Autosomal recessive polycystic kidney disease

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Autosomal recessive polycystic kidney disease
Other namesARPKD
Autorecessive.svg
ARPKD is inherited in an autosomal recessive pattern
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
Symptoms Polyuria [1]
CausesMutations in the PKHD1 gene [2]
Diagnostic method Ultrasound [3]
TreatmentMedications for hypertension [4]

Autosomal recessive polycystic kidney disease (ARPKD) is the recessive form of polycystic kidney disease. It is associated with a group of congenital fibrocystic syndromes. [5] Mutations in the PKHD1 (chromosomal locus 6p12.2) cause ARPKD. [6] [7]

Contents

Signs and symptoms

Symptoms and signs include abdominal discomfort, polyuria, polydipsia, incidental discovery of hypertension, and abdominal mass. [1] The classic presentation for ARPKD is systemic hypertension with progression to end-stage kidney disease (ESKD) by the age of 15. In a typical presentation, a small number of individuals with ARPKD live to adulthood with some kidney function; but with significant deterioration in liver function. [8] This outcome is postulated to result from expression of the polycystic kidney and hepatic disease gene PKHD1, which is located on chromosome 6p. [9] In severe cases, a fetus will present with oligohydramnios and as a result, may present with Potter sequence. [10]

Genetics

The cause of ARPKD is linked to mutations in the PKHD1 gene. [2] The PKHD1 gene encodes for the protein forfibrocystin, that is found in the epithelial cells of both the renal tubule and the bile ducts; deficiency leads to the characteristic polycystic dilation of both structures[ citation needed ]

Micrograph of von Meyenburg complex. Von Meyenburg complex low mag.jpg
Micrograph of von Meyenburg complex.

ARPKD is a significant hereditary renal disease in that appears in childhood. [11] The prevalence is estimated to be of 1 in 20,000 live births, [11] with a reported carrier frequency of up to 1:70. PKHD1 is the only gene that is found to be responsible for the disease presentation of ARPKD. [11] PKHD1 is located on the human chromosome region 6p21.1–6p12.2. [11] It is also one of the largest genes in the genome as it occupies approximately 450 kb of DNA, and contains at least 86 exons. [11]

It is capable of producing multiple alternatively spliced transcripts. [11] The largest known transcript encodes fibrocystin /polyductin (FPC), which is a large receptor-like integral membrane protein of 4074 amino acids. [11] The structure of the FPC consist of a single transmembrane, a large N-terminal extracellular region, and a short intracellular cytoplasmic domain. [11] The FPC protein is found on the primary cilia of epithelia cells of cortical and medullary collecting ducts and cholangiocytes of bile ducts, and show similarity to polycystins and several other ciliopathy proteins. [11] FPC is also found to be expressed on the basal body and plasma membrane. [11] It is presumed that the large extracellular domain of FPC binds to a ligand(s) that is yet unknown and that is also involved in cell-cell and cell-matrix interactions. [11]

It is known that FPC interacts with ADPKD protein PC2 and may also participate in this regulation pathway of the mechanosensory function of the primary cilia, calcium signaling, and PCP. [11] This is suggesting a common mechanism underlying cystogenesis between ADPKD and ARPKD. [11] The FPC protein is also found on the centrosomes and mitotic spindle and may regulate centrosome duplication and mitotic spindle assembly during cell division. [11] There have been a large number of various single-gene mutations found throughout PKHD1 and are unique to individual families. Most of the patients are compound heterozygotes for PKHD1 mutations. [11] Patients with two nonsense mutations appear to have an earlier onset of the disease. [11]

Diagnosis

Autosomal recessive polycystic kidney disease with a normal kidney inset Autosomal recessive polycystic kidney disease.svg
Autosomal recessive polycystic kidney disease with a normal kidney inset

Ultrasonography is the primary method to evaluate autosomal recessive polycystic kidney disease, particularly in the perinatal and neonatal stages. [3]

Differential diagnosis

The differential diagnoses of this condition include: [5]

Treatment

The treatment options for autosomal recessive polycystic kidney disease, given there is no current cure, are: [4]

Related Research Articles

<span class="mw-page-title-main">Autosomal dominant polycystic kidney disease</span> Medical condition

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life-threatening inherited human disorders and the most common hereditary kidney disease. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. It is also the most common of the inherited cystic kidney diseases — a group of disorders with related but distinct pathogenesis, characterized by the development of renal cysts and various extrarenal manifestations, which in case of ADPKD include cysts in other organs, such as the liver, seminal vesicles, pancreas, and arachnoid membrane, as well as other abnormalities, such as intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse, and abdominal wall hernias. Over 50% of patients with ADPKD eventually develop end stage kidney disease and require dialysis or kidney transplantation. ADPKD is estimated to affect at least one in every 1000 individuals worldwide, making this disease the most common inherited kidney disorder with a diagnosed prevalence of 1:2000 and incidence of 1:3000-1:8000 in a global scale.

