RESUMO
A 5-year-old male child with complaints of failure to thrive (since 4 months of age) and developmental delay presented to the nephrology department with complaints of weakness in all four limbs for 5 days. On examination, he was hypotensive, dehydrated, and had reduced tone in all four limbs. Biochemistry revealed acute kidney injury (AKI), hyponatremia, hypocalcemia, and hypokalemia. Renal needle biopsy (in view of unexplained AKI) revealed ropy, granular pigment casts with marked tubular injury. Myoglobin stain was positive. The positive genetic analysis of the patient (CLCNKB gene) confirmed the clinical diagnosis of Bartter syndrome (BS). The child was managed with aggressive intravenous hydration with potassium and calcium supplementation, and AKI recovered.
Assuntos
Injúria Renal Aguda , Síndrome de Bartter , Mioglobina , Humanos , Masculino , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Síndrome de Bartter/complicações , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/diagnóstico , Pré-Escolar , Mioglobina/sangueRESUMO
Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.
Assuntos
Envelhecimento , Estresse Oxidativo , Sistema Renina-Angiotensina , Sirtuína 1 , Humanos , Sistema Renina-Angiotensina/fisiologia , Envelhecimento/metabolismo , Sirtuína 1/metabolismo , Sirtuína 1/genética , Espécies Reativas de Oxigênio/metabolismo , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/genética , Síndrome de Bartter/metabolismo , Síndrome de Bartter/genética , Sódio/metabolismo , Angiotensina II/metabolismoRESUMO
The clinical presentation, treatment, and follow-up of two boys with type 1 Dent disease who exhibited a Bartter-like phenotype were retropectively analysed. The related literature of pediatric patients with type 1 Dent disease who had hypokalemia and metabolic alkalosis was screened through databases such as PubMed, CNKI, and Wanfang until February 1, 2024, and common features among these patients were summarized through literature review. A total of 7 literatures were included, and 9 children were included in the analysis. All patients were male, presenting with significant low molecular weight proteinuria and hypercalciuria. Other prominent characteristic phenotypes included short stature (7/8), hypophosphatemia (8/9), and rickets (6/8). Seven previously reported patients had missense or nonsense mutations, while 2 patients in this study carried possible pathogenic mutations in the CLCN5 gene, c.315+2T>A (p.?) and c.584dupT (p.I196Yfs*6), respectively. Five patients were able to maintain blood potassium levels around 3 mmol/L with oral potassium chloride solution combined with non-steroidal anti-inflammatory drugs (ibuprofen or indomethacin). The follow-up showed that 2 patients developed chronic kidney disease stage 4 and stage 3 at the age of 13 and 21 years, respectively. The phenotypic overlap between Dent disease and Batter syndrome is considerable,with the distinguishing feature being the presence of significant low molecular weight proteinuria. Patients with type 1 Dent disease presenting with the Bartter-like phenotype have a high prevalence of short stature, hypophosphatemia, and rickets. Non-steroidal anti-inflammatory drugs can be used to correct hypokalemia in patients under periodic renal function assessment.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Nefrolitíase , Criança , Humanos , Masculino , Síndrome de Bartter/genética , Síndrome de Bartter/diagnóstico , Canais de Cloreto/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hipercalciúria/diagnóstico , Hipercalciúria/genética , Hipopotassemia/diagnóstico , Hipopotassemia/genética , Hipofosfatemia/diagnóstico , Hipofosfatemia/genética , Mutação , Nefrolitíase/diagnóstico , Nefrolitíase/genética , Fenótipo , Proteinúria/diagnóstico , Proteinúria/genética , Raquitismo/diagnósticoRESUMO
BACKGROUND: Type III Bartter syndrome (BS) is an autosomal recessive renal tubular disease caused by the mutation of the chloride voltage-gated channel Kb (CLCNKB) gene. This condition is characterized by renal sodium loss, hypokalemia, metabolic alkaliosis, high renin, and high aldosterone levels. METHODS: We report a case of adult type III BS caused by a novel complex heterozygous mutation of the CLCNKB gene. The peripheral blood was extracted for whole genome DNA extraction, and the genome exon region of BS- related genes, was predicted by high-throughput sequencing and protein function prediction software. The selected mutation sites were verified by sequencing with Sanger method. RESULTS: The new complex heterozygous mutations of CLCNKB include heterozygous deletion of exon 2 - 20 of CLCNKB and nonsense mutation of exon 19, c.2010G>A (p.W670X). This complex heterozygous mutation has not been reported in humans. CONCLUSIONS: For patients with high clinical suspicion of BS, a clear diagnosis should be made through genetic test-ing to improve patients' quality of life and provide genetic guidance.
Assuntos
Síndrome de Bartter , Canais de Cloreto , Heterozigoto , Humanos , Síndrome de Bartter/genética , Síndrome de Bartter/diