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Genetics diseases in urinary tract
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Genetics diseases in urinary tract
objectives• Understand several genetics diseases in kidneys
Cystic Kidney Disease Polycystic Kidney disease (autosom dominant, autosome recessive)medulla cystic diseaseMeckel–Gruber Syndrome Nephronophthisis
• Dent's disease• Alport syndrome• Potter syndrome
Gen
• Genes are segments of DNA, the long molecules that reside in each of a person’s cells. Genomes are total gen in the cell
• Genes : race, inheritance; the smallest unit of genetic material, coded by DNA; DNA spiral strain (double helix) compose chromosome
• The genes, through complex processes, build proteins for growth and maintenance of the body. Dogma gene expression: DNA – RNA - protein
• At conception, DNA—or genes—from both parents are passed to the child.
• Genetics constitution: genotype; its expression : phenotype (in many stages: biochemistry; physiology, histology, anatomy, psychology)
Genetic diseases
• A genetic disease occurs when one or both parents pass abnormal genes to a child at conception.
• Abnormal genes caused by mutation• genetic disease: genopathic disease (gene
mutation) and chromosomal diseases• Genopathy: malformative (embryonic stage);
tissue stage, molecular stage• Mutant gene : single effect or multiple
(pleiotrophic: sindromology)
Autosomal dominant& recessive, x-linkage
• If receiving an abnormal gene from just one parent is enough to produce a disease in the child, the disease is said to have dominant inheritance.
• If receiving abnormal genes from both parents is needed to produce disease in the child, the disease is said to be recessive.
• A genetic disease can also occur through a spontaneous mutation.
• The chance of acquiring a dominant disease is higher than the chance of acquiring a recessive disease.
• A child who receives only one gene copy for a recessive disease at conception will not develop the genetic disease—such as autosomal recessive Polycystic Kidney Disease—but could pass the gene to the following generation
Autosomal recessive pattern inheritance
Meckel–Gruber Syndrome MIM 249000 (ciliopathy) mitotic spindle(note: first;1: dominant2: recessive;3: recessive x linkageNephronophthisis MIM 256100 (ciliopathy) Signaling Autosomal recessive PKDGitelman syndrome
Autosomal dominant PKD
polycystic kidney disease MIM173900Papillorenal syndrome Medullary cystic kidney disease(ciliopathy receptor)
X-linked dominant disorders are caused by mutations in genes on the X chromosome
Dent's disease Alport syndrome
Polycystic kidney disease (PKD) • polycystic kidney syndrome• is a genetic disorder characterized by the growth of
numerous cysts in the kidneys.• When cysts form in the kidneys, they are filled with fluid. • PKD cysts can profoundly enlarge the kidneys while
replacing much of the normal structure, resulting in reduced kidney function and leading to kidney failure.
• In the United States, about 600,0001 people have PKD, and cystic disease is the fourth leading cause of kidney failure.
Two major inherited forms of PKD exist:
• Autosomal dominant PKD is the most common inherited form. Symptoms usually develop between the ages of 30 and 40, but they can begin earlier, even in childhood. About 90 percent of all PKD cases are autosomal dominant PKD.
• Autosomal recessive PKD is a rare inherited form. Symptoms of autosomal recessive PKD begin in the earliest months of life, even in the womb
• The cysts grow out of nephrons, the tiny filtering units inside the kidneys.
• The cysts eventually separate from the nephrons and continue to enlarge. The kidneys enlarge along with the cysts—which can number in the thousands—while roughly retaining their kidney shape.
• In fully developed autosomal dominant PKD, a cyst-filled kidney can weigh as much as 20 to 30 pounds. High blood pressure is common and develops in most patients by age 20 or 30.
Autosomal dominant PKD • is the most common inherited disorder of the kidneys. The
phrase “autosomal dominant” means that if one parent has the disease, there is a 50 percent chance that the disease gene will pass to a child. In some cases—perhaps 10 percent—autosomal dominant PKD occurs spontaneously in patients. In these cases, neither of the parents carries a copy of the disease gene.
