Gitelman syndrome
Gitelman syndrome 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 located in the distal convoluted tubule of the kidney. The distal convoluted tubule of the kidney serves a minimal role in salt absorption and a greater role in managing the excretion of electrolytes like magnesium and calcium to produce more concentrated urine.
Genetic mutations along the sodium chloride symporter, lead to inadequate transport of multiple electrolytes along this channel such as sodium, chloride, calcium, magnesium, and potassium. The net effect is an electrolyte imbalance consistent with thiazide diuretic therapy
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 hypokalemic metabolic alkalosis, but it derives from a mutation to the NKCC2 found in the thick ascending limb of the loop of Henle.
Signs and symptoms
Affected individuals may not have symptoms in some cases. Symptomatic individuals present with symptoms identical to those of patients who are on thiazide diuretics, given that the affected transporter is the exact target of thiazides,.Clinical signs of Gitelman syndrome include a high blood pH in combination with low levels of chloride, potassium, and magnesium in the blood and decreased calcium excretion in the urine. In contrast to people with Gordon's syndrome, those affected by Gitelman syndrome generally have low or normal blood pressure. Individuals affected by Gitelman syndrome often complain of severe muscle cramps or weakness, numbness, thirst, waking up at night to urinate, salt cravings, abnormal sensations, chondrocalcinosis, or weakness expressed as extreme fatigue or irritability. Though cravings for salt are most common and severe, cravings for sour foods have been noted in some persons affected. More severe symptoms such as seizures, tetany, and paralysis have been reported. Abnormal heart rhythms and a prolonged QT interval can be detected on electrocardiogram and cases of sudden cardiac death have been reported due to low potassium levels. Quality of life is decreased in Gitelman syndrome
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. In a study by Riviera-Munoz et al. identified a subset of individuals with Gitelman syndrome with a severe phenotypic expression. The clinical manifestations observed in this group were neuromuscular manifestations, growth retardation, and ventricular arrhythmias. The patients were mostly male and were found to have at least one allele of a splice defect on the SLC12A3 gene.
Cause
The sodium chloride symporter is a protein made up of 1021 amino acids and 12 transmembrane domains. Mutations that occur on the SLC12A3 gene range from missense, nonsense, frame-shift and splice-site mutations which occur throughout the gene.Most cases of Gitelman syndrome are linked to inactivating mutations in the SLC12A3 gene, resulting in a loss of function of the thiazide-sensitive sodium-chloride co-transporter. This genetic mutation in SLC12A3 is present in 80% of adults with Gitelman syndrome. More than 180 mutations of this transporter protein have been described. This cell membrane protein participates in the control of ion homeostasis at the distal convoluted tubule portion of the nephron. Loss of this transporter also has the indirect effect of increasing calcium reabsorption in a transcellular fashion. This has been suggested to be the result of a putative basolateral Na+/Ca2+ exchanger and apical calcium channel.
When the sodium-chloride cotransporter is inactivated, continued action of the basolateral Na+/K+-ATPase creates a favourable sodium gradient across the basolateral membrane. This increases the reabsorption of divalent cations by secondary active transport. It is currently unknown why calcium reabsorption is increased while magnesium absorption is decreased, often leading to a low level of magnesium in the blood.
A secondary effect of the inactivated sodium-chloride cotransporter is the subsequent activation of the renin-angiotensin aldosterone system. 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 Gitleman 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 Henle's 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.
Diagnosis
Diagnosis of Gitelman syndrome can be confirmed after eliminating of other common pathological sources of hypokalemia and metabolic alkalosis. A complete metabolic panel or basic metabolic panel 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. Urinary fractional excretion potassium is high or inappropriately normal in the context of hypokalaemia, and high levels or urinary sodium and chloride are observed. Other clinical indicators include elevated serum renin and aldosterone in the blood stream, and metabolic alkalosis. The symptomatic features of this syndrome are highly variable ranging from asymptomatic to mild manifestations to severe symptoms. Symptom severity is multi-factorial, with phenotypic expression varying amongst individuals within the same family. Genetic testing is another measure of identifying the underlying mutations which cause the pathologic symptoms of the disease. This mode of testing is available at select laboratories.Work-up to exclude the differential diagnosis of the electrolyte abnormalities is key.
- In Gitelman syndrome hypocalcuria is present, and a urine calcium:creatinine ratio may help distinguish it from Bartter syndrome as the two disorders can be clinically indistinguishable. Additionally in Bartter syndrome maximal urine concentrating ability is lost.
- Laxative abuse can mimic the serum electrolyte abnormalities, but fractional excretion of potassium will be low
- Diuretic abuse could be suspected if urinary chloride excretion varies by time of day, but may require a diuretic assay to detect
- Surreptitious vomiting can cause metabolic alkalosis and hypokalaemia, but urinary chloride levels will be low
- Medication history; Proton-pump inhibitors can cause an isolated hypomagnesaemia phenotype, and aminoglycosides such as gentamicin can cause a transient metabolic alkalosis with hypokalaemia and hypomagnesaemia that resolves 2–6 weeks after drug termination.
- Primary aldosteronism will cause metabolic alkalosis and hypokalaemia, but hypertension will be present and serum renin will be low
- EAST syndrome, though neurological features will predominate
- Renal cysts and diabetes syndrome can cause hypomagnesaemia and hypocalcuria, but is distinguished by early onset chronic kidney disease and an autosomal dominant inheritance pattern of renal cysts and/or diabetes
Treatment
In patients with early onset of the disease such as infants and children, indomethacin is the drug of choice utilized to treat growth disturbances. Indomethacin in a study by Blanchard et. al 2015 was shown to increase serum potassium levels, and decrease renin concentration. Adverse effects of indomethacin include a decrease in the glomerular filtration rate, and gastrointestinal distrubances.
Cardiac evaluation is promoted in the prevention of dysrhythmias and monitoring of QT interval activity. Medications that extend or prolong the QT interval should be avoided in these patients to prevent cardiac death.