gene causing
the disease, and the risk of transmitting this to the offspring is 50% in every
pregnancy, although it may not always be expressed. Because the gene is not always
expressed, one of the parents may carry it without yet showing any signs of the
disease. In families with many affected members, each affected individual has a
50% risk of recurrence in subsequent pregnancies, including in each of the more
distant family members found to have signs of the disease. The risk of transmitting
the condition is less than 2% - 3% if the parents have undergone testing as above
and have been found not to carry the gene, and if there are no other cases of affected
family members in previous generations in either of the patient's parents - i.e.
the disease in the child has been caused by a new mutation.
Molecular genetic information
The gene for the disease
There are at least 2 different genes that are responsible for adult type polycystic
kidney disease. One is called APKD1, which is responsible for 90% of cases, and
the other is APKD2, responsible for all the other cases. It is not possible to distinguish
clinically which gene is involved in any specific family. Before any diagnostic
test is performed, the gene responsible for the disease in the family in question
must be determined.
The location
APKD1 is situated on chromosome 16, and APKD2 on chromosome 4.
Genetic testing
Diagnostic testing
The direct genetic test for identifying the mutation is relatively complex. There
are a number of major problems:
The genes are large and determining the sequence of the bases comprising them in
order to identify the mutation is a difficult, time-consuming, expensive and currently
impractical process, although it may well become simpler in the future. See information
sheet:
Finding the gene (mutation) by establishing the gene sequence - autosomal dominant
diseases.
Each family has its own specific mutation. Because of this, in order to identify
the specific mutation responsible for the disease in the family being investigated,
it is necessary to read the entire sequence of the gene. It is not practicable to
concentrate on a limited region of the sequence in the relevant genes, although
it is possible to do this for
cystic fibrosis, in which there are common, recurrent mutations in different
families. See the information sheet: Testing
the disease-causing gene for mutations that are common in a specific ethnic group
- autosomal dominant diseases.
Therefore, instead of performing a direct test to identify a mutation in one of
the genes in the affected individuals in the family being investigated, an indirect
test can be performed. This test, which is relatively simple, available, and can
be completed within a short space of time (about a month), uses the method of linkage
analysis. Genetic markers that are situated on the
chromosome near to the gene for polycystic kidney disease are used - these
markers define a unique pattern for each gene without examining whether there is
a mutation in the gene. Using these markers, the transmission of the genes in the
family is followed - the genetic pattern common to the affected individuals is probably
the one containing a mutation. Every individual who in family or fetal tests has
been found to have this same pattern will have received the abnormal gene.
Because the test is indirect, and because there are 2 different genes that can cause
the disease, the test is more reliable the more family members are tested. The more
subjects there are in the family, the greater the confidence with which the relationship
between a specific pattern and the disease can be established, and the greater the
confidence for absolute certainty for which gene (APKD1 or APKD2) is causing the
disease in that specific family. Of course, an error in defining the gene responsible
for the disease in the family being investigated will lead to a mistaken conclusion
as to the determinant gene in that family. The test is usually deemed reliable only
if at least 5 known affected individuals in the family are tested. When there is
no choice, it is possible to manage with fewer patients, but this is undesirable
because the reliability of the test is reduced from 98% to 90%. See information
sheet: Indirect testing for genetic markers in a family that has a number
of patients - when there are a number of genes that can each cause the disease -
all genes having been located / identified / mapped - autosomal dominant diseases.
Carrier testing
The test for detecting a carrier of an abnormal gene in an autosomal dominant disease where the condition is not clinically
expressed is in fact the same as the diagnostic test.
Fetal testing
This is an indirect test as specified above. See information sheet: Indirect testing for genetic markers in a family that has a number
of patients - when there are a number of genes that can each cause the disease -
all genes having been located / identified / mapped - autosomal dominant diseases.
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The severe, congenital type
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Clinical signs
This is the severe type of polycystic kidney disease. It manifests as a large number
of cysts that cause renal failure at a very early stage - in some cases in utero
- in which case there is significant
oligohydramnios (lack of amniotic fluid), which causes undeveloped lungs
and death due to respiratory failure after birth, a condition called Potter's sequence.
In less severe cases there may be mild oligohydramnios, or a normal amount of amniotic
fluid, with renal failure appearing after birth or when the child is older. Early
onset of renal failure is relatively difficult to treat and it has an effect on
growth.
The cysts can be detected by
ultrasound examination - however, sometimes cysts are not seen, only hyperechogenicity
of the kidneys (excess reflection of ultrasound waves shown as bolder whiteness
of the kidney tissue). Demonstration of this by ultrasound at a young age, particularly
if intrauterine, is evidence of the more severe, younger onset type of renal failure.
Inheritance pattern
The disease is transmitted by
autosomal recessive inheritance.
Penetrance
Penetrance is full and the disease is fully expressed - every person who receives
2 copies of the abnormal gene will develop the disease at an early age.
Associated features that can be demonstrated by imagery
Oligohydramnios that can be severe when the disease appears in utero. When the onset
of renal failure is later, characteristic cysts or hyperechogenicity of the kidneys
as an expression of these cysts may be detected by ultrasonography. In some patients
there may also be dilation (widening) of the bile ducts or cysts in the liver.
What is the risk of recurrence in a subsequent pregnancy?
The risk of recurrence for a couple that has an affected child is 25% in every subsequent
pregnancy.
For more distant relatives: the risk of having a child with this condition is relatively
low. Healthy siblings of the patient have a risk of less than 1:500 of having an
affected child and the risk is even lower for more distant relatives.
Molecular genetic information
The gene for the disease
ARPKD
Its location
6p21.1-p12
Genetic testing
Diagnostic testing
A direct test to identify the mutation in the gene can be undertaken - this is an
expensive and time-consuming process, but it does, however, offer the great advantage
of enabling prenatal diagnosis to be carried out. See: Finding the defect
(mutation) by establishing the gene sequence - autosomal recessive diseases.
Carrier testing
For identifying carriers in the patient's
family: In order to identify carriers in the family, the indirect tests
specified below in the section on fetal testing can be performed. See: Indirect testing for genetic markers
in a family that has a single patient - when there is only one gene that can cause
the disease - autosomal recessive diseases. However, because the risk is
low and the feasibility of testing their partners is limited, these tests are not
usually performed.
Carrier testing in partners of carriers
or in the general population: There are no common mutations, and therefore
the entire sequence of the ARPKD gene must be examined in order to identify carriers
in the general population. This is a time-consuming, expensive test that is not
performed routinely at the present time. See: Finding the gene (mutation)
by establishing the gene sequence - autosomal recessive diseases.
Fetal testing
The genetic test that can be used for prenatal diagnosis in a couple that has already
had one affected child is relatively simple as long as DNA from the affected child
is available. Usually it is sufficient to carry out linkage analysis. See: Indirect testing for genetic
markers in a family that has one or more patients - when there is only one gene
that can cause the disease - autosomal recessive diseases.
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