• Many people with autosomal dominant PKD live for several decades without developing symptoms. For this reason, autosomal dominant PKD is often called “adult polycystic kidney disease.” Yet, in some cases, cysts may form earlier in life and grow quickly, causing symptoms in childhood.
autosomal dominant PKD • ADPKD (or "Adult-onset PKD") is much more common but less
severe than autosomal recessive polycystic kidney. In 85% of patients, ADPKD is caused by mutations in the gene PKD1 on chromosome 16 (TRPP1); in 15% of patients mutations in PKD2 (TRPP2) are causative. A third locus PKD3 is the cause of a very small percentage of cases.
• Polycystic kidney disease is the most common life-threatening genetic disease, affecting approximately 7 million people worldwide. Autosomal dominant polycystic kidney disease affects up to 1 in 1000 people, while the autosomal recessive type is estimated to occur in approximately 1 in 20,000 people.[1][2]
Autosomal dominant
• ADPKD is a late-onset disorder characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts.
• It is a genetic disorder resulting from mutations in either the PKD-1 or PKD-2 gene. Cyst formation begins in utero from any point along the nephron, although fewer than 5% of nephrons are thought to be involved.
• As the cysts accumulate fluid, they enlarge, separate entirely from the nephron, compress the neighboring renal parenchyma, and progressively compromise renal function.
The most common symptoms • are pain in the back and the sides—between the ribs and hips—and
headaches. The pain can be temporary or persistent, mild or severe.
• People with autosomal dominant PKD also can experience the following complications:
• urinary tract infections—specifically, in the kidney cysts• hematuria—blood in the urine• liver and pancreatic cysts• abnormal heart valves• high blood pressure• kidney stones• aneurysms—bulges in the walls of blood vessels—in the brain• diverticulosis—small pouches bulge outward through the colon
• In most cases of autosomal dominant PKD, patients have no symptoms and their physical condition appears normal for many years, so the disease can go unnoticed.
• Physical checkups and blood and urine tests may not lead to early diagnosis.
• Because of the slow, undetected progression of cyst growth, some people live for many years without knowing they have autosomal dominant PKD.
Autosomal dominant PKD is usually diagnosed
• by kidney imaging studies• The most common form of diagnostic kidney
imaging is ultrasound, but more precise studies, such as computerized tomography (CT) scans or magnetic resonance imaging (MRI) are also widely used.
USG (ultrasonography)
-Machine-Sound-Echo-Density (solidity)-Operator-MRI
How is autosomal dominant PKD treated?
• Although a cure for autosomal dominant PKD is not available, treatment can ease symptoms and prolong life.
• When PKD causes kidneys to fail—which usually happens after many years—the patient requires dialysis or kidney transplantation.
• About one-half of people with the most common type of PKD progress to kidney failure, also called end-stage renal disease (ESRD).
Autosomal recessive PKD • is caused by a mutation in the autosomal recessive PKD gene, called PKHD1.
The recessive form of polycystic kidney, called ARPKD (autosomal recessive polycystic kidney disease) is less common than autosomal dominant polycystic kidney.
• Mutations in the PKHD1 (chromosomal locus 6p12.2) cause ARPKD• Other genes for the disease might exist but have not yet been discovered by
scientists. • We all carry two copies of every gene. Parents who do not have PKD can
have a child with the disease if both parents carry one copy of the abnormal gene and both pass that gene copy to their baby.
• The chance of the child having autosomal recessive PKD when both parents carry the abnormal gene is 25 percent. If only one parent carries the abnormal gene, the baby cannot get autosomal recessive PKD but could ultimately pass the abnormal gene to his or her children.
The signs & symptoms • of autosomal recessive PKD frequently begin before birth, so it is
often called “infantile PKD.” • Children born with autosomal recessive PKD often, but not
always, develop kidney failure before reaching adulthood. • Severity of the disease varies. Babies with the worst cases die
hours or days after birth due to respiratory difficulties or respiratory failure.
