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Caused by Different Mutations in the Thiazide-Sensitive Na-Cl

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Caused by Different Mutations in the Thiazide-Sensitive Na-Cl CASE REPORT Three Cases of Gitelman's Syndrome Possibly Caused by Different Mutations in the Thiazide-Sensitive Na-Cl Cotransporter Kazuhisa Takeuchi, Taro Kato, Yoshihiro Taniyama, Kazuo Tsunoda, Nobuyuki Takahashi, Yukio Ikeda, Ken Omata, Yutaka Imai, Takao Saito, Sadayoshi Ito and Keishi Abe Three adult Japanese cases of Gitelman's syndromewere characterized by secondary aldosteronism, hypokalemic alkalosis, hypomagnesemia, and hypocalciuria. Twowere revealed to be familial cases. Amutation in the thiazide-sensitive Na-Cl cotransporter gene, which had already been confirmed in one family (Takeuchi et al. J Clin Endocrinol Metab 81: 4496, 1996), was not detected in the other twocases. These observations maypossibly support the previous report (Simon et al. Nature Genet 12: 24, 1996) that Gitelman's syndrome is caused by a variety of mutations in the thiazide-sensitive Na-Cl cotransporter. (Internal Medicine 36: 582-585, 1997) Key words: Bartter' s syndrome, secondary aldosteronism, missense mutation, restriction fragment length polymorphism Introduction Case Reports "Bartter's syndrome" has recently been divided into two Case1 subsets, true Bartter's syndrome and Gitelman's syndrome (1 , A 45-year-old Japanese female had noticed mild periodic 2). Bartter' s syndrome is characterized by hypokalemic alkalo- paralysis and tetany since the age of28. In March1994, she felt sis, and secondary aldosteronism without hypertension, and discomfort in her lower abdomen, and a tumor was felt palpable with blunted pressor responsiveness to angiotensin (Ang) II (3). in the region. Uterine myomawas identified by a gynecologist, True Bartter's syndromealso refers to patients with normal or and she was admitted to her neighboring hospital for resection. hypercalciuria, and typically normal magnesium levels. Laboratory examination disclosed her hypokalemia (2.4 mmol/ Gitelman's syndrome (4), however, refers to patients with /), metabolic alkalosis, secondary aldosteronism and normoten- hypocalciuria and hypomagnesemia. Genetic analyses have sion. She had no history of chronic diarrhea, vomiting, or shownthat Bartter's syndromeis due to mutations in Na-K-2C1 diuretics abuse. Bartter's syndromewas suspected, and the cotransporter NKCC2(5) or K+ channel ROMK(6), and that operation was postponed. For the therapy, either potassium 32 Gitelman's syndrome is attributable to mutations in thiazide- mmol/day, non-steroidal anti-inflammatory drug (diclofenac sensitive Na-Cl cotransporter (TSC) (7). Wehave recently sodium 1 00 mg/day), or mineralocorticoid receptor antagonist reported the close association of a mutation in TSCwith (spironolactone 50 mg/day) was administered. Hypokalemia familial Gitelman's syndrome (8), which further supports the was however not completely corrected. In February 1995, the report by Simon et al (7) that a mutation in TSCgene (probably patient was referred to our department in TohokuUniversity leading to inhibition of the transporter activity) causes Gitelman ' s Hospital for further investigation of hypokalemia and resection syndrome. Here we report three cases ofGitelman's syndrome, of uterine myoma. and suggest apossible variety of mutations in TSCin Gitelman' s Her parents and grandparents are consanguineous. Individu- syndrome. als in her family had a tendency towards hypotension. Her blood pressure was 106/70 mmHg:she was 155 cm tall and weighed 65 kg. Laboratory data are listed in Table 1. Pressor response to From the Second Department of Internal Medicine, Tohoku University School of Medicine, Sendai Received for publication January 13, 1997; Accepted for publication April 25, 1997 Reprint requests should be addressed to Dr. Kazuhisa Takeuchi, the Second Department of Internal Medicine, TohokuUniversity School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-77 582 Internal Medicine Vol. 36, No. 8 (August 1997) Gitelman' s Syndromeand Na-Cl Cotransporter Table 1. Representative Laboratory Data in Three Cases of Gitelman's Syndrome C a se 1 C a s e 2 C a s e 3 N o r m a l ra n g e Se ru m e le c tr ol y te l ev e ls N a 1 4 3 1 4 0 1 3 5 1 3 5 - 1 4 7 m m o l K 2 .6 2 .7 3.4 3 . 4 - 5 . 0 m m o l C l 1 0 1 1 0 5 9 6 9 8 - 1 0 8 m m o l C a 8 .9 9 . 2 9. 1 8 . 6 - 1 0. 5 m g /d l M g 1. 8 1. 1 1.3 1 . 8 -2 . 4 m g / d l U ri na r y el ec tr o ly te e xc r et io ns N a 1 8 1 1 1 2 9 2 K 5 9 6 1 4 7 c ¥ 17 0 1 1 7 1 0 8 C a 2. 3 1 6 6 .0 > 5 0 m g / d a y P la sm a r en i n ac t iv it y 8 3 .6 48 . 6 7 8 .4 5- 3 0 n g A n g l / m l / 6 h P la s m a a l d os t e r on e co n c en t r a ti o n 26 . 