RAAS activation is a byproduct of the failure of the distal convoluted tubule in reuptaking electrolytes specifically sodium and chloride leading to cellular dehydration. RAAS attempts to compensate for this dehydration resulting in low serum blood potassium.A small percentage of Gitelman syndrome cases can be attributed to mutations in the CLCNKB gene. This gene is related to the function of the renal chloride channel CLC-Kb located at the basolateral membrane of cells in the thick ascending limb of the Henles loop. Genetic variations or mutations in the CLCNKB was initially linked to classic Bartter Syndrome. When mutations are not found within the SLC12A3 gene, screening can be done to rule out involvement of CLCNKB gene.Gitelman syndrome is inherited in an autosomal-recessive manner: one defective allele has to be inherited from each parent.In 2021, mutations in the tRNAs encoding Isoleucine (MT-TI) and Phenylalanine (MT-TF) in the mitochondrial DNA were described to cause Gitelman syndrome. These homomplasmic mtDNA mutations are maternally inherited. Diagnosis
Diagnosis of Gitelman syndrome can be confirmed after eliminating other common pathological sources of hypokalemia and metabolic alkalosis. A complete metabolic panel (CMP) or basic metabolic panel (BMP) can be used to evaluate serum electrolyte levels. Renin and aldosterone can be tested in the blood. Electrolyte measurement and aldosterone levels can be done via urine. The pathognomonic clinical markers include low serum levels of potassium, sodium, chloride, and magnesium in the blood as a result of urinary excretion.
Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. The disorder is caused by genetic mutations resulting in improper function of the thiazide-sensitive sodium-chloride symporter (SLC12A3, also known as NCC, NCCT, or TSC) located in the distal convoluted tubule of the kidney. The distal convoluted tubule of the kidney plays an important homoestatic role in sodium and chloride absorption as well as of the reabsorption of magnesium and calcium.Genetic mutations of NCC, lead to loss of function and subsequently, reduced transport of sodium and chloride via NCC. Secondary derangement of calcium, magnesium, and potassium concentrations are caused by secondary effects in the distal tubule and collecting duct. The effect is an electrolyte imbalance similar to that seen with thiazide diuretic therapy (which causes pharmacological inhibition of NCC activity).Gitelman syndrome was formerly considered a subset of Bartter syndrome until the distinct genetic and molecular bases of these disorders were identified. Bartter syndrome is also an autosomal recessive cause of hypokalemic metabolic alkalosis, but it derives from a mutations of a number of genes that reduce NKCC2 activity. NKCC2 is found in the thick ascending limb of the loop of Henle. Signs and symptoms
Affected individuals may not have symptoms in some cases.