• Some people with autosomal recessive PKD do not develop symptoms until later in childhood or even adulthood.
• Liver scarring occurs in all patients with autosomal recessive PKD and tends to become more of a medical concern with increasing age.
Children with autosomal recessive PKD
• experience high blood pressure, urinary tract infections, and frequent urination.
• The disease usually affects the liver and spleen, resulting in low blood cell counts, varicose veins, and hemorrhoids.
• Because kidney function is crucial for early physical development, children with autosomal recessive PKD and decreased kidney function are usually smaller than average size.
• Recent studies suggest that growth problems may be a primary feature of autosomal recessive PKD
autosomal recessive PKD diagnosed &treated?
• Ultrasound imaging of the fetus or newborn reveals enlarged kidneys with an abnormal appearance, but large cysts such as those in autosomal dominant PKD are rarely seen.
• Because autosomal recessive PKD tends to scar the liver, ultrasound imaging of the liver also aids in diagnosis.
• Medicines can control high blood pressure in autosomal recessive PKD, and antibiotics can control urinary tract infections.
• Eating increased amounts of nutritious food improves growth in children with autosomal recessive PKD.
• In some cases, growth hormones are used. In response to kidney failure, autosomal recessive PKD patients must receive dialysis or transplantation.
• If serious liver disease develops, some people can undergo combined liver and kidney transplantation.
Medullary sponge kidney (MSK) • is a birth defect of the tubules—tiny tubes inside the kidneys. • In a normal kidney, urine flows through these tubules as it is being
formed. In MSK, tiny sacs called cysts form in the medulla—the inner part of the kidney—creating a sponge-like appearance. The cysts keep urine from flowing freely through the tubules.
• MSK is present at birth but most cases do not appear to be inherited. • Problems caused by MSK include hematuria, or blood in urine; kidney
stones; and urinary tract infections (UTIs). But these problems do not usually appear until the ages of 30 to 40. MSK affects about 1 person per 5,000 to 20,000 people in the United States.1 Researchers have reported that up to 20 percent of people who form kidney stones have MSK.2 MSK rarely
Medullary cystic kidney disease medullary sponge kidney
• Medullary cystic kidney disease has an autosomal dominant pattern of inheritance.
• MCKD1 has been associated with chromosome 1, but not a specific gene yet.[1]
• MCKD2 has been associated with UMOD on chromosome 16.[2
• • Also known as Cacchi Ricci disease, medullary sponge kidney is a
congenital disorder of the kidneys characterized by cystic dilatation of the collecting tubules in one or both kidneys. It has been estimated to occur with a frequency of 1 in every 5,000 individuals in a population[citation needed]. The disease is bilateral in 70% of cases. Individuals with medullary sponge kidney are at increased risk for nephrolithiasis (kidney stones) and urinary tract infection.
• Medullary sponge kidney is frequently discovered incidentally on IVP (intravenous pyelogram).
symptoms.
• For many people, MSK causes no symptoms. The first sign that a person has MSK is usually a UTI or kidney stone. UTIs and kidney stones share many of the same symptoms:
• burning or painful urination• pain in the back, lower abdomen, or groin• cloudy, dark, or bloody urine• foul-smelling urine• fever and chills• vomiting
To confirm the diagnosis,
• A doctor may suspect MSK when a person has repeated UTIs or kidney stones.
• an x ray called an intravenous pyelogram (IVP). In an IVP, dye is injected into a vein. The dye travels through the blood to the kidneys. As the dye is filtered into the urinary tract, it makes urine visible on the x ray and shows any blockage in the urinary tract. Cysts show up as clusters of light in an IVP.
In an intravenous pyelogram of a medullary sponge kidney, cysts appear as clusters of light.
management• No treatment can get rid of cysts in the affected kidneys. Once a doctor is
sure that a person has MSK, treatment focuses on curing existing infection, removing any stones, and preventing future infection and stone formation.
