APKD, INCLUDED
POTTER TYPE III POLYCYSTIC KIDNEY DISEASE, INCLUDED
POLYCYSTIC KIDNEY DISEASE, ADULT, TYPE I
APKD1 POLYCYSTIC KIDNEY DISEASE, ADULT, INCLUDED
PKD1
Adult polycystic kidney disease is an autosomal dominant disorder with the cardinal manifestations of renal cysts, liver cysts, and intracranial aneurysm. Genetic heterogeneity is recognized, with one locus (PKD1), responsible for the most common form.
- ... Adult polycystic kidney disease is an autosomal dominant disorder with the cardinal manifestations of renal cysts, liver cysts, and intracranial aneurysm. Genetic heterogeneity is recognized, with one locus (PKD1), responsible for the most common form. - Genetic Heterogeneity of Polycystic Kidney Disease Polycystic kidney disease-2 (613095) is caused by mutation in the PKD2 gene (173910) on chromosome 4q21-q23. At least 1 other locus exists; see 600666.
The phenotypic variability in APKD involves differences in the rate of loss of glomerular filtration, the age of reaching end-stage renal disease (ESRD), and the occurrence of hypertension, symptomatic extrarenal cysts, and subarachnoid hemorrhage from intracranial 'berry' aneurysm. ... The phenotypic variability in APKD involves differences in the rate of loss of glomerular filtration, the age of reaching end-stage renal disease (ESRD), and the occurrence of hypertension, symptomatic extrarenal cysts, and subarachnoid hemorrhage from intracranial 'berry' aneurysm. - Kidney Age at onset of renal failure is variable, even within families. Shokeir (1978) described families with typical adult cystic kidney disease in which single individuals died early in life from polycystic renal disease. Zerres et al. (1984) suggested that in patients at risk, detection of 'solitary cysts,' even in 1 kidney, and enlargement of the kidney should be taken as signs of the disease. Zerres et al. (1985) suggested that early manifestation of APKD may aggregate in families because of genetic modifier(s). They diagnosed such a case in utero by ultrasound. A brother and a cousin also had early manifestation. Reeders (1986) described a phenomenal family ascertained through a fetus found incidentally on ultrasonography to have polycystic kidney disease. Adults had more conventional PKD in an autosomal dominant pedigree pattern. This is a situation comparable to the ascertainment of familial tuberous sclerosis by the finding of cardiac rhabdomyomata on prenatal ultrasonography (see 191100). Among 321 offspring of probands with polycystic kidney disease, Ravine et al. (1991) identified 68 (21%) who had ultrasound evidence of polycystic kidney disease. Of this previously undiagnosed group, 25 (37%) had one or more treatable complications at the time of diagnosis, including 20 cases of hypertension, 7 cases of impaired renal function, and 4 cases of bacterial urinary tract infection. The findings underscored the importance of screening at-risk family members. In 13 large Spanish families, Coto et al. (1992) found that all subjects over the age of 30 who were shown by linkage to carry the mutation had renal cysts by ultrasonography, whereas 40% of carriers of the mutation younger than 30 did not have renal cysts. Hypertension was found to be more frequent in those with renal cysts. Wirth et al. (1987) studied 6 kindreds in which polycystic kidney disease had early onset with cystic enlargement of the kidneys detected by prenatal sonography in some cases and with death soon after birth in several. Linkage analysis indicated that the gene locus mutant in these families is the same as that in standard adult-onset cases, i.e., the locus on chromosome 16p. Jeffery et al. (1998) presented a family with adult-onset autosomal dominant polycystic kidney disease in 2 generations, linked to the PKD1 locus and with paternal transmission to the fetus. The fetus carried the PKD1 haplotype and was, therefore, a gene carrier. Progressive hyperechogenic renal enlargement, but no cysts, was documented by serial fetal ultrasounds at 21, 23, and 34 weeks of gestation. Unexpectedly, the newborn renal scan showed normal-sized kidneys with apparently normal corticomedullary differentiation. However, at 11 months of age, the evolution of cysts in 1 kidney, and then in the other kidney at 20 months, was documented by ultrasound in the absence of clinical symptoms or signs. Germino (1998) indicated that approximately 50% of polycystic kidney disease leads to ESRD and that 4 to 5% of ESRD is due to PKD. The kidneys may achieve an enormous size, approximately 50 pounds in the case of a woman 62 inches tall. - Gastrointestinal Dalgaard (1963) found liver cysts in 43% of 173 autopsied cases in Denmark. In a review of cases, largely from the literature, Poinso et al. (1954) found that polycystic kidneys occurred in 53% of 224 cases of polycystic livers. Dalgaard (1963) said he had found a regular transition from polycystic liver degeneration to the solitary liver cyst in association with