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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2016  |  Volume : 27  |  Issue : 2  |  Page : 407-410
Quadriparesis due to Gitelman's syndrome diagnosed with thiazide diuretic test response

Department of Internal Medicine, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India

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Date of Web Publication11-Mar-2016


Gitelman's syndrome is characterized by hypocalciuria, severe hypomagnesemia, and prominent muscular involvements such as fatigue, weakness, cramps, and tetany. It is due to mutations in the thiazide sensitive NaCl co-transporter in the distal convoluted tubule. The administration of thiazide diuretics may induce a subnormal increase of urinary Cl excretion in patients with Gitelman's syndrome, consistent with the hypothesis that less than normal Cl is reabsorbed by the thiazide-inhibitable transporter in Gitelman's syndrome. Thus, we report a case of Gitelman's syndrome presenting with quadriparesis diagnosed by using thiazide clearance test.

How to cite this article:
Mukhopadhyay S, Jana S, Chatterjee A, Roy M, Sarkar A, Mukhopadhyay J. Quadriparesis due to Gitelman's syndrome diagnosed with thiazide diuretic test response. Saudi J Kidney Dis Transpl 2016;27:407-10

How to cite this URL:
Mukhopadhyay S, Jana S, Chatterjee A, Roy M, Sarkar A, Mukhopadhyay J. Quadriparesis due to Gitelman's syndrome diagnosed with thiazide diuretic test response. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2022 Jan 18];27:407-10. Available from: https://www.sjkdt.org/text.asp?2016/27/2/407/178584

   Introduction Top

Gitelman's syndrome is an autosomal-recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. [1],[2] It is caused by inactivating mutations in the gene for the thiazide-sensitive NaCl co-transporter (NCCT) of the distal convoluted tubule. [3] Most patients with Gitelman's syndrome are asymptomatic or complain of mild intermittent cramps, fatigue, muscle weakness, or irritability. However, severe symptoms such as tetany and paralysis have been reported, [4] and phenotypic variations are common in Gitelman's syndrome. [5] The phenotypic variations and the absence of standard diagnostic method make the definite diagnosis of Gitelman's syndrome more difficult.

In this report, a young patient presented with Gitelman's syndrome as fluctuating paralysis diagnosed by using thiazide clearance test.

   Case Report Top

A 45-year-old man presented with insidious onset of progressive weakness of all four limbs for the last two months. Initially, he had difficulty in getting up from squatting position and raising arms above head followed by slipping of footwear with knowledge and difficulty in mixing food and buttoning of a shirt. There was no diurnal variation of weakness, but it fluctuated on day-to-day basis with difficulty in turning in bed and lifting his head from bed on two occasions. There was no history of fasciculation, atrophy, sensory loss, bowel or bladder involvement, bulbar symptoms or cranial nerve involvement, fever, rash, sore throat, diarrhea, vomiting, arthritis, headache, seizure, diabetes mellitus, hypertension, or chronic drug intake.

On examination, the patient was conscious, alert, and cooperative with no pallor, icterus, cyanosis, clubbing, edema, or lymphadenopathy. His vitals were stable except for his blood pressure, which was 86/52 mm Hg with no signs of dehydration. On neurological examination, there was hypotonia of all four limbs. Power was one-fifth in both lower limbs and three-fifth in both upper limbs. Truncal and neck muscles were weak. All deep tendon reflexes were diminished, and superficial reflexes were present with bilateral plantar flexor response. Cranial nerve, sensory, cerebellar, and meningeal involvement was absent on examination.

Laboratory investigations revealed normal blood counts. Fasting blood sugar was 94 mg/ dL, and serum urea and creatinine were 38 mg/dL and 1 mg/dL, respectively. Liver function tests were normal. X-ray of the chest and ultrasonography of the abdomen were within normal limits. Serum lactate, creatine phosphokinase, and thyroid function were within the normal range.

The electromyogram and the nerve conduction velocity of all four limbs with the repetitive nerve stimulation test were normal. Serum electrolytes revealed Na+ = 125 mmol/ L, K+ = 1.7 mmol/L, Cl− = 96 MEq/L, Ca +2 = 8.7 mg/dL, and Mg +2 = 1.3 mg/dL. Arterial blood cases revealed pH = 7.56, PaO 2 = 80.6, SaO 2 = 96%, PaCO 2 = 49, and HCO 3− = 30.1 mmol/L. Twenty-four hour urine analysis showed hypocalciuria [Table 1], and it was negative for diuretic screen. A confirmatory test was performed. The patient was started on potassium and magnesium supplementation with spironolactone. He showed a dramatic improvement and is still doing well after 8 months of follow-up.
Table 1: 24-hour urine analysis report in our indexed case.

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   Discussion Top

Gitelman's syndrome has some similar aspects with Bartter's syndrome (BS), which is a hereditary condition transmitted as an autosomal recessive (Bartter types 1-4) or dominant trait (Bartter type 5) and can cause hypokalemia. The disease associates hypokalemic alkalosis with varying degrees of hypercalciuria. There is a defective reabsorption of NaCl in a specific structure of the kidney called the "loop of Henle." A first consequence of the tubular defect in BS is polyuria. Indeed, high urine volume is already present during fetal life, and is responsible for particular complications of pregnancy, i.e., polyhydramnios and premature delivery. Low potassium levels in the blood may result from over activity of the renin-angiotensin II-aldosterone hormone system that is essential in controlling blood pressure. [6] The defective genes of BS have been cloned. [7],[8] The different types of BS are usually symptomatic early in life (occasional patients with BS type 3 or type 4 may even reach adulthood with a few or no symptoms of the disease), and growth is usually below the age standards, and final height may also be compromised.