• UTIs. To treat UTIs, the doctor may prescribe a medicine called an antibiotic that kills bacteria. A person with MSK may need to continue taking a low-dose antibiotic to prevent recurrent infections.
• Kidney stones. Stone removal may require a procedure called lithotripsy, which uses sound waves to break stones into sand-like particles. The particles can then pass easily through the urinary tract with the flow of urine.
• Another way to remove stones is to insert a thin tube called a ureteroscope through the urethra and bladder to catch the stone and retrieve it. A person with MSK may be able to prevent more stones from forming through diet changes or taking medicine. Increasing fluid intake so the person makes more urine is also very important to reduce the risk of new stone formation.
Nephronophthisis
• is a genetic disorder of the kidneys which affects children.
• It is classified as a medullary cystic kidney disease.• The disorder is inherited in an autosomal recessive
fashion and, although rare, is the most common genetic cause of childhood kidney failure.
• It is a form of ciliopathy. A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies,[or of ciliary function
cilia
Signs & Symptoms• Infantile, juvenile, and adolescent forms of nephronophthisis have
been identified.• Although the range of characterizations is broad, patients typically
present with polyuria (production of large volume of urine), polydipsia (excessive liquid intake), and mild proteinuria (the abnormal appearance of protein in the urine), and after several months to years, end-stage kidney disease, a condition necessitating either dialysis or a kidney transplant in order to survive.
• Approximately 10% of individuals with nephronophthisis also have so-called "extra-renal symptoms" which can include blindness, liver problems, severe global developmental delay or mental retardation, and neurologic involvement in which the cerebellum is affected.
Meckel–Gruber Syndrome,
• Meckel syndrome (also known as Gruber Syndrome, Dysencephalia Splanchnocystica) is a rare, lethal, ciliopathic, genetic disorder, characterized by renal cystic dysplasia, central nervous system malformations, polydactyly, hepatic developmental defects, and pulmonary hypoplasia due to oligohydramnios.
• Meckel-Gruber syndrome is named for Johann Meckel and Georg Gruber
• While not precisely known, it is estimated that the general rate of incidence, according to Bergsma,[7] for Meckel syndrome is 0.02 per 10,000 births. According to another study done six years later, the incidence rate could vary from 0.07 to 0.7 per 10,000 births.[8]
• This syndrome is a Finnish heritage disease. Its frequency is much higher in Finland, where the incidence is as high as 1.1 per 10,000 births. It is estimated that Meckel syndrome accounts for 5% of all neural tube defects there
Dysplastic kidneys • are prevalent in 95% to 100% of all identified cases. When this occurs,
microscopic cysts develop within the kidney and slowly destroy it, causing it to enlarge to 10 to 20 times its original size. The level of amniotic fluid within the womb may be significantly altered or remain normal, and a normal level of fluid should not be criteria for exclusion of diagnosis.
• Occipital encephalocele is present in 60% to 80% of all cases, and post-axial polydactyly is present in 55% to 75% of the total number of identified cases. Bowing or shortening of the limbs are also common.
• Finding at least two of the three features of the classical triad, in the presence of normal karyotype, makes the diagnosis solid. Regular ultrasounds and pro-active prenatal care can usually detect symptoms early on in a pregnancy.
Meckel–Gruber syndrome (MKS) is an autosomal recessive lethal malformation
• Recently, two MKS genes, MKS1 and MKS3, have been identified.
• A study done recently has described the cellular, sub-cellular and functional characterization of the novel proteins, MKS1 and meckelin, encoded by these genes.[4] The malfunction of this protein production is mainly responsible for this lethal disorder
• Thus, Meckel–Gruber syndrome is a ciliopathy. Other known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alstrom syndrome, and some forms of retinal degeneration.[5] The MKS1 gene has been explicitly identified as a ciliopathy.
Alport Syndrome• Hereditary Nephritis• The primary indicator of Alport syndrome is a family history of
chronic glomerular disease, although it may also involve hearing or vision impairment.