<span class="mw-page-title-main">Joubert syndrome</span> Medical condition

Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the brain that controls balance and coordination.

<span class="mw-page-title-main">Kidney disease</span> Damage to or disease of a kidney

Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.

<span class="mw-page-title-main">Alagille syndrome</span> Medical condition

Alagille syndrome (ALGS) is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 30,000 to 1 in every 40,000 live births. It is named after the French pediatrician Daniel Alagille, who first described the condition in 1969.

<span class="mw-page-title-main">Cystic kidney disease</span> Medical condition

Cystic kidney disease refers to a wide range of hereditary, developmental, and acquired conditions and with the inclusion of neoplasms with cystic changes, over 40 classifications and subtypes have been identified. Depending on the disease classification, the presentation may be at birth, or much later into adult life. Cystic disease may involve one or both kidneys and may, or may not, occur in the presence of other anomalies. A higher incidence is found in males and prevalence increases with age. Renal cysts have been reported in more than 50% of patients over the age of 50. Typically, cysts grow up to 2.88 mm annually and may cause related pain and/or hemorrhage.

<span class="mw-page-title-main">Sodium-chloride symporter</span> Protein-coding gene in the species Homo sapiens

The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.

<span class="mw-page-title-main">Medullary cystic kidney disease</span> Medical condition

Medullary cystic kidney disease (MCKD) is an autosomal dominant kidney disorder characterized by tubulointerstitial sclerosis leading to end-stage renal disease. Because the presence of cysts is neither an early nor a typical diagnostic feature of the disease, and because at least 4 different gene mutations may give rise to the condition, the name autosomal dominant tubulointerstitial kidney disease (ADTKD) has been proposed, to be appended with the underlying genetic variant for a particular individual. Importantly, if cysts are found in the medullary collecting ducts they can result in a shrunken kidney, unlike that of polycystic kidney disease. There are two known forms of medullary cystic kidney disease, mucin-1 kidney disease 1 (MKD1) and mucin-2 kidney disease/uromodulin kidney disease (MKD2). A third form of the disease occurs due to mutations in the gene encoding renin (ADTKD-REN), and has formerly been known as familial juvenile hyperuricemic nephropathy type 2.

Pendrin is an anion exchange protein that in humans is encoded by the SLC26A4 gene . Pendrin was initially identified as a sodium-independent chloride-iodide exchanger with subsequent studies showing that it also accepts formate and bicarbonate as substrates. Pendrin is similar to the Band 3 transport protein found in red blood cells. Pendrin is the protein which is mutated in Pendred syndrome, which is an autosomal recessive disorder characterized by sensorineural hearing loss, goiter and a partial organification problem detectable by a positive perchlorate test.

<span class="mw-page-title-main">Fibrocystin</span>

Fibrocystin is a large, receptor-like protein that is thought to be involved in the tubulogenesis and/or maintenance of duct-lumen architecture of epithelium. FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway.

Alstrom syndrome 1 also known as ALMS1 is a protein which in humans is encoded by the ALMS1 gene.

<span class="mw-page-title-main">Polycystin 1</span> Family of transport proteins

Polycystin 1 is a protein that in humans is encoded by the PKD1 gene. Mutations of PKD1 are associated with most cases of autosomal dominant polycystic kidney disease, a severe hereditary disorder of the kidneys characterised by the development of renal cysts and severe kidney dysfunction.

<span class="mw-page-title-main">Polycystin 2</span> Protein and coding gene in humans

Polycystin-2 is a protein that in humans is encoded by the PKD2 gene.

<span class="mw-page-title-main">SCNN1G</span> Protein-coding gene in the species Homo sapiens

The SCNN1G gene encodes for the γ subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1B, and SCNN1D.

<span class="mw-page-title-main">IFT88</span> Protein-coding gene in the species Homo sapiens

Intraflagellar transport protein 88 homolog is a protein that is encoded by the IFT88 gene.

