Original investigation: pathogenesis and treatment of kidney disease and hypertension
Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter

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Abstract

Background: Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter (NCC). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare. Methods: Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K+) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed. Results: The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS—less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB. Conclusion: Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.

Section snippets

Subjects

The pedigrees of 2 Chinese families are shown in Fig 1, Fig 2. In both families, the proband was male. Their current ages are 29 and 23, respectively. Seven additional members of the first family (aged from 7 to 58) and 3 additional members of the second family (aged from 21 to 54) were also evaluated including clinical symptoms and signs, biochemical features, and molecular analysis for NCC and CLCNKB mutation. The study protocol was approved by the Ethics Committee on Human Studies at

Clinical symptoms

Clinical symptoms included general, musculoskeletal, renal, gastrointestinal, cardiovascular, and neurologic aspects as previously described.13 In the general symptom category, there was fatigue, dizziness, fainting, and exercise intolerance. Musculoskeletal symptoms included weakness, muscle stiffness or pain, muscle cramp, carpopedal spasm/tetany, and paralysis. Renal symptoms included nocturia, polyuria, polydipsia, thirst, enuresis, and salt craving. Gastrointestinal symptoms included

Clinical symptoms

As shown in Table 1, the initial presentation in the proband of the first family was characterized by progressive muscle weakness including several episodes of paralysis beginning at age 12. He denied nausea, vomiting, diarrhea, heart palpitations, heat intolerance, excessive perspiration, and changes in bowel habits. He did not take laxatives or diuretics, nor did he abuse alcohol or street drugs. His other clinical symptoms included fatigue, dizziness, carpopedal spasm/tetany, nocturia,

Discussion

The clinical, biochemical, and genetic characteristics in the 2 apparently unrelated Chinese families who have 2 novel NCC mutations (S710stop and 2881–2delAG) are described. Affected female patients appear to have findings consistent with a clinical diagnosis of GS. They were virtually asymptomatic on presentation. In contrast, affected male patients appear to have findings consistent with a clinical diagnosis of BS. They were very symptomatic on presentation as teenagers with severe

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    Supported by a grant from the National Science Council, Taiwan (NSC 92-2314-B-016-039).

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