• This syndrome affects both men and women, but men are more likely to experience chronic kidney disease and sensory loss.
• Alport syndrome (Hereditary Nephritis) is a genetic disorder[1] characterized by glomerulonephritis, endstage kidney disease, and hearing loss.[2] Alport syndrome can also affect the eyes (lenticonus). The presence of blood in the urine (hematuria) is almost always found in this condition.
• It was first identified in a British family by Dr. Cecil A. Alport in 1927
Alport syndrome• Alport syndrome is caused by mutations in COL4A3, COL4A4, and
COL4A5, collagen biosynthesis genes. • Mutations in any of these genes prevent the proper production
or assembly of the type IV collagen network, which is an important structural component of basement membranes in the kidney, inner ear, and eye. Basement membranes are thin, sheet-like structures that separate and support cells in many tissues.
• When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine normally, allowing blood and protein into the urine. T
Alport syndrome• abnormalities of type IV collagen in kidney basement
membranes cause gradual scarring of the kidneys, eventually leading to kidney failure in many people with the disease.
• Progression of the disease leads to basement membrane thickening and gives a "basket-weave" appearance from splitting of the lamina densa.
• Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nanomechanical behavior of mutated molecules, notably leading to a bent molecular shape with kinks.[6]
inheritance patterns that are dependent on the genetic mutation.
• In most people with Alport syndrome, the condition is inherited in an X-linked pattern, due to mutations in the COL4A5 gene. A condition is considered X-linked if the gene involved in the disorder is located on the X chromosome. In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome, explaining why most affected males eventually develop kidney failure. In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in blood in the urine, but most affected females do not develop kidney failure.
• Alport syndrome can be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2, have been mutated. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.
• Past descriptions of an autosomal dominant form are now usually categorized as other conditions,[7] though some uses of the term in reference to the COL4A3 and COL4A4 loci have been published.[8][9]
• Men with Alport syndrome usually first show evidence of renal insufficiency while in their twenties and reach total kidney failure by age 40.
• Women rarely have significant renal impairment, and hearing loss may be so slight that it can be detected only through testing with special equipment.
• Usually men can pass the disease only to their daughters. Women can transmit the disease to either their sons or their daughters. Treatment focuses on controlling blood pressure to maintain kidney function.
• As there is no known cure for the condition, treatments are symptomatic. Patients are advised on how to manage the complications of kidney failure, and the proteinuria that develops is often treated with ACE inhibitors, although they are not always used simply for the elevated blood pressure.[12]
• Once kidney failure has developed, patients are given dialysis or can also benefit from a kidney transplant, although this can also cause problems. The body may reject the new kidney as it contains normal type IV collagen, which may be recognized as foreign by the immune system.[13]
• Gene therapy as a possible treatment option has been discussed
nephronophthisis • is characterized by fibrosis and the formation of cysts in a specific
region of the kidney. In contrast to other cystic diseases of the kidney in which the kidneys are larger than usual, in nephronophthisis the kidneys are small to normal in size.
• • From sequencing the DNA of individuals and families with
nephronophthisis, scientists have identified thus far 8 different genes in which mutations can cause the disease. These genes are called NPHP1, NPHP2, NPHP3, NPHP4, NPHP5, NPHP6, NPHP7, and NPHP8, and the proteins for which they encode are known as the nephrocystins. Although the biological function of these proteins is not yet known, they all localize at least in part to an organelle in the cell called the primary cilia.
nephronophthisis• Infantile, juvenile, and adolescent forms of nephronophthisis have been identified.
Although the range of characterizations is broad, patients typically present with polyuria (production of large volume of urine), polydipsia (excessive liquid intake), and mild proteinuria (the abnormal appearance of protein in the urine), and after several months to years, end-stage kidney disease, a condition necessitating either dialysis or a kidney transplant in order to survive.
• Approximately 10% of individuals with nephronophthisis also have so-called "extra-renal symptoms" which can include blindness, liver problems, severe global developmental delay or mental retardation, and neurologic involvement in which the cerebellum is affected.
