Clinical Severity of Gitelman Syndrome Determined by Serum Magnesium

Abstract

Background/Aims: Normomagnesemia is considered atypical in Gitelman syndrome (GS). Here, we describe clinical, pathological and genetic characteristics in Chinese GS patients with or without hypomagnesemia in order to determine whether serum magnesium concentration indicates the severity of the disease. Methods: 7 normomagnesemic and 25 hypomagnesemic GS patients who were confirmed by direct sequencing of SLC12A3 gene were included. Clinical manifestation and laboratory tests were documented. Supine and upright plasma renin activity, angiotensin II and aldosterone were determined by radioimmunoassay. Transient receptor potential channel melastatin subtype 6 (TRPM6) was detected by immunohistochemistry in paraffin-embedded renal biopsy sections of 12 GS patients. 14 patients with glomerular minor lesion served as controls. The distribution of the mutations on the predicted NCC protein was analyzed and compared between two subgroups. Results: Clinical manifestations, electrolyte abnormalities, metabolic alkalosis and renin-angiotensin-aldosterone system activation were found to be milder in normomagnesemic compared with the hypomagnesemic group. Compared with glomerular minor lesion controls, the TRPM6-positive area was significantly decreased in hypomagnesemic patients (4.96 ± 1.88 vs. 8.63 ± 2.67%) while it was near normal (7.82 ± 5.23%) in 2 normomagnesemic GS patients. A higher percentage of intracellular mutations was observed in normomagnesemic patients than hypomagnesemic patients (92.31 vs. 56.52%, p = 0.02). Conclusions: Normomagnesemia is not rare in GS. Serum magnesium may indicate the severity of GS.

Increased urinary prostaglandin E2 metabolite: A potential therapeutic target of Gitelman syndrome

“…A blunt reaction to HCT indicated impaired reabsorption function of the DCT. The relationship between the NCC disorder and the clinical manifestations of GS was shown in our previous studies [15, 17, 18]. Because of the limited sample size, we didn’t find significant association between genotype and phenotype, nor the relationship between PGE2 levels and the mutations (including the type of mutations: homozygous, compound heterozygous and heterozygous; locations of NCC protein encoding by different mutations: cytoplasmic sequence, transmembrane regions, intracellular or extracellular).…”

“…The SLC12A3 gene encoding the NCC was sequenced directly as we previously described [17]. Briefly, genomic DNA was isolated and purified from peripheral blood lymphocyte of the patients and used for polymerase chain reaction amplfication of individual exons of the SLC12A3 gene.…”

Hypokalemia, hypomagnesemia, hypocalciuria, and recurrent tetany: Gitelman syndrome in a Chinese pedigree and literature review

“…Our analysis based on the previous reports showed that GS patients with lower potassium were more symptomatic, and usually had a younger age at diagnosis and lower serum magnesium level. It has been reported the co‐localization of NCCT and TRPM6 proteins , which might indicate the functional status of NCCT might regulate the Mg 2+ channel TRPM6.…”

“…Previous studies have shown that the SLC12A3 mutations scattered through the whole coding sequence of the NCCT protein, but most of the mutations are frequently found in the intracellular domains of the protein [30], and the phenotype of GS is highly heterogeneous [11]. Jiang et al found the percentage of mutated alleles distributed extracellularly was greater in hypo-than normomagnesemic patients [17]. In our review of Chinese GS, most of the SLC12A3 mutation alleles were located on the intracellular domains of NCCT, and we found the average serum potassium and magnesium was significantly lower in subjects with SLC12A3 mutations extracelluarly than those with mutations intracellularly or transmembranally ( Table 2).…”

“…To find the possible explanation for the severe clinical manifestations of the GS patient in our current study, the data of all Chinese GS patients in previous publications, which could be found in the PubMed database to date, were collected to analyze the associations between the types and sites of SLC12A3 gene mutations and severity of clinical manifestations in GS. As shown in Table 1, 252 patients (157 male and 95 female) with GS have been described in the literature [6,[13][14][15][16][17][18][19][20][21][22][23][24][25]. The average age at onset was 23.6, and hypomagnesemia and hypocalciuria were found in 92% and 88% of GS patients ( Table 1).…”