polycystic kidney. Ellis and Putschar (1968) presented the case of a 42-year-old woman with polycystic kidneys and portal hypertension for which splenorenal shunt was performed. Liver biopsy showed 'disseminated microcystic biliary hamartomas, with congenital fibrosis.' The mother died with hypertension, renal disease, and stroke at age 64. Two of her sisters died of renal disease. Two sisters of the proband were said to have polycystic kidney disease. Congenital hepatic fibrosis may occur with normal kidneys or with a variety of renal malformations, most often ectatic renal tubules resembling medullary sponge kidneys (see polycystic kidney, infantile, type I, 263200). Terada and Nakanuma (1988) demonstrated nonobstructive diffuse dilatation of intrahepatic bile ducts in 3 autopsy cases of autosomal dominant adult polycystic disease. Meyenburg complexes and liver cysts not communicating with the biliary tract lumen were also seen. Jordon et al. (1989) described the very rare association of Caroli disease with adult-type polycystic kidney disease. Caroli disease is a rare form of fibropolycystic disease of the hepatobiliary system characterized by segmental cystic dilatation of intrahepatic ducts and associated with intrahepatic cholelithiasis, cholangitis, and hepatic abscesses. It is found more commonly with other forms of cystic renal disease (see 263200). Telenti et al. (1990) reviewed 5 cases of infected hepatic cyst in polycystic kidney disease together with 9 reported cases. Clinical and laboratory features and the use of scanning techniques facilitated diagnosis. The treatment of choice was a combination of percutaneous drainage and antimicrobial therapy. Scheff et al. (1980) pointed out the high incidence of diverticulosis and diverticulitis in patients with chronic renal failure from polycystic disease. Colonic diverticula affect about 80% of patients with end-stage renal disease (Scheff et al., 1980), and colonic perforation is rather frequent in these patients. Involvement of the liver is more frequent, more striking, and earlier in onset in females than in males (Germino, 1998). - Cerebrovascular and Cardiovascular Ditlefsen and Tonjum (1960) described a family in which there were 15 verified and 2 suspected cases of polycystic kidney disease. Six of the patients suffered from cerebral hemorrhage. In 1 of the 6, aneurysm of the middle cerebral artery was verified. Intracranial 'berry' aneurysm is a rather frequently associated malformation. Levey et al. (1983) used decision analysis to assess whether patients with polycystic renal disease should have routine cerebral arteriography for intracranial aneurysms and prophylactic surgery if an aneurysm is detected. They concluded 'no' because the benefit exceeds 1 year only if the prevalence of aneurysm exceeds 30%, the surgical complication rate is 1% or less, and the patient is under 25 years of age. Newer noninvasive tests, such as digital-subtraction angiography, may change this decision. To determine the prevalence of intracranial aneurysms, Chapman et al. (1992) studied 92 subjects with autosomal dominant polycystic kidney disease who had no symptoms or signs of any neurologic disorder. High-resolution computed tomography (CT) was performed in 60 subjects, 4-vessel cerebral angiography in 21, and both procedures in 11. In 4 of the 88 subjects in whom the radiologic studies were successfully completed, intracranial aneurysms were found, as compared with the prevalence of 1% reported for an angiographic study of the general population. Multiple aneurysms were found in 3 of the 4 subjects. Chapman et al. (1992) concluded that an increased frequency of asymptomatic intracranial aneurysms occurs with polycystic kidney disease, although the 95% confidence interval for their finding (0.1 to 9%) included the possibility of no difference from the prevalence of 1% reported in the general population. They recommended high-resolution CT as a screening test. Chapman and Hilson (1980) suggested a relationship between polycystic kidneys and abdominal aortic aneurysm. Of 31 patients on chronic dialysis for polycystic kidneys, 3 had aortic aneurysm. Torra et al. (1996) examined this question in detail by means of a sonographic study of the abdominal aorta in 139 ADPKD patients and in 149 healthy family members. In both groups, an increase in aortic diameter related to age and sex was found, the aortic diameter being wider in older men than in women. In ADPKD patients, neither a wider aortic diameter nor a higher prevalence of abdominal aortic aneurysms could be found in any age group. They concluded that, although these patients are prone to develop aortic aneurysms because of hypertension and possibly associated connective tissue disorders, abdominal aortic aneurysm does not appear to be a frequent feature. Hossack et al. (1988) used echocardiography, including Doppler analysis, to assess the prevalence of cardiac abnormalities in 163 