Gitelman's syndrome: a pathophysiological and clinical update

Abstract

Gitelman's syndrome (GS), also known as familial hypokalemic hypomagnesemia, is a rare autosomal recessive hereditary salt-losing tubulopathy, characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria, which is usually caused by mutations in the SLC12A3 gene encoding the thiazide-sensitive sodium chloride contrasporter. Because 18-40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements must account for unidentified mutations. The clinical manifestations of GS are highly variable in terms of age at presentation, severity of symptoms, and biochemical abnormalities. Molecular analysis in our sibling's patients revealed compound heterozygous mutations in the coding region of SLC12A3 as underlying their disease. Such compound heterozygosity can result in disease phenotype for such loss of function mutations in the absence of homozygosis through consanguineous inheritance of mutant alleles, identical by descent. Missense mutations account for approximately 70% of the mutations in GS, and there is a predisposition to large rearrangements caused by the presence of repeated sequences within the SLC12A3. We report two adult male siblings of Jewish origin with late onset GS, who presented in their fifth decade of life with muscle weakness, hypokalemia, hypomagnesaemia, and metabolic alkalosis. Rapid clinical and biochemical improvement was achieved by replacement therapy with potassium and magnesium.

Gitelman’s Syndrome Associated with Chondrocalcinosis: A Case Study from the Azores Islands (Portugal)

“…The assumption that GS is caused by a defect in the NCCT cotransporter in the renal distal tubule has been proven by the identification of numerous variations in the SLC12A3 gene in patients with GS [1,4,19,21]. In the present study the specific involvement of this cotransporter in the etiology of this disorder is further substantiated by the finding that the proband is homozygous for the S615L variation.…”

A Rare Cause of Gitelman Syndrome: Celiac Disease: An Interesting Case

“…Birçok GS hastası asemptomatiktir veya hafif aralıklı kas krampları, yorgunluk, kas güçsüzlüğü veya irritabilite gibi semptomlar tarifleyebilir (15). GS kliniği başlangıç yaşı, semptom ciddiyeti ve biyokimyasal anormallikler açısından değişkenlik gösterir (3). Bu bulguların sınıflandırılmasının zor olması nedeniyle hastalar genellikle geç tanı almaktadır (13).…”

“…Gitelman sendromu (GS), hipokalemi varlığında hatırlanması gereken (2), otozomal resesif geçiş gösteren tuz kaybettiren bir tübülopatidir (3). Genellikle distal tübülde bulunan tiyazid duyarlı sodyum klorür kotransporter'ini (NCCT) kodlayan 16.…”

A Rare Case of Hypokalemia and Hypomagnesemia

“…2 alleles (9 ); 25% are homozygous, and 20% harbor only 1 mutant allele (9 ). Disease-causing mutations in SLC12A3 decrease NCCT activity and reduce NaCl reabsorption in the distal collecting duct, which leads to volume depletion.…”