Andersen-Tawil syndrome (ATS) is a multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, prolonged QT interval, and facial dysmorphisms occurring in the first/second decade of life. High phenotypic variability and incomplete penetrance of the genes causing the disease make its diagnosis still a challenge. We describe a three-generation family with six living individuals affected by ATS. The proband is a 37-year-old woman presenting since age 16, with episodes of muscle weakness and cramps in the pre-menstrual period. The father, two brothers, one paternal uncle and one cousin also complained of cramps, muscle stiffness, and weakness. Despite normal serum potassium concentration, treatment with potassium, magnesium, and acetazolamide alleviated paralysis attacks suggesting a dyskalemic syndrome. Dysmorphic features were noted in the proband, only later. On the ECG, all but one had normal QT intervals. The affected males developed metabolic syndrome or obesity. The father had two myocardial infarctions and was implanted with an intracardiac cardioverter defibrillator (ICD). A genetic investigation by WES analysis detected the heterozygous pathogenic variant (NM_000891.2: c.652C>T, p. Arg218Trp) in the KCNJ2 gene related to ATS, confirmed by segregation studies in all affected members. Furthermore, we performed a review of cases with the same mutation in the literature, looking for similarities and divergences with our family case.

Neonatal diabetes mellitus (NDM) is a rare genetic disease characterized by severe hyperglycemia requiring insulin therapy with onset mostly within the first 6 months and rarely between 6-12 months of age. The disease can be classified into transient (TNDM) or permanent neonatal diabetes mellitus (PNDM), or it can be a component of a syndrome. The most frequent genetic causes are abnormalities of the 6q24 chromosomal region and mutations of the ABCC8 or KCNJ11 genes coding for the pancreatic beta cell\'s potassium channel (KATP). After the acute phase, patients with ABCC8 or KCNJ11 mutations treated with insulin therapy can switch to hypoglycemic sulfonylureas (SU). These drugs close the KATP channel binding the SUR1 subunit of the potassium channel and restoring insulin secretion after a meal. The timing of this switch can be different and could affect long-term complications. We describe the different management and clinical outcome over the time of two male patients with NDM due to KCNJ11 pathogenetic variants. In both cases, continuous subcutaneous insulin infusion pumps (CSII) were used to switch therapy from insulin to SU, but at different times after the onset. The two patients kept adequate metabolic control after the introduction of glibenclamide; during the treatment, insulin secretion was evaluated with c-peptide, fructosamine, and glycated hemoglobin (HbA1c), which were within the normal range. In neonates or infants with diabetes mellitus, genetic testing is an indispensable diagnostic tool and KCNJ11 variants should be considered. A trial of oral glibenclamide must be considered, switching from insulin, the first line of NDM treatment. This therapy can improve neurological and neuropsychological outcomes, in particular in the case of earlier treatment initiation. A new modified protocol with glibenclamide administered several times daily according to continuous glucose monitoring profile indications, was used. Patients treated with glibenclamide maintain good metabolic control and prevent hypoglycemia, neurological damage, and apoptosis of beta cells during long-term administration.

Due to the central role in insulin secretion, the potassium inwardly-rectifying channel subfamily J member 11 (KCNJ11) gene is one of the essential genes for type 2 diabetes (T2D) predisposition. However, the relevance of this gene to T2D development is not consistent among diverse populations. In the current study, we aim to capture the possible association of common KCNJ11 variants across Iranian adults, followed by a meta-analysis. We found that the tested variants of KCNJ11 have not contributed to T2D incidence in Iranian adults, consistent with similar insulin secretion levels among individuals with different genotypes. The integration of our results with 72 eligible published case-control studies (41,372 cases and 47,570 controls) as a meta-analysis demonstrated rs5219 and rs5215 are significantly associated with the increased T2D susceptibility under different genetic models. Nevertheless, the stratified analysis according to ethnicity showed rs5219 is involved in the T2D risk among disparate populations, including American, East Asian, European, and Greater Middle Eastern, but not South Asian. Additionally, the meta-regression analysis demonstrated that the sample size of both case and control groups was significantly associated with the magnitude of pooled genetic effect size. The present study can expand our knowledge about the KCNJ11 common variant\'s contributions to T2D incidence, which is valuable for designing SNP-based panels for potential clinical applications in precision medicine. It also highlights the importance of similar sample sizes for avoiding high heterogeneity and conducting a more precise meta-analysis.