patients with autosomal dominant polycystic kidney disease, 130 unaffected family members, and 100 control subjects. In these 3 groups the prevalence of mitral valve prolapse was 26, 14, and 2%, respectively. A higher prevalence of mitral regurgitation, aortic regurgitation, tricuspid regurgitation, and tricuspid valve prolapse was also found in the patients with polycystic kidney disease. Hossack et al. (1988) interpreted these findings as reflecting the systemic nature of polycystic kidney disease and supporting the hypothesis that the disorder results from a defect in the extracellular matrix and that the cardiac abnormalities are an expression of that defect. A combination of hypertension and fundamental defect may be involved in the occurrence of dissecting aneurysm of the aorta, as described in an African American man in his twenties (Germino, 1998). (The patient had a history of PKD and was known to have hypertension at the age of 18 years, 2 intracranial aneurysms at the age of 24 years, and dissecting aneurysm at the age of 27 years.) Both intracranial and aortic aneurysm appear to cluster in families. McConnell et al. (2001) described a family unlinked to PKD1 or PKD2 in which the presenting feature was subarachnoid hemorrhage in 3 sisters. Two of the 3 sisters also had cysts, one of liver and kidney and one of liver alone. The remaining sister did not have any cysts, but had a parent with multiple renal cysts and a son with renal cysts. The individuals who presented with subarachnoid hemorrhage secondary to cerebral aneurysm were normotensive at the time of presentation. - Miscellaneous Emery et al. (1967) observed the coincidence of myotonic dystrophy (160900) and polycystic kidneys in at least 3 members of a family. Zerres et al. (1984) gave a comprehensive review of all forms of cystic kidney disease. They suggested that since the Potter type III is pathogenetically and genetically heterogeneous, the term should not be used synonymously for autosomal dominant polycystic kidney disease. Zerres et al. (1985) pointed out that patients on long-term renal hemodialysis develop cystic kidneys that can be nearly impossible to distinguish from autosomal dominant cystic kidney disease. Gabow (1993) reviewed all aspects of the genetics, pathogenesis, clinical manifestations, and diagnosis of autosomal dominant polycystic kidney disease. She indicated that approximately 50% of patients have hepatic cysts and that these increase with age. Hypertension affects more than 80% of patients with end-stage renal disease. Renal failure is estimated to affect 45% of patients by the age of 60. In the 10 families with a PKD1 mutation (i.e., linked to markers on chromosome 16) reported by Parfrey et al. (1990), 46% of the members less than 30 years old who had a 50% risk of inheriting a mutation had renal cysts, as compared with 11% of such members in the 2 families without linkage (P less than 0.001). In the PKD1 families, all 67 diagnoses made by ultrasonography were confirmed by determination of the genotype as inferred from linkage. Of the 48 members less than 30 years old who inherited the PKD1 mutation, 40 had renal cysts. All 27 members 30 years old or older who inherited the mutation had renal cysts, suggesting that the probability of a false-negative diagnosis did not exceed 0.13 in this age group. The mean age at onset of end-stage renal disease among members of the PKD1 families was 56.7 +/- 1.9 years, as compared with 69.4 +/- 1.7 years among members of the unlinked families (P = 0.0025). Hypertension and renal impairment were less frequent and occurred later in the families without the PKD1 mutation. In a survey in France involving 889 affected subjects, Simon (1995) found no difference in the cumulative survival to end-stage renal disease between males and females. By the age of 50 years, 22% of the patients had ESRD, by the age of 58, 42%, and by the age of 73, 72%. They found that males under 65 years of age have a rate of progression toward renal failure that is significantly more rapid than in females of the same age group. The risk linked to gender disappeared after 65 years of age. Somlo et al. (1993) described a family in which an overlap connective tissue disorder (OCTD) cosegregated with the chromosome 16-linked form of APKD. The connective tissue phenotype in this family included aortic root dilation, aortic and vertebral artery aneurysms with dissection, and aortic valve incompetence, as well as pectus abnormalities, pes planus, joint laxity, arachnodactyly, scoliosis, dolichostenomelia, and high arched palate. Two markers flanking the PKD1 region were tightly linked to both APKD and OCTD. Perrone (1997) led a discussion of extrarenal manifestations of ADPKD. The increased frequency of diverticular disease was reviewed, including the increased risk of colonic perforation after renal transplantation. The mechanism of this, as well as other extrarenal complications, is unclear.