• Histology• Histologically, nephronophthisis is characterized by fibrosis and the formation of
cysts in a specific region of the kidney. In contrast to other cystic diseases of the kidney in which the kidneys are larger than usual, in nephronophthisis the kidneys are small to normal in size.
Nephronophthisis is a ciliopathy• Recent findings in genetic research have suggested that a
large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely-varying, phenotypically-observed disorders.
• Thus, Nephronophthisis is a ciliopathy. Other known ciliopathies include primary ciliary dyskinesia, Bardet-Biedl syndrome, polycystic kidney and liver disease, Alstrom syndrome, Meckel-Gruber syndrome and some forms of retinal degeneration
Dent's disease • (or Dent disease) is a rare X-linked recessive inherited
condition that affects the proximal renal tubules[1] of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, hypercalciuria, calcium nephrolithiasis, nephrocalcinosis and chronic renal failure.
• "Dent's disease" is often used to describe an entire group of familial disorders, including X-linked recessive nephrolithiasis with renal failure, X-linked recessive hypophosphataemic rickets, and both Japanese and idiopathic low molecular weight proteinuria.[2]
Dent's disease • was first described by Dent, C. E. and Friedman, M in 1964 when
they reported 2 unrelated British boys with rickets associated with renal tubular damage characterized by hypercalciuria, hyperphosphaturia, proteinuria, and aminoaciduria.[3] This is a genetic disorder caused by the genetic mutations in the renal chloride channel CLCN5 which encodes a kidney-specific voltage gated chloride channel and a 746 amino acid protein (CLC-5), with 12 to 13 transmembrane domains; it manifests itself through low molecular weight proteinuria, hypercalciuria, aminoaciduria and hypophosphataemia. Because of its rather rare occurrence, Dent's disease is often diagnosed as idiopathic hypercalciuria (IH), i.e. excess calcium in urine with undetermined causes.
Dent disease 1 & 2
• Dent disease 1• Dent's disease is a X-linked recessive disorder. The males are prone to
manifesting symptoms in early adulthood with symptoms of calculi, rickets or even with renal failure in more severe cases.
• In humans, gene CLCN5 is located on chromosome Xp11.22 and has a 2238-bp coding sequence that consists of 11 exons that span 25 to 30 kb of genomic DNA and encode a 746 amino acid protein.[4] CLCN5 belongs to the family of voltage-gated chloride channel genes (CLCN1-CLCN7, and CLCKa and CLCKb) that have approximately 12 transmembrane domains. These chloride channels have an important role in the control of membrane excitability, transepithelial transport, and possibly cell volume.[5]
• The mechanisms by which CLC-5 dysfunction results in hypercalciuria and the other features of Dent's disease remain to be elucidated. The identification of additional CLCN5 mutations may help in these studies, and we have pursued such studies in patients with Dent's disease.[6]
Dent's disease often produces symptoms of:
• Extreme thirst combined with dehydration which leads to frequent urination• Nephrolithiasis (kidney stones)• Hypercalciuria (high urine calcium - >300 mg/d or >4 mg/kg per d) with normal
levels blood/serum calcium)• Dent's disease may also be associated with:• Aminoaciduria (amino acids in urine)• Phosphaturia (phosphate in urine)• Glycosuria (glucose in urine)• Kaliuresis (potassium in urine)• Hyperuricosuria (excessive amounts of uric acid in the urine.)• Impaired urinary acidification• Rickets• In a very large study of patients with Dent's disease, 9 out of 15 men, and 1 out of
10 women suffered end-stage renal failure by the age of 47
Dent's disease• As of today, there is no agreed-upon treatment of Dent's disease and no therapy has been
formally accepted. Most treatment measures are mostly supportive in nature and they include:
• Thiazide diuretics (i.e. Hydrochlorothiazide) which have been used with success in reducing the calcium output in urine, but they are also known to cause hypokalemia. – In rats with diabetes insipidus thiazide diuretics inhibit the NaCl co-transporter in the renal distal
convoluted tubule leading indirectly to less water and solutes being delivered to the distal tubule. [10]
• Amiloride which also increases distal tubular calcium reabsorption and has been used as a therapy for idiopathic hypercalciuria. – A combination of 25 mg of chlorthalidone plus 5 mg of amiloride daily led to a substantial reduction
in urine calcium in Dent's patients, however urine pH was "significantly higher in patients with Dent’s disease than in those with idiopathic hypercalciuria (P < 0.03), and supersaturation for uric acid was consequently lower (P < 0.03)."[11]
• For patients with osteomalacia, Vitamin D or derivatives have been employed, apparently with success.