暂无摘要。

BACKGROUND Bartter syndrome is a rare genetic disease characterized by hypokalemia, metabolic alkalosis, and hyperreninemic hyperaldosteronism. Five different subtypes have been described based on the genetic defect identified. Bartter syndrome type II is caused by homozygous or compound heterozygous loss-of-function mutations in the KCNJ1 gene encoding ROMK. This subtype is typically described as a severe antenatal form of the disease, often presenting with polyhydramnios before childbirth. CASE REPORT Here, we describe the case of a 26-year-old man who presented with generalized body weakness and hypokalemia and was ultimately diagnosed with Bartter syndrome type II based on his clinical features coupled with the identification of a homozygous missense mutation in KCNJ1. CONCLUSIONS To the best of our knowledge, this is the fifth case of late-onset Bartter syndrome type II. Interestingly, the mutation identified in our patient has been previously described in patients with antenatal Bartter\'s Syndrome. The late presentation in our patient suggests a surprising degree of phenotypic variability, even in patients carrying the identical disease-causing mutation.

The KCNJ11 gene encodes the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium (KATP ) channel, which plays a key role in insulin secretion. Monogenic diseases caused by KCNJ11 gene mutation are rare and easily misdiagnosed. It has been shown that mutations in the KCNJ11 gene are associated with neonatal diabetes mellitus (NDM), maturity-onset diabetes of the young 13 (MODY13), type 2 diabetes mellitus (T2DM), and hyperinsulinemic hypoglycemia. We report four patients with KCNJ11 gene mutations and provide a systematic review of the literature. A boy with diabetes onset at the age of 1 month was misdiagnosed as type 1 diabetes mellitus (T1DM) for 12 years and received insulin therapy continuously, resulting in poor glycemic control. He was diagnosed as NDM with KCNJ11 E322K gene mutation, and glibenclamide was given to replace exogenous insulin. The successful transfer time was 4 months, much longer than the previous unsuccessful standard of 4 weeks. The other three patients were two sisters and their mother; the younger sister was misdiagnosed with T1DM at 13 years old, while the elder sister was diagnosed with diabetes (type undefined) at 16 years old. They were treated with insulin for 3 years, with poor glycemic control. Their mother was diagnosed with T2DM and achieved good glycemia control with glimepiride. They were diagnosed as MODY13 because of the autosomal dominant inheritance of two generations, early onset of diabetes before 25 years of age in the two sisters, and the presence of the KCNJ11 N48D gene mutation. All patients successfully transferred to sulfonylureas with excellent glycemic control. Therefore, the wide spectrum of clinical phenotypes of glucose dysmetabolism caused by KCNJ11 should be recognized to reduce misdiagnosis and implement appropriate treatment.
KCNJ11基因编码胰岛β细胞上ATP敏感性钾通道( KATP )的Kir6.2亚基, 是调节胰岛素分泌的重要基因。KCNJ11基因突变引起的单基因疾病较罕见, 在临床工作中容易误诊。研究表明, KCNJ11基因突变不仅可导致新生儿糖尿病(NDM), 还与青少年发病的成人糖尿病13(MODY13)、2型糖尿病(T2DM)、婴儿持续性高胰岛素血症性低血糖症(PHHI)的发生有关。本文报告了4例KCNJ11基因突变的患者并对文献进行系统回顾。 病例1是1例病程长达12年, 长期误诊为1型糖尿病(T1DM)而接受胰岛素治疗, 但血糖控制不佳、频发低血糖的糖尿病患者。询问病史发现患者为出生后1月龄起病, 行基因检测明确为KCNJ11 E322K基因突变。诊断为NDM, 予以格列本脲成功有效地替代外源性胰岛素治疗, 但转换成功的时间长达4个月, 远长于目前国际所报道的不成功标准4周。其他三例患者为一个家系, 包括两姐妹及其母亲, 先证者为家系中的妹妹, 她在13岁时被诊为T1DM, 同时姐姐在16岁时发现血糖升高, 被诊断为糖尿病(分型待定)。两姐妹使用胰岛素治疗3年, 血糖控制不佳。她们的母亲在36岁时诊断为T2DM, 口服格列美脲取得良好血糖控制。该家系有两代直系亲属患有糖尿病, 且符合常染色体显性遗传规律; 两姐妹均在25岁以前诊断糖尿病, 行基因检测明确存在KCNJ11 N48D基因突变。因此被诊断为MODY13。使用格列本脲治疗后, 两姐妹成功脱离胰岛素治疗, 且血糖控制理想。 以上病例提示我们应认识到临床上存在KCNJ11基因突变所致不同类型和不同程度的糖代谢异常, 我们需要根据患者疾病特征及时发现, 减少误诊并予以合理的精准治疗。.