<span class="mw-page-title-main">Keutel syndrome</span> Medical condition

Keutel syndrome (KS) is a rare autosomal recessive genetic disorder characterized by abnormal diffuse cartilage calcification, hypoplasia of the mid-face, peripheral pulmonary stenosis, hearing loss, short distal phalanges (tips) of the fingers and mild mental retardation. Individuals with KS often present with peripheral pulmonary stenosis, brachytelephalangism, sloping forehead, midface hypoplasia, and receding chin. It is associated with abnormalities in the gene coding for matrix gla protein (MGP). Being an autosomal recessive disorder, it may be inherited from two unaffected, abnormal MGP-carrying parents. Thus, people who inherit two affected MGP genes will likely inherit KS.

<span class="mw-page-title-main">Polycystic kidney disease</span> Congenital disorder of urinary system

Polycystic kidney disease is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cysts may begin to develop in utero, in infancy, in childhood, or in adulthood. Cysts are non-functioning tubules filled with fluid pumped into them, which range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well.

Glomerulocystic kidney disease (GCKD) is a cystic disorder of the kidneys. GCKD involves cystic dilation of Bowman's capsule. It can occur with or without congenital abnormality.

The Polycystin Cation Channel (PCC) Family consists of several transporters ranging in size from 500 to over 4000 amino acyl residues (aas) in length and exhibiting between 5 and 18 transmembrane segments (TMSs). This family is a constituent of the Voltage-Gated Ion Channel (VIC) Superfamily. These transporters generally catalyze the export of cations. A representative list of proteins belonging to the PCC family can be found in the Transporter Classification Database.

<span class="mw-page-title-main">Polycystic kidney disease 3 (autosomal dominant)</span> Protein in humans

Polycystic kidney disease 3 (autosomal dominant) is a protein that in humans is encoded by the PKD3 gene.

<span class="mw-page-title-main">HUPRA syndrome</span> Human disease

HUPRA syndrome is a rare syndrome that was first described in 2010 in two infants of Palestinian origin from the same village in the Jerusalem area. One of the two infants' parents were related. It was later described in a third infant from the same village, whose parents were not related.

References

  1. 1 2 "Autosomal recessive polycystic kidney disease - Symptoms - NHS Choices". www.nhs.uk. Retrieved 2015-07-28.
  2. 1 2 "Polycystic kidney disease". Genetics Home Reference. Retrieved 2015-07-28.
  3. 1 2 "Imaging in Autosomal Recessive Polycystic Kidney Disease: Overview, Radiography, Computed Tomography". 2017-03-30.{{cite journal}}: Cite journal requires |journal= (help)
  4. 1 2 "Polycystic Kidney Disease". www.niddk.nih.gov. Retrieved 2015-07-28.
  5. 1 2 Sweeney, William (1993). "Polycystic Kidney Disease, Autosomal Recessive". Polycystic kidney Disease. NIH. Gene Review. PMID   20301501 . Retrieved 28 July 2015.
  6. ↑ Bergmann C, Küpper F, Dornia C, Schneider F, Senderek J, Zerres K (March 2005). "Algorithm for efficient PKHD1 mutation screening in autosomal recessive polycystic kidney disease (ARPKD)". Hum. Mutat. 25 (3): 225–31. doi: 10.1002/humu.20145 . PMID   15706593. S2CID   21321253.
  7. ↑ Zhang MZ, Mai W, Li C, et al. (February 2004). "PKHD1 protein encoded by the gene for autosomal recessive polycystic kidney disease associates with basal bodies and primary cilia in renal epithelial cells". Proc. Natl. Acad. Sci. U.S.A. 101 (8): 2311–6. Bibcode:2004PNAS..101.2311Z. doi: 10.1073/pnas.0400073101 . PMC   356947 . PMID   14983006.
  8. ↑ Bisceglia M, Galliani CA, Senger C, Stallone C, Sessa A (January 2006). "Renal cystic diseases: a review". Adv Anat Pathol. 13 (1): 26–56. doi:10.1097/01.pap.0000201831.77472.d3. PMID   16462154. S2CID   12417947.
  9. ↑ Sweeney, WE; Avner ED (2006). "Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPDK)". Cell and Tissue Research. 326 (3): 671–685. doi:10.1007/s00441-006-0226-0. PMID   16767405. S2CID   33829528.
  10. ↑ Shastry SM, Kolte SS, Sanagapati PR. Potter's Sequence. J Clin Neonatol. 2012 Jul;1(3):157-9. doi: 10.4103/2249-4847.101705. PMID 24027716; PMCID: PMC3762025.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Shanahan, James F.; Davis, Kim J. (2015). Harrison's Principles of Internal Medicine (19th ed.). United States of America: McGraw-Hill Education. ISBN   978-0-07-1802161.

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