9 4 1.4 2 5 .7 2 - 12 n g /d l S e r u m p H 7. 4 7 7. 4 8 7 .4 5 7 . 3 5 - 7 .4 5 S e r um b ic a r bo n a t e l e ve l s 32 . 5 3 0. 3 2 8. 5 2 1 - 2 5 m m o l / / JZhr-0 0=H2 å I 6 I I I I 6°j*h\ ^ (Tali Case 1 Case 2 Case 3 Figure 1. Pedigrees of kindred of the three patients with Gitelman's syndrome. Probands are indicated by arrows. Ang II (9, 10) was normal, and hypomagnesemia and marked she has been followed up in the outpatient clinic. Hypokalemia hypocalciuria were confirmed. Based on these clinical findings, (2.4-3. 1 mmol//) and hypomagnesemia (1.6-1.8 mg/dl) how- Gitelman's syndrome was diagnosed. Familial relationships everpersisted. She had no history of chronic diarrhea, vomiting, are shown in Fig. 1. and diuretics abuse. Her height was 146.7 cm, and weight, 47.4 kg. Blood pressure levels were less than 1 10/70 mmHg. Case2 In February 1996, urinary calcium levels were determined, A 5 1 -year-old Japanese female had suffered from diabetes and marked hypocalciuria was confirmed. Gitelman's syn- mellitus since the age of 40. When diabetes mellitus was drome was therefore diagnosed. Laboratory data during the diagnosed, hypokalemia (2.4 mmol//) was also observed, and admission are listed in Table 1. Pressor response to Ang II was she was admitted to our department. Byintense examinations, normal. Family relationships are shown in Fig. 1. Her father hypotension, hypokalemia, metabolic alkalosis, and suffered from cerebral infarction in August 1994. During his hyperreninemic hyperaldosteronism were identified. Pressor admission in a hospital, persistent hypokalemia (2.4-2.7 mmol/ response to Ang II was normal. Hypomagnesemia ( 1.6-1.8 mg/ /), hyponatremia ( 1 24-1 34 mmol//), hypomagnesemia ( 1.6 mg/ dl) was also observed. A variant of Bartter's syndrome was dl), and hypocalciuria (12 mg/day) were observed. A diagnosis diagnosed because of the lack of blunted pressor response to of Gitelman's syndrome was also likely for him. Ang II. Potassium (32 mmol/day) has been administered, and Internal Medicine Vol. 36, No. 8 (August 1997) 583 Takeuchi et al Case3 A 66-year-old Japanese female had suffered from recurrent Discussion pyelonephritis. She was first admitted to a neighboring hospital in 1983 because of pyelonephritis. Mild muscle paralysis was Gitelman's syndrome was diagnosed in three patients with felt, and laboratory examination disclosed low serum potas- hypokalemia, secondary aldosteronism, and normotension in sium levels (2.0-3.0 mmol//). Although pyelonephritis im- conjunction with hypomagnesemiaand hypocalciuria. Although proved, hypokalemia and secondary aldosteronism were per- Gitelman ' s syndrome is similar to Bartter' s syndrome, both are sistently observed. Potassium 32 mmol/day and spironolactone distinguished on the basis of urinary calcium excretion because 50 mg/day were then administered, and she was followed up in true Bartter ' s syndrome shows a tendency towards hypercalciuria the outpatient clinic. She had no history of chronic diarrhea, whereasGitelman's syndromeshowsmarkedhypocalciuria. vomiting, and diuretics abuse. Blood pressure levels were Mild secondary aldosteronism was observed in the patients, and within the normal range. In July 1995, hypokalemia worsened pressor response to AngII was not impaired in the three (serum potassium, 1.9 mmol//), and she was referred to our subjects. Onthe other hand, true Bartter's syndrome is known department for further examinations. Representative labora- to showthe blunted pressor response. In the three patients, tory data during admission are listed in Table 1. Pressor re- secondary aldosteronism was not persistent, and the plasma sponse to Angll was normal. Based on these findings, Gitelman' s renin activity was normal in the experimental periods. In syndrome was diagnosed. Familial relationships are shownin Gitelman's syndrome, secondary reninism due to salt wasting Fig.1. is not so severe, and therefore desensitization of AngII re- ceptor may not necessarily occur. Congenital disorder of DNArestriction fragment length polymorphism Gitelman's syndrome was first diagnosed in adults in these Wehave reported (8) a mutation in TSC gene (T to C change patients. Since the clinical findings ofGitelman' s syndrome are at 1,868 nucleic acid position) in the Gitelman's syndrome so mild compared to those of true Bartter' s syndrome, Gitelman ' s kindred including Case 1 , which causes substitution of leucine abnormalities may possibly be discovered by chance in adults for proline at the 623 amino acid position, and creates Nci I such as in the present cases, in which the disorder was un- restriction site in the exon 15.
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