• Some lab tests on mice with CLC-5 related tubular damage showed that a high citrate diet preserved renal function and delayed progress of renal disease
Gitelman syndrome
• is a rare inherited defect in the distal convoluted tubule of the kidneys. It causes the kidneys to pass sodium, magnesium, chloride, and potassium into the urine, rather than allowing it to be resorbed into the bloodstream.
• Gitelman syndrome is not to be confused with Bartter syndrome, which is a rare inherited defect in the thick ascending limb of the loop of Henle.
Gitelman syndrome• Gitelman syndrome has an autosomal recessive pattern of
inheritance.• Gitelman's syndrome is linked to inactivating mutations in
the SLC12A3 gene resulting in a loss of function of the encoded thiazide-sensitive sodium-chloride co-transporter (NCCT). This cell membrane protein participates in the control of ion homeostasis at the distal convoluted tubule portion of the nephron.
• Gitelman's syndrome is an autosomal-recessive disorder: one defective gene has to be inherited from each parent.
Gitelman's syndrome• People suffering from Gitelman's syndrome present symptoms which are
identical to those of patients who are on thiazide diuretics[1]
• Clinical symptoms for this disease are hypochloremic metabolic alkalosis, hypokalemia, and hypocalciuria. Hypomagnesemia is present in many but not all cases. In contrast to patients with Gordon's syndrome, those suffering from Gitelman's syndrome are generally normotensive. Carriers of Gitelman's syndrome-linked mutations are often asymptomatic while some complain of mild muscular cramps or weakness expressed as fatigue or irritability. More severe symptoms such as tetany and paralysis have however also been reported. Phenotypic variations observed among patients probably result from differences in their genetic background and may depend on which particular amino acid in the NCCT protein has been mutated.
• See Naesens et al. for a recent review.[2]
• Eponym• It is named for Hillel Gitelman
Papillorenal syndrome,
• also called Renal-coloboma syndrome or isolated renal hypoplasia,[1] is an autosomal dominant[2] genetic disorder marked by underdevelopment (hypoplasia) of the kidney and colobomas of the optic nerve
Papillorenal syndrome • is an autosomal dominant disorder that results from
a mutation of one copy of the PAX2 gene, located on chromosome 10q24.3-q25.1.[2][3] The gene is important in the development of both the eye and the kidney.
• Autosomal dominant inheritance indicates that the gene responsible for the disorder is located on an autosome (chromosome 10 is an autosome), and only one defective copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder
Potter's syndrome, • Potter sequence (also known as Potter's sequence or Oligohydramnios sequence)
is the atypical physical appearance of a fetus or neonate due to oligohydramnios experienced in the womb.[1] Oligohydramnios is the decrease in amniotic fluid volume sufficient to cause in morphogenesis of the fetus.
• Oligohydramnios is the causative agent of Potter sequence, but there are many things that can lead to oligohydramnios.
• It can be caused by renal diseases such as bilateral renal agenesis (BRA), atresia of the ureter or urethra causing obstruction of the urinary tract, polycystic or multicystic kidney diseases, renal hypoplasia, , uteroplacental insufficiency from maternal hypertension or toxemia.
• Potter's sequence is known in the medical field as clubbed feet, pulmonary hypoplasia and cranial anomalies related to the oligohydramnios.
