Extracranial Aneurysms in 2 Patients with Autosomal Recessive Polycystic Kidney Disease

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Abstract

Unlike autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD) is not generally known to be associated with vascular abnormalities. Only 4 cases of ARPKD patients with intracranial aneurysms have been reported previously. We present 2 ARPKD patients with extracranial vascular abnormalities: a young man with infrarenal aortic and iliac artery aneurysms complicated by dissection and a teenage girl with multiple splenic and gastric artery aneurysms and arterial vascular malformations. These cases raise the question of whether vascular integrity and development may be impaired in ARPKD, perhaps through molecular mechanisms overlapping with ADPKD. This possibility is supported by studies in mice that show ARPKD gene expression in the walls of large blood vessels.

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Most cited references 48

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Polycystic kidney disease.

Peter Harris, Vicente Torres (2009)

A number of inherited disorders result in renal cyst development. The most common form, autosomal dominant polycystic kidney disease (ADPKD), is a disorder most often diagnosed in adults and caused by mutation in PKD1 or PKD2. The PKD1 protein, polycystin-1, is a large receptor-like protein, whereas polycystin-2 is a transient receptor potential channel. The polycystin complex localizes to primary cilia and may act as a mechanosensor essential for maintaining the differentiated state of epithelia lining tubules in the kidney and biliary tract. Elucidation of defective cellular processes has highlighted potential therapies, some of which are now being tested in clinical trials. ARPKD is the neonatal form of PKD and is associated with enlarged kidneys and biliary dysgenesis. The disease phenotype is highly variable, ranging from neonatal death to later presentation with minimal kidney disease. ARPKD is caused by mutation in PKHD1, and two truncating mutations are associated with neonatal lethality. The ARPKD protein, fibrocystin, is localized to cilia/basal body and complexes with polycystin-2. Rare, syndromic forms of PKD also include defects of the eye, central nervous system, digits, and/or neural tube and highlight the role of cilia and pathways such as Wnt and Hh in their pathogenesis.

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The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia.

X Hou, Bradley K. Yoder, Lisa M. Guay-Woodford (2002)

Recent evidence has suggested an association between structural and/or functional defects in the primary apical cilium of vertebrate epithelia and polycystic kidney disease (PKD). In Caenorhabditis elegans, the protein orthologues of the PKD-related proteins, polycystin-1 (LOV-1), polycystin-2 (PKD2), and polaris (OSM-5), co-localize in the cilia of male-specific sensory neurons, and defects in these proteins cause abnormalities of cilia structure and/or function. This study sought to determine whether the mammalian polycystins are expressed in primary cilia of renal epithelia and whether these proteins co-localize with polaris and cystin, the newly described, cilia-associated protein that is disrupted in the cpk mouse. To begin to address this issue, the expression of the protein products encoded by the PKD1, PKD2, Tg737, and cpk genes were examined in mouse cortical collecting duct (mCCD) cells using an immunofluorescence-based approach with a series of previously well-characterized antibodies. The mCCD cells were grown on cell culture inserts to optimize cell polarization and cilia formation. The data demonstrate co-localization in cilia of polycystin-1 and polycystin-2, which are the principal proteins involved in autosomal dominant polycystic kidney disease, with polaris and cystin, which are proteins that are disrupted in the Tg737(orpk)and cpk mouse models of autosomal recessive polycystic kidney disease, respectively. These data add to a growing body of evidence that suggests that primary cilium plays a key role in normal physiologic functions of renal epithelia and that defects in ciliary function contribute to the pathogenesis of PKD.

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Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.

Q. M. Zhang, Lisa M. Guay-Woodford, Sandro Rossetti … (2007)

Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available.

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Journal

Journal ID (publisher-id): CND

Journal ID (pmc): CND

Journal ID (doi): 10.1159/issn.2296-9705

Title: Case Reports in Nephrology and Dialysis

Publisher: S. Karger AG

ISSN (Electronic): 2296-9705

Publication date Subscription-year: 2017

Publication date Collection: May – August 2017

Publication date (Electronic): 02 May 2017

Volume: 7

Issue: 2

Pages: 34-42

Affiliations

[_a] _aEmory University, Atlanta, Georgia, USA

[_b] _bDepartment of Radiology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

[_c] _cDepartment of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA

[_d] _dDivision of Nephrology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

[_e] _ePerelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Author notes

*Erum A. Hartung, MD, MTR, Division of Nephrology, Children’s Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104 (USA), E-Mail hartunge@email.chop.edu

Author information

Erum A. Hartung https://orcid.org/0000-0001-5617-6505

Article

Publisher ID: 475492 Pmcid ID: PMC5465521 Other ID: Case Rep Nephrol Dial 2017;7:34–42

DOI: 10.1159/000475492

PMC ID: PMC5465521

PubMed ID: 28612004

SO-VID: a5d8beb9-5b27-49cb-84fd-95767e3ced7a

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History

Date received : 01 February 2017

Date accepted : 02 April 2017

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Figures: 2, Pages: 9

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Extracranial Aneurysms in 2 Patients with Autosomal Recessive Polycystic Kidney Disease

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Abstract

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Karger: Nephrology

Most cited references 48

Polycystic kidney disease.

The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia.

Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.

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