Bartter syndrome subtypes are a group of rare renal tubular diseases characterized by impaired salt reabsorption in the tubule, specifically the thick ascending limb of Henle\'s loop. Clinically, they are characterized by the association of hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II. Bartter syndrome type II is caused by mutations in the renal outer medullary potassium channel (ROMK) gene (KCNJ1), can present in the newborn period and typically requires lifelong therapy.
We describe a case of a prematurely born female infant presenting with antenatal polyhydramnios, and postnatal dehydration and hyponatremia. After 7 weeks of sodium supplementation, the patient demonstrated complete resolution of her hyponatremia and developed only transient metabolic alkalosis at 2 months of age but continues to be polyuric and exhibits hypercalciuria, without development of nephrocalcinosis. She was found to have two pathogenic variants in the KCNJ1 gene: a frameshift deletion, p.Glu334Glyfs*35 and a missense variant, p. Pro110Leu. While many features of classic ROMK mutations have resolved, the child does have Bartter syndrome type II and needs prolonged pediatric nephrology follow-up.
Transient neonatal hyponatremia warrants a multi-system workup and genetic variants of KCNJ1 should be considered.

暂无摘要。

BACKGROUND: Bartter syndrome is an autosomal-recessive inherited disease in which patients present with hypokalemia and metabolic alkalosis. We present 1 case with Bartter syndrome, due to a novel compound heterozygous mutation in the KCNJ1 gene encoding the ATP-sensitive inward rectifier potassium channel in the thick ascending limb of the loop of Henle.
UNASSIGNED: A patient was admitted to our hospital because of weakness, polyuria, and polydipsia. At presentation to our hospital, the female Chinese patient was 34 years old and her physical examination was normal. Laboratory studies revealed hypokalemia, metabolic alkalosis, hypercalciuria, hyperparathyroidemia, and hyper-reninemia. In addition, urinary potassium was obviously higher. Computer tomography scan confirmed the patient had the bilateral medullary nephrocalcinosis.
METHODS: Blood samples were received from the patient and her parents, and deoxyribonucleic acid was extracted. The genetic analysis of SLC12A1, SLC12A3, KCNJ1, CLCNKB, BSND, and CASR was performed. The compound heterozygous KCNJ1 gene mutation was validated using conventional Sanger sequencing methods.
METHODS: The patient was treated with potassium supplementation. Her blood and urine chemistries improved over the next week. Serum potassium normalized with improvement in polyuria and polydipsia over the next month.
RESULTS: Our patient was compound heterozygous for Thr234Ile and Thr71Met in the KCNJ1 gene. The c.701C>T variant predicted a change from a threonine codon to an isoleucine codon (p.Thr234Ile). The c.212C>T variant predicted a change from a threonine codon to a methionine codon (p.Thr71Met). The unaffected mother was heterozygous for the Thr234Ile mutation, whereas unaffected father was heterozygous for the Thr71Met mutation.
CONCLUSIONS: The phenotypes of the patient were similar to other patients with Bartter syndrome. The phenotypes of the patient could eventually be explained by the presence of the novel compound heterozygous p.Thr234Ile/p.Thr71Met variants in the KCNJ1 gene.

Type 2 diabetes mellitus is believed to be a polygenic disorder that develops as a result of a complex interaction between multiple genes and environmental factors. KCNJ11 gene encodes a Kir6.2 protein which forms the inner section of the potassium channels in pancreatic beta cells. Several studies found that KCNJ11 polymorphism increases T2DM risk. Our study aimed to investigate the association between rs5219 polymorphism of the KCNJ11 gene and T2DM in Syrian patients.
This case-control study involved 75 T2DM patients and 63 healthy controls. The KCNJ11 rs5219 polymorphism was genotyped by Restriction Fragment Length Polymorphism (RFLP).
The frequency of the risk allele K was similar between the two groups (38.7% vs. 38.1%, P = 0.132). The frequency of the KK genotype was higher among the patients\' group (16% vs. 4.8%), and the frequency of the EK genotype was higher among the control group (45.3% vs. 66.6%); however, the differences were statistically insignificant. The KK genotype was significantly associated with T2DM in the recessive model with an OR of 3.81 (95% CI 1.024-14.17, P = 0.035).
This study showed that rs5219 polymorphism of the KCNJ11 gene is an important risk factor for type 2 diabetes mellitus in a sample of the Syrian population.