Hypokalemia, hypomagnesemia, hypocalciuria, and recurrent tetany: Gitelman syndrome in a Chinese pedigree and literature review.
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ABSTRACT:
SUBMITTER: Xia MF
PROVIDER: S-EPMC5412754 | biostudies-literature | 2017 May
REPOSITORIES: biostudies-literature
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Hypokalemia, hypomagnesemia, hypocalciuria, and recurrent tetany: Gitelman syndrome in a Chinese pedigree and literature review.
Xia Ming-Feng MF Bian Hua H Liu Hong H Wu Hui-Juan HJ Zhang Zhi-Gang ZG Lu Zhi-Qiang ZQ Gao Xin X
Clinical case reports 20170317 5
Gitelman syndrome is an autosomal recessive disease mostly associated with loss-of-function mutations of the <i>SLC12A3</i> gene and featured by clinical hypokalemia, hypomagnesemia, hypocalciuria, and histologically hypertrophy of the juxtaglomerular apparatus. A novel homozygous mutation (p.Arg399Pro) at the extracellular domain of SLC12A3 was found and correlated with the severe clinical manifestations. ...[more]
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Project description:BACKGROUND:Gitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT). Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation. Different SLC12A3 variants may lead to phenotypic variability and severity. METHODS:In this study, we reported the clinical features and genetic analysis of a Chinese pedigree diagnosed with Gitelman syndrome. RESULTS:The proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalciuria and kidney stone formation. The increased urinary calcium excretion made it confused to Bartter syndrome. The persistent renal potassium wasting resulted in renal tubular lesions, and might affect urinary calcium reabsorption and excretion. Genetic analysis revealed mutations of SLC12A3 gene with c.433C?>?T (p.Arg145Cys), c.1077C?>?G (p.Asn359Lys), and c.1666C?>?T (p.Pro556Ser). Potential alterations of structure and function of NCCT protein due to those genetic variations of SLC12A3 are predicted. Interestingly, one sibling of the proband carried the same mutant sites and exhibited similar clinical features with milder phenotypes of hypokalemia and hypomagnesemia, but hypocalciuria rather than hypercalciuria. Family members with at least one wild type copy of SLC12A3 had normal biochemistry. With administration of spironolactone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained within normal ranges. CONCLUSIONS:In this study, we identified compound mutations of SLC12A3 associated with varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of Gitelman syndrome and its correlation with specific SLC12A3 mutations.
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Project description:IntroductionGitelman syndrome(GS) is a rare inherited tubular disorder which is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. Here, we report a case of schizophrenia-like psychosis concomitant with GS and related literatures are reviewed.Case descriptionAn 18-year-old male patient with 1-week history of auditory hallucinations, sense of insecurity, delusions of reference and feelings of being followed and controlled by others unknown, insomnia was admitted to Psychiatry department in December, 2013. Hypokalemia and hypomagnesemia were noted. He was diagnosed as schizophrenia-like psychosis. Treatment with paliperidone at the dose of 6 mg/day and magnesium and potassium supplementations was commenced. However, electrolyte disturbances failed to improve following psychosis remission. Therefore, other underlying diseases resulting in electrolyte disturbances were suspected. Along with hypokalemia and hypomagnesemia, additional investigation showing metabolic alkalosis, hypocalciuria, renal loss of potassium, were consistent with GS. Gene analysis revealed this patient carried out c. 2687 G > A homozygous mutation of exon 23 in the SLC12A3 gene which led to p.Arg896Gln. Eventually, GS was identified. Thus, additional spironolactone (40 mg/day) combined with increased doses of oral potassium chloride sustained-release tablets (3.0 g/day) and potassium magnesium aspartate (0.3 g/day) were administered. During next half a year, fatigue resolved, paliperidone gradually tapered and eventually discontinued while psychosis maintained complete remission. His serum potassium was near normal (3.2-3.5 mmol/L), hypomagnesemia significantly improved (0.57-0.67 mmol/L).Discussion and evaluationElectrolyte abnormalities secondary to GS might cause or contribute to development of neuropsychiatric symptoms. In turn, hypokalemia was common among acute psychiatric inpatients. As a consequence, when concomitant with psychosis, GS was readily concealed.ConclusionElectrolyte disturbances are common in acute psychiatric patients. However, when electrolyte disturbances are not improved following psychosis remission, other underlying diseases such as GS should be considered.
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Project description:Mutations in the KCNA1 gene encoding the voltage-gated potassium (K+) channel Kv1.1 have been linked to rare neurological syndromes, episodic ataxia type 1 (EA1) and myokymia. In 2009, a KCNA1 mutation was identified in a large family with autosomal dominant hypomagnesemia. Despite efforts in establishing a genotype-phenotype correlation for the wide variety of symptoms in EA1, little is known on the serum magnesium (Mg2+) levels in these patients. In the present study, we describe a new de novo KCNA1 mutation in a Polish patient with tetany and hypomagnesemia. Electrophysiological and biochemical analyses were performed to determine the pathogenicity of the mutation. A female patient presented with low serum Mg2+ levels, renal Mg2+ wasting, muscle cramps, and tetanic episodes. Whole exome sequencing identified a p.Leu328Val mutation in KCNA1 encoding the Kv1.1 K+ channel. Electrophysiological examinations demonstrated that the p.Leu328Val mutation caused a dominant-negative loss of function of the encoded Kv1.1 channel. Cell surface biotinylation showed normal plasma membrane expression. Taken together, this is the second report linking KCNA1 with hypomagnesemia, thereby emphasizing the need for further evaluation of the clinical phenotypes observed in patients carrying KCNA1 mutations.
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Project description:BackgroundGitelman syndrome (GS) is an autosomal recessive disorder caused by genic mutations of SLC12A3 (Solute carrier family 12 member 3), which encodes the Na-Cl cotransporter (NCC), and presents with characteristic metabolic abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. In this study, we report a case of a GS pedigree, including analysis of GS-associated gene mutations.MethodsWe performed next-generation sequencing analysis and Sanger sequencing to explore the SLC12A3 mutations in a GS pedigree that included a 35-year-old female patient with GS and five family members within three generations. Furthermore, we summarized their clinical manifestations and analyzed laboratory parameters related to GS.ResultsThe female proband (the patient with GS) presented with intermittent fatigue and transient periods of tetany, along with significant hypokalemia, hypomagnesemia, and hypocalciuria. All other members of the pedigree had normal laboratory results without obvious GS-related symptoms. Genetic analysis of the SLC12A3 gene identified two novel missense mutations (c.1919A > G, p.N640S in exon 15; c.2522A > G, p.D841G in exon 21) in the patient with GS. Moreover, we demonstrated that her mother, younger maternal uncle, and cousin were carriers of one mutation (c.1919A > G), and her father was the carrier of the other (c.2522A > G).ConclusionThis is the first report of these two novel pathogenic variants of SLC12A3 and their contribution to GS. Further functional studies are particularly warranted to explore the underlying molecular mechanisms.
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| S-EPMC9315244 | biostudies-literature