Gitelman Syndrome, Orphanet Journal of Rare Diseases
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands,
Orphanet Journal of Rare Diseases 2008, 3:22doi:10.1186/1750-1172-3-22
Nine VAM Knoers and Elena N Levtchenko,
The electronic version of this article is the complete one and can be found online at: http://www.ojrd.com/content/3/1/22
© 2008 Knoers and Levtchenko; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood.
Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia.
GS is transmitted as an autosomal recessive trait. Mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified.
Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria). Bartter syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.
Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent.
Disease name and synonyms
Definition and epidemiology
Gitelman syndrome (GS) (OMIM 263800), also referred to as familial hypokalemia-hypomagnesemia, is an autosomal recessive salt-losing renal tubulopathy that is characterized by hypomagnesemia, hypocalciuria and secondary aldosteronism, which is responsible for hypokalemia and metabolic alkalosis . The prevalence is estimated at ~25 per million and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders.
GS patients usually present above six years of age and in many cases the diagnosis is only made at adult age. Most patients suffer from tetany, especially during periods of fever or when extra magnesium is lost due to vomiting or diarrhea. Paresthesias, especially in the face, frequently occur. Some patients experience severe fatigue interfering with daily activities, while others never complain of tiredness. The severity of fatigue in GS is not completely related to the degree of hypokalemia. In contrast to Bartter syndrome (a genetically distinct and clinically more severe tubular transport disorder, which shares the hypokalemic metabolic alkalosis with GS) polyuria is usually absent or only mild. In general, growth is normal in GS patients, however, it can be delayed in patients with severe hypokalemia and hypomagnesemia .
Some adult GS patients suffer from chondrocalcinosis, which is assumed to result from chronic hypomagnesemia. It causes swelling, local heat, and tenderness over the affected joints. In earlier clinical reports additional symptoms, such as ataxia, vertigo, and blurred vision have been reported.
Cruz and colleagues have challenged the generally shared idea that GS is a mild disorder . They evaluated the symptoms and quality of life (QOL) in 50 adult patients with molecularly proven GS and compared this cohort of patients with 25 age- and sex-matched controls. They found that GS patients had significantly more complaints than controls, mainly salt craving, musculoskeletal symptoms such as tetany and cramps, muscle weakness and aches, and constitutional symptoms such as fatigue, generalized weakness and dizziness, and nocturia and polydipsia. In addition, measures of QOL were significantly lower in GS patients compared to controls.
Potassium and magnesium depletion prolong the duration of the action potential of cardiomyocytes and consequently increase the risk for development of ventricular arrhythmia. Electrocardiograms of patients with Gitelman syndrome have shown that in about 50% of cases the QT interval is indeed slightly to moderately prolonged but, fortunately, is not associated with clinically relevant cardiac arrhythmias in the far majority of cases . Sudden cardiac arrest reported in few patients with GS [2,5], warrants systematic cardiac screening for identifying other possible triggering mechanisms or underlying conditions. Blood pressure in GS patients is lower than in the general population, indicating that even the modest salt wasting of this disease reduces blood pressure. The results from a recent study in 35 GS-carriers (with one mutant gene allele) suggest that GS carriers also have lower blood pressure and may be protected from hypertension . Another study in a large cohort also demonstrated reduced blood pressure in subjects having SLC12A3 mutations on one allele . These results are distinct from a previous study in an Amish kindred, in which no reduction of blood pressure was demonstrated in adult patients, despite increased Na+ excretion . Thus, further studies are required to investigate whether the incidence of cardio-vascular events differs between GS patients or carries compared to control population.
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