title: Gitelman syndrome in a South African family presenting with hypokalaemia and unusual food cravings.
abstract: Gitelman syndrome (GS) is an autosomal recessive renal tubular disorder characterised by renal salt wasting with hypokalaemia, metabolic alkalosis, hypomagnesaemia and hypocalciuria. It is caused by mutations in SLC12A3 encoding the sodium-chloride cotransporter on the apical membrane of the distal convoluted tubule. We report a South African family with five affected individuals presenting with hypokalaemia and unusual food cravings.
  
  
  
  The affected individuals and two unaffected first degree relatives were enrolled into the study. Phenotypes were evaluated through history, physical examination and biochemical analysis of blood and urine. Mutation screening was performed by sequencing of SLC12A3, and determining the allele frequencies of the sequence variants found in this family in 117 ethnically matched controls.
  
  
  
  The index patient, her sister, father and two aunts had a history of severe salt cravings, fatigue and tetanic episodes, leading to consumption of large quantities of salt and vinegar. All affected individuals demonstrated hypokalaemia with renal potassium wasting. Genetic analysis revealed that the pseudo-dominant pattern of inheritance was due to compound heterozygosity with two novel mutations: a S546G substitution in exon 13, and insertion of AGCCCC at c.1930 in exon 16. These variants were present in the five affected individuals, but only one variant each in the unaffected family members. Neither variant was found in any of the controls.
  
  
  
  The diagnosis of GS was established in five members of a South African family through clinical assessment, biochemical analysis and mutation screening of the SLC12A3 gene, which identified two novel putative pathogenic mutations.
authors.affiliation: Division of Nephrology, Department of Medicine, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa.
authors.forename: Pieter Du Toit
authors.initials: PD
authors.lastname: van der Merwe
authors.affiliation: Division of Chemical Pathology, Stellenbosch University and National Health Laboratory Service, Cape Town, South Africa.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Rensburg
authors.affiliation: Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa.
authors.forename: William L
authors.initials: WL
authors.lastname: Haylett
authors.affiliation: Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa.
authors.forename: Soraya
authors.initials: S
authors.lastname: Bardien
authors.affiliation: Division of Nephrology, Department of Medicine, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa. mrd@sun.ac.za.
authors.forename: M Razeen
authors.identifier: 0000-0003-4900-0231
authors.initials: MR
authors.lastname: Davids
mesh_terms: D000328:Adult; D000368:Aged; D000471:Alkalosis / Q000209:etiology; D002118:Calcium / Q000652:urine; D066249:Craving; D005190:Family; D005260:Female; D005820:Genetic Testing; D053579:Gitelman Syndrome / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007008:Hypokalemia / Q000209:etiology*; D008274:Magnesium / Q000097:blood; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics; D013019:South Africa; D014883:Water-Electrolyte Imbalance / Q000097:blood / Q000209:etiology
chemical_list: C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3; D008274:Magnesium; D002118:Calcium
keywords: Gitelman syndrome; Hypokalaemia; Mutation; Pseudo-dominant inheritance; Salt craving; South Africa; Tubular disorders