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Polycystic kidney disease


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.

The adult type

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

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.

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.

The severe, congenital type

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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