Familial clustering of intracranial aneurysms suggested that genetic factors are important in the etiology of ADPKD. Rossetti et al. (2003) characterized mutations in 58 ADPKD families with vascular complications; 51 were PKD1 (88%) and 7 were PKD2 (12%). ... Familial clustering of intracranial aneurysms suggested that genetic factors are important in the etiology of ADPKD. Rossetti et al. (2003) characterized mutations in 58 ADPKD families with vascular complications; 51 were PKD1 (88%) and 7 were PKD2 (12%). The median position of the PKD1 mutation was significantly further 5-prime in the vascular population than in the 87 control pedigrees (amino acid position 2163 vs. 2773, p = 0.0034). Subsets of the vascular population with aneurysmal rupture, early rupture, or families with more than 1 vascular case had median mutation locations even further 5-prime.
The European Polycystic Kidney Disease Consortium (1994) isolated the PKD1 gene, which they called PBP for 'polycystic breakpoint', by analysis of the translocation breakpoint in a family with polycystic kidney disease. The mother and daughter, who both carried ... The European Polycystic Kidney Disease Consortium (1994) isolated the PKD1 gene, which they called PBP for 'polycystic breakpoint', by analysis of the translocation breakpoint in a family with polycystic kidney disease. The mother and daughter, who both carried a balanced translocation, 46,XX t(16;22)(p13.3;q11.21), had clinical features of PKD1. The authors then identified mutations in the PBP gene in other patients with PKD1. Peral et al. (1995) sought mutations in the PKD1 gene in this disorder. Analysis of 3 regions in the 3-prime part of the gene revealed 2 mutations that occurred by a novel mechanism. Both were deletions (of 18 or 20 bp) within the same 75-bp intron and, although these deletions did not disrupt the splice donor or acceptor sites at the boundary of the intron, they nevertheless resulted in aberrant splicing. Two different transcripts were produced in each case; one included the normally deleted intron while the other had a 66-bp deletion due to activation of a cryptic 5-prime splice site. No normal product was generated from the deletion-mutant gene. Peral et al. (1995) speculated that aberrant splicing probably occurred because the deletion made the intron too small for spliceosome assembly using the authentic splice sites. They also identified a 9-bp direct repeat within the intron, which probably facilitated the intronic deletion by promoting misalignment of sequence. Qian et al. (1996) developed a novel method for isolating renal cystic epithelia from single cysts and showed that individual renal cysts in PKD1 are monoclonal. Loss of heterozygosity (LOH) was discovered within a subset of cysts for 2 closely linked polymorphic markers located within the PKD1 gene. Genetic analysis revealed that it was the normal haplotype that was lost. The findings provided a molecular explanation for the focal nature of cyst formation and a probable mechanism whereby mutations cause disease. The high rate at which 'second hits' must occur to account for the large number of cysts observed suggested to Qian et al. (1996) that unique structural features of the PKD1 gene may be responsible for its mutability. (This is a remarkable example of the Knudson 2-hit mechanism, which has been established in a considerable number of neoplasms whose causation is based on inactivation of both copies of a tumor-suppressor gene.) They previously reported an extremely unusual 2.5-kb polypyrimidine tract within intron 21 of the PKD1 gene that they postulated as being responsible for the gene's increased rate of mutation (Burn et al., 1995). Qian et al. (1996) postulated that the polypyrimidine tract may cause ongoing errors in its transcription-coupled repair, thus resulting in a high frequency of somatic mutation. Thus, they concluded that PKD1 is a recessive disorder when viewed at the level of the individual renal lesions. Brasier and Henske (1997) likewise found evidence of clonal chromosomal abnormalities in some renal cyst epithelial cells with loss of the wildtype copy of PKD1. Twenty nine cysts from 4 patients were studied using microsatellite markers from the 16p13 region and looking for LOH. This supported a loss-of-function model for autosomal dominant PKD, with a germline mutation inactivating one copy of PKD1 and somatic mutation or deletion inactivating the remaining wildtype copy. For a review of the molecular mechanisms underlying ADPKD, see Wu and Somlo (2000).
Dalgaard (1957) published a comprehensive landmark study in Denmark which showed that autosomal dominant PKD is one of the most common genetic diseases in humans (approximately 1 in 1,000 individuals affected).
In Wales, Davies et al. ... Dalgaard (1957) published a comprehensive landmark study in Denmark which showed that autosomal dominant PKD is one of the most common genetic diseases in humans (approximately 1 in 1,000 individuals affected). In Wales, Davies et al. (1991) estimated an apparent prevalence of ADPKD of 1 in 2,459 in the general population, an estimate that included predicted affected family members. Higashihara et al. (1998) estimated the prevalence to be 1 in 4,033 based solely on hospital admissions and with no inclusion of family members. They suggested that the fact that these frequencies were lower than those based on autopsy studies indicated that a considerable number of ADPKD patients were asymptomatic or not sufficiently symptomatic to seek medical attention.