• The term Potter sequence was initially intended to only refer to cases caused by BRA,[citation needed] however, it has been mistakenly used by many clinicians and researchers to refer to any case that presents with oligohydramnios or anhydramnios regardless of the source of the loss of amniotic fluid.[
Bilateral renal agenesis (BRA) • was first recognized as a defect of human fetal development in 1671 by Wolfstrigel• In 1946 when Edith Potter (b.1901 - d.1993) described a series of 20 cases with
absent kidneys, noting the characteristic appearance of the head and lungs.[3][4]• Up until this time the condition itself was considered to be extremely rare.
However, in part to Potter's work it has come to light that the condition presents far more frequently than previously reported. Potter analyzed approximately 5000 autopsy cases performed on fetuses and newborn infants over a period of ten years and found that 20 of these infants presented with BRA, all of which had distinctive facial characteristics.
• These facial characteristics have subsequently be termed as being known as Potter facies. From her analysis she was able to deduce the sequence of events that leads to what is now known as Potter sequence.
• Potter went on to become a pioneer in the field of human renal development and her contributions are still employed and appreciated by clinicians and researchers to this day.
bilateral renal agenesis (BRA)• meaning that kidneys do not develop (malformation of the
ureteric bud). • True BRA also presents with bilateral agenesis of the ureters.
After the creation of the nomenclature system for this sequence,
• BRA was recognized as possibly being an extreme variation of Potter sequence II. However, some clinicians and researchers still use the term classic Potter sequence so as to emphasize that they are specifically referring to cases of BRA and not another form.
Type I
• Type I is due to autosomal recessive polycystic kidney disease (ARPKD), which occurs at a frequency of approximately one in 16,000 infants. The kidneys of the fetus/neonate will be enlarged, have many small cysts filled with fluid and will fail to produce an adequate volume of fetal urine. The liver and pancreas of the fetus may also show fibrosis and/or a cystic change.
Type II• Type II is usually due to renal agenesis,[5] which can also fall
under the category known as hereditary urogenital adysplasia or hereditary renal adysplasia (HRA). This is characterized by the complete agenesis or absence of one kidney and the remaining solitary kidney being small and malformed. Bilateral renal agenesis is believed to be the most extreme phenotypic variation of HRA. However, BRA is often referred to as classic Potter sequence, as it was this particular phenotype of neonates and fetuses that Potter originally reported in her 1946 manuscripts when characterizing this birth defect.
Type III
• Type III is due to Autosomal dominant polycystic kidney disease (ADPKD) linked to mutations in the genes PKD1 and PKD2. While ADPKD is considered to be an adult-onset polycytic kidney disease, it can also present in the fetus and neonate in rare cases. Like ARPKD, ADPKD can also present with hepatic cysts and an enlarged spleen. An increased prevalence of vascular disease is also observed in these cases of ADPKD.
Classic Potter• Classic Potter sequence occurs when the developing fetus has
bilateral renal agenesis, which also presents with agenesis of the ureters.
• BRA has been estimated to occur at a frequency of approximately 1:4000 to 1:8000 fetuses and neonates.
• However, recent analysis has estimated that the condition may occur at a much greater frequency.
• The condition has been reported to occur twice as common in males as in females, suggesting that certain genes of the Y chromosome may act as modifiers. However, no candidate genes on the Y chromosome have yet been identified.
BRA• BRA appears to have a predominantly genetic etiology and many cases
represent the most severe manifestation of an autosomal dominant condition with incomplete penetrance and variable expressivity.
• There are several genetic pathways that could result in this condition. To date, few of these pathways or candidate genes have been considered or analyzed regarding BRA.
• The majority of possible candidate genetic pathways are autosomal recessive in nature and do not coincide with the frequency or penetrance at which BRA occurs in the human population. Additionally, candidate genetic pathways would be expected to involve genes expressed in the developing urogenital system (UGS). Often, these same genes and/or pathways of interacting genes are also expressed in the developing UGS as well as the central nervous system (CNS), gut, lung, limbs, and eyes
