Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare genetic disorder characterized by the development of cysts in the kidneys and, in some cases, other organs. It is caused by mutations in the PKHD1 gene, leading to a deficiency of the protein fibrocystin. The condition is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the mutated gene (one from each parent) to manifest the disease. Autosomal recessive polycystic kidney disease is a rare pathology with an incidence of 1 case per 20.000 live births that is of special importance in pediatric nephrology.
Autosomal recessive polycystic kidney disease genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Key features and aspects of Autosomal Recessive Polycystic Kidney Disease include:
- Renal Cysts: ARPKD is primarily associated with the formation of fluid-filled cysts in the kidneys. These cysts can affect the normal functioning of the kidneys and lead to progressive renal impairment.
- Liver Involvement: Besides renal involvement, ARPKD can also affect the liver. Liver-related complications may include enlargement of the liver (hepatomegaly) and the presence of cysts in the liver (hepatic fibrosis).
- Congenital Hepatic Fibrosis: Congenital hepatic fibrosis is a common feature of ARPKD. It involves the abnormal development of the bile ducts in the liver, contributing to liver-related complications.
- Respiratory and Cardiovascular Complications: In severe cases, respiratory and cardiovascular complications may arise due to the compression of adjacent organs by enlarged kidneys.
- Variable Presentation: The severity and presentation of ARPKD can vary widely among affected individuals. Some may have a milder form of the disease, while others may experience more severe complications.
- Prenatal and Neonatal Presentation: ARPKD may be diagnosed prenatally through imaging studies, as enlarged kidneys and cysts can be detected during pregnancy. In severe cases, symptoms may be apparent in the neonatal period.
Management focuses on supportive care, addressing complications, and optimizing kidney and liver function. In some cases, renal replacement therapy, such as dialysis or kidney transplantation, may be necessary. Due to the complexity of ARPKD and its potential impact on multiple organ systems, a multidisciplinary approach involving nephrologists, hepatologists, geneticists, and other specialists is often necessary to provide comprehensive care. Genetic counseling is crucial for families affected by ARPKD to understand the inheritance pattern and assess the risk for future generations.
Diagnosis involves genetic testing to identify mutations in the PKHD1 gene. Prenatal testing can also be performed for families at risk.
Mutations in the PKHD1 gene have been identified as the main molecular cause of ARPKD. The PKHD1 gene is large, consisting of 86 exons, which codes for fibrocystin, a protein present in the primary cilia of the renal tubules that are thought to be involved in maintaining the size and structure of the tubules. Fibrocystin is also found in smaller amounts in the liver and pancreas. To date, over 500 pathogenic variants in PKHD1 have been identified.
Mutations in the DZIP1L gene also cause ARPKD to a lesser extent. Only seven pathogenic variants have been described. This gene also codes for a protein located in the primary cilia of the renal tubules. It has only been observed in some patients with ARPKD who present with moderate symptomatology.
The c.107C>T mutation is among the most frequent mutations found in ARPKD patients of diverse ethnic origin, accounting for 10-20% of the alleles detected. It produces an amino acid change that affects the structure and function of fibrocystin.
Pathogenic variants are more frequent in certain populations, such as c.1486C>T and c.10412T>G, found in 60% of ARPKD cases in Finland.
ARPKD can also develop when an individual carries two different mutations in the PKHD1 gene, known as compound heterozygosis. An example would be the case of the c.664A>G variant that has been found in several patients combined with another mutation. c.664A>G has been identified in individuals from countries such as the United States, Germany, Spain, Israel, South Africa, Italy, Austria, and Brazil.
The genetic test of Autosomal Recessive Polycystic Kidney Disease analyzes the 34 most frequent pathogenic mutations of the PKHD1 gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).