Although the mutation of the genes responsible for specific abnormalities of tubular solute reabsorption disorders have been defined, [9],[10],[11] the genetic diagnosis of hypokalemic disorders still remains largely confined to a few laboratories and is very complex and time-consuming, mainly due to the following reasons: (1) Most studied genes have huge dimensions, (2) the number of recognized mutations in each gene is very large, (3) mutations are evenly distributed along the whole gene without any hot spot, and (4) several mutations are still missed, as a result of their localization in the unknown regulatory regions or of complex mechanisms such as silent polymorphisms that lead to exon skipping. [12]

The diuretic (thiazide) challenge test [1] is very simple to perform and interpret, and it has very high sensitivity and specificity and may substantially improve phenotyping of tubular hypokalemic disorders. Because diuretics of the different classes exert their effect by selectively interacting with specific tubular transporters/channels, [13] it is a logical expectation that abnormal functional activity of their target proteins results in parallel changes in the pharmacological response. The administration of thiazide diuretics may induce a subnormal increase of urinary Na+ and Cl− excretion in patients with Gitelman's syndrome, consistent with the hypothesis that less Na+ and Cl− than normal is reabsorbed by the thiazide-inhibitable transporter in the Gitelman's syndrome. [1],[14] In our patient, having subnormal fractional excretion of chloride (1.3%) following the thiazide challenge test compared to normal (3.6%) confirms the diagnosis of the Gitelman's syndrome [Figure 1]. [14]
Figure 1: Procedure and results (control taken from reference 1) of the thiazide diuretic test for diagnosis of renal tubular hypokalemic disorders. Quantification of the diuretic effect was done by taking the maximum increases of urine chloride excretion over mean basal levels calculated by the maximum excretion at any time minus the mean of the two basal clearances. Chloride excretion was evaluated as fractional excretion with creatinine as a glomerular filtration rate marker.

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In our patient presenting with fluctuating paralysis, the serum electrolyte level, arterial blood gas analysis, 24-h urine assay, and the thiazide challenge test resulted in the diagnosis of the Gitelman's syndrome and proper management of the patient. Pitfalls of the thiazide challenge test include the precipitation of severe hypokalemia, which can cause severe muscle paralysis including respiratory muscle weakness. Indomethacin can blunt the effect of thiazide diuretics.

Hence, we recommend that thiazide challenge test may allow selective evaluation of thiazide sensitive NCCT in clinical practice and may translate into a reliable diagnostic test for the Gitelman's syndrome.

   References Top

Colussi G, Rombolà G, Brunati C, De Ferrari ME. Abnormal reabsorption of Na+/CIby the thiazide-inhibitable transporter of the distal convoluted tubule in Gitelman's syndrome. Am J Nephrol 1997;17:103-11.  Back to cited text no. 1
Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 1966;79:221-35.  Back to cited text no. 2
Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996;12:24-30.  Back to cited text no. 3
Shaer AJ. Inherited primary renal tubular hypokalemic alkalosis: a review of Gitelman and Bartter syndromes. Am J Med Sci 2001;322:316-32.  Back to cited text no. 4
Lin SH, Cheng NL, Hsu YJ, Halperin ML. Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter. Am J Kidney Dis 2004; 43:304-12.  Back to cited text no. 5
Bettinelli A, Vezzoli G, Colussi G, Bianchetti MG, Sereni F, Casari G. Genotype-phenotype correlations in normotensive patients with primary renal tubular hypokalemic metabolic alkalosis. J Nephrol 1998;11:61-9.  Back to cited text no. 6
Konrad M, Vollmer M, Lemmink HH, et al. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J Am Soc Nephrol 2000;11:1449-59.  Back to cited text no. 7
Watanabe S, Fukumoto S, Chang H, et al. Association between activating mutations of calcium-sensing receptor and Bartter's syndrome. Lancet 2002;360:692-4.  Back to cited text no. 8
Mastroianni N, Bettinelli A, Bianchetti M, et al. Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome. Am J Hum Genet 1996; 59:1019-26.  Back to cited text no. 9
Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 1996;13:183-8.  Back to cited text no. 10
Simon DB, Bindra RS, Mansfield TA, et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet 1997;17:171-8.  Back to cited text no. 11
Buratti E, Baralle FE, Pagani F. Can a 'patch' in a skipped exon make the pre-mRNA splicing machine run better? Trends Mol Med 2003;9:229-32.  Back to cited text no. 12
Rose BD, Post TW. Mechanism of action of diuretics. In: Rose BD, editor. UpToDate. Ver. 14.1. Waltham, MA: UpToDate; 2005.  Back to cited text no. 13
Tsukamoto T, Kobayashi T, Kawamoto K, Fukase M, Chihara K. Possible discrimination of Gitelman's syndrome from Bartter's syndrome by renal clearance study: report of two cases. Am J Kidney Dis 1995;25:637-41.  Back to cited text no. 14

Correspondence Address:
Sumanto Mukhopadhyay
Department of Internal Medicine, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal
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DOI: 10.4103/1319-2442.178584

PMID: 26997401

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