Gitelman Syndrome

Gitelman syndrome is a genetic condition that affects the renal tubules, leading to hypomagnesemia, hypokalemia and hypocalciuria, as well as acid-base imbalance (metabolic alkalosis). Although Gitelman syndrome was previously thought to be a milder form of a tubular transport disorder ascribed to Bartter syndrome, it is now recognized as a distinct medical entity that should not be confused with Bartter's syndrome [1] [2] [3] [4].

Gitelman syndrome is characterized by a wide variety of symptoms; not all patients experience the full spectrum. Diarrhea, vomiting and tetany, as a result of significant hypomagnesemia related to fluid loss, are some of the reported symptoms. Paresthesias may be described, as well as weakness and fatigue that discourages the individuals from engaging in physical activity. However, there have been cases reported that do not display serious symptoms; a young adult has been described in the literature as exhibiting only leg cramps, weakness, vomiting, and malaise [5]. Growth is hindered only in cases of profound hypomagnesemia and hypokalemia [6].

Some Gitelman syndrome patients may also report swollen, burning and tender joints; this is attributed to the chondrocalcinosis that may accompany the rest of the symptoms. Some isolated reports have described neurological symptoms such as ataxia, visual impairment and vertigo as well. As for the cardiovascular system, although Gitelman syndrome causes ventricular arrhythmias, they only rarely result in any considerable symptomatology, with only a few patients experiencing cardiac arrest [7] [8]. Patients are usually hypotensive.

A detailed medical history, clinical examination and symptomatology, as well as laboratory testing are all used to diagnose Gitelman syndrome. Laboratory blood abnormalities include:

• Hypomagnesemia: less than 0.65 mmol/L
• Hypokalemia: between 2.3 and 3.1 mmol/L
• Hypocalciuria: less than 0.5 mg/kg/day

Although low serum magnesium and urine calcium had been regarded as a necessary part of the Gitelman syndrome diagnosis, a 2004 study reported two families with a valid diagnosis of Gitelman syndrome (corroborated by genetic tests), with women presenting with hypokalemia but normal urine calcium and serum magnesium [9]. The female patients of these families were also found to exhibit less severe hypokalemia and were generally asymptomatic. Patients with Gitelman syndrome tend to respond to diuretics, which suggests that the syndrome mainly affects the distal tubules. Genetic testing to confirm a diagnosis can be performed, if indicated. The gene involved is the SLC12A3 gene, encoding for the thiazide-sensitive NaCl cotransporter (NCC); the majority of patients affected by Gitelman syndrome exhibit SLC12A3 mutations. Genetic counseling is available for families affected by Gitelman syndrome.

Differential diagnosis should include Bartter's syndrome, laxative abuse and chronic vomiting. Other diagnostic modalities, such as electrocardiography or joint magnetic resonance imaging scans (MRI) can be employed depending on the symptoms reported by each individual.

1. Geven WB, Willem JL, Schroder CH. Study of the path physiology of Bartter/Gitelman's syndrome. Attempt of classification-role of renal magnesium depletion. Magnesium B. 1994;16:29–36.
2. Bettinelli A, Bianchetti MG, Girardin E. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. Pediatr J. 1992;120:38–43.
3. Simon DB, Nelson-Williams C, Bia MJ. Gitelman's variant of Bartters syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet. 1996;12:24–30.
4. Gladziwa U, Schwarz R, Gitter AH. Chronic hypokalaemia of adults: Gitelman's syndrome is frequent but classical Bartter's syndrome is rare. Nephrol Dial Transplant. 1995;10:1607–1613.
5. M Gjata, M Tase, A Gjata, and Zh Gjergji. Gitelman's Syndrome (Familial hypokalemia-hypomagnesemia). Hippokratia. 2007 Jul-Sep; 11(3): 150–153.
6. Riveira-Munoz E, Chang Q, Godefroid N, Hoenderop JG, Bindels RJ, Dahan K, Devuyst O. Belgian network for study of gitelman syndrome. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J Am Soc Nephrol. 2007;1:1271–1283.
7. Foglia PEG, Bettineli A, Tosetto C, Cortesi C, Crosazzo L, Edefonti A, Bianchetti MG. Cardiac work up in primary hypokalemia-hypomagnesemia (Gitelman syndrome) Nephrol Dial Transplant. 2004;19:1398–1402.
8. Scognamiglio R, Negut C, Calò LA. Aborted sudden cardiac death in two patients with Bartter's/Gitelman's syndromes. Clin Nephrol. 2007;67:193–197.
9. Lin SH, Cheng NL, Hsu YJ, Halperin ML. Intrafamiliar phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter. Am J Kidney Dis. 2004;43:304–312.

• Giltleman syndrome
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