Characteristics And Follow-Up Of Pedigrees With Gitelman Syndrome

Context and ObjectiveGitelman syndrome（GS,OMIM 263800）,one of the most common causes of hereditary hypokalemia,is characterized by hypokalemia,hypomagnesemia,and hypocalciuria without hypertension.GS is an autosomal renal recessive tubular disease caused by the mutation of SLC12A3 gene（Gene ID:6559;MIM:600968;Gene Bank:NC₀00016.10）,which encodes the thiazide-sensitive sodium-chloride cotransporter（NCC）located in distal convoluted tubules of kidney.The disease is highly phenotypically and genetically heterogeneous.However,the genotype and phenotype correlation has not been well established.Though the long-term prognosis is considered to be favorable,hypokalemia is difficult to cure.Moreover,long-term electrolyte disorders can lead to abnormal glucose metabolism,impaired renal function,and serious complications such as cartilage calcification,arrhythmia.Therefore,genetic and clinical research on GS can provide new insights into the disease,and further understanding of phenotype and genetic diversity.Follow-up study is imperative for in-depth research to seek out a better method for GS treatment and to prevent further exacerbation of the disease.We analyzed the genetic and clinical characteristics of 13 GS family were analyzed in order to provide scientific basis for early diagnosis and refinement treatment of GSSubjects and MethodsThe clinical data and blood and urine samples of 13 pedigree members（86 members,17 GS patients）were collected.Genotype identified by SLC12A3 gene mutation screening and genotype-phenotype associations among all the members were analyzed.The curative effect and prognosis were analyzed after 3 years of continuous follow-up.Results1.Genotype Analysis:A total of 18 mutants were detected.There were nine missense,two nonsense,three deletion,one insertion,one insertion and deletion,and two splice-site mutations.Two mutations（c.2816G>A,p.W939X and c.634G>A,p.G212S）were reported for the first time.Bioinformatics analysis showed that these two mutations could lead to functional defects in the NNC protein encoded by SLC12A3 gene.2.Phenotype Analysis:1)Gender differences is an important factor affecting the phenotype:a)the average age of onset in males is 10 years earlier than in females（male vs.female,22.7± 8.8 vs.33.9±8.6 yrs,P<0.05）.b)Muscle paralysis was the primary presenting symptom in affected males,while fatigue was more common in females（P<0.05）.c)males had more significant hypokalemia than females（male vs.female,2.31 ± 0.24 mmol/L vs.2.77± 0.43 mmol/L,P<0.05）,as well as the clinical symptoms.2)In addition to the sexual effect on phenotype,genotype could also account for phenotype variability:patients carrying intronic or nonframeshift mutations had more severe hypokalemia（P<0.005）.3.According to the genotyping and clinical symptoms,pedigree members were divided into three groups:patient（n=17）,carrier（n=35）,and healthy control（n=34）.Blood pressure and serum K+ and Mg2+levels were significantly lower in the patient group than in the carrier and healthy control groups.It is noteworthy that the 24-hour urinary Na+ excretion in the carrier group was also significantly higher than that in the healthy control group（P<0.0001）although there was no significant difference in blood pressure.4.Follow-up study:Patients generally take 2-3 kinds of drugs and most them usually have no obvious symptoms.Although the levels of blood potassium and magnesium are significantly improved,only 41.2%of the patients reached normal blood potassium levels.Compared to potassium,serum magnesium levels were easier to improve.More than 80%of patients achieved normal magnesium levels after treatment.Six patients were taking spironolactone simultaneously,but no significant elevation in the serum potassium level was observed.Conclusion24-hour urinary sodium excretion may be a predictor of early NCC dysfunction,which may make them more susceptible to diuretic-induced hypokalemia.Genotype-phenotype association of GS and therapeutic strategies deserve further research to improve GS diagnosis and prognosis.