NDT Advance Access originally published online on July 19, 2006
Nephrology Dialysis Transplantation 2006 21(11):3340-3341; doi:10.1093/ndt/gfl361
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atypical Gitelman syndrome with L623P mutation of the thiazide-sensitive Na–Cl cotransporter gene exhibiting lack of hypocalciuria and increased proximal tubule salt reabsorption
Email: smuto{at}jichi.ac.jpSir,
Gitelman syndrome (GS) is an inherited disorder caused by loss of function of the thiazide-sensitive Na–Cl cotransporter gene (SLC12A3) in the distal convoluted tubule (DCT). GS is distinguished from classical Bartter syndrome by the presence of hypocalciuria [1]. We report here an atypical GS with a mutation of the SLC12A3.
A 50-year-old Japanese woman was diagnosed with hypokalaemia 30 years ago, but was asymptomatic. In 2002, she was again found to have severe hypokalaemia (2.4 mEq/l) at our hospital. She had no history of renal calculi, vomiting, diarrhoea, or abuse of diuretics or laxatives. Her parents were non-consanguineous. Blood pressure was 104/68 mmHg; the physical examination was normal. Blood tests showed: hypokalaemia (2.5 mEq/l), hypomagnesaemia (1.4 mg/dl), metabolic alkalosis (HCO3: 33.0 mEq/l), high plasma renin activity (7.8 ng/ml/h), creatinine (0.4 mg/dl), albumin (4.3 g/dl), Na (139 mEq/l), Cl (98 mEq/l), Ca (8.7 mg/dl) and inorganic phosphorus (P) (3.5 mg/dl).
In our case, the distal fractional chloride reabsorption during hypotonic saline diuresis was moderately decreased before administration of the diuretics and was further markedly decreased after furosemide administration, but was unchanged after hydrochlorothiazide administration (Table 1). The genetic analyses of the SLC12A3, the thick ascending limb basolateral Cl channel (ClC-Kb) gene, and the ClC-Kb ß-subunit gene revealed only a homozygous missense mutation of the SLC12A3, which substitutes proline for leucine at 623 amino acid position (L623P) (Figure 1). Therefore, she was diagnosed with GS.
|
|
One of the striking features in our patient was that both urinary Ca excretion rate (140 mg/day) and urinary Ca/creatinine molar ratio (0.35–0.53) were normal. It has recently been reported that some patients with GS do not show hypocalciuria [2, 3]. Another striking feature was that proximal tubule solute reabsorption was enhanced in this patient, because both fractional distal delivery of solute and fractional urine flow rate were decreased during hypotonic saline diuresis before administration of the diuretics (Table 1). This idea is also supported by the reduced fractional excretion of P (3.1%) in the patient, because P is exclusively reabsorbed through Na-coupled carriers located at the apical membrane of the proximal tubule.
The L623P mutation has been previously reported in Japanese patients with GS [4, 5], but the renal clearance study using furosemide or thiazide was not performed in those patients. We first demonstrated that the DCT was functionally impaired in this mutation. Furthermore, those cases exhibited marked hypocalciuria and were from the same geographical region in Japan, suggesting that the mutation in these patients might have been introduced by a single founder. However, our patient differed from them, in that she exhibited an absence of hypocalciuria and enhanced proximal tubule salt reabsorption, and was from a different geographical region in Japan.
Conflict of interest statement. None declared.
1Department of Medicine
Public Muraoka Hospital Hyogo
2Department of Nephrology
Jichi Medical School Tochigi
3Department of Nephrology
Tokyo Medical and Dental University
Tokyo, Japan
References
- Bettinelli A, Giovanni M, Bianchetti MG, et al. (1992) Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndrome. J Pediatr 120:38–43.[CrossRef][Web of Science][Medline]
- Lin S-H, Cheng N-L, Hsu Y-J, Halperin ML. (2004) Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter. Am J Kidney Dis 43:304–312.[CrossRef][Web of Science][Medline]
- Kamel KS, Harvey E, Douek K, Halperin ML. (1998) Studies on the pathogenesis of hypokalemia in Gitelman's syndrome: role of bicarbonaturia and hypomagnessemia. Am J Nephrol 18:42–49.[CrossRef][Web of Science][Medline]
- Takeuchi K, Kure S, Kato T, et al. (1996) Association of a mutation in the thiazide-sensitive Na-Cl cotransporter with familial Gitelman's syndrome. J Clin Endocr Metab 81:4496–4499.[Abstract]
- Tajima T, Kobayashi Y, Abe S, et al. (2002) Two novel mutations of thiazide-sensitive Na-Cl cotransporter (TSC) gene in two sporadic Japanese patients with Gitelman syndrome. Endocr J 49:91–96.[Web of Science][Medline]
- Tsukamoto T, Kobayashi T, Kawamoto K, Fukase M, Chihara K. (1995) Possible discrimination of Gitelman's syndrome from Bartter's syndrome by renal clearance study: report of two cases. Am J Kidney Dis 25:637–641.[Web of Science][Medline]
- Baehler RW, Work J, Kotchen TA, McMorrow G, Guthrie G. (1980) Studies on the pathogenesis of Bartter's syndrome. Am J Med 69:933–938.[Web of Science][Medline]
- Uribarri J, Alverabga D, Oh MS, Kukar NM, Del Monte ML, Carroll HJ. (1985) Bartter's syndrome due to a defect in salt reabsorption in the distal convoluted tubule. Nephron 40:52–56.[Web of Science][Medline]
- Stein JH. (1985) The pathogenetic spectrum of Bartter's syndrome. Kidney Int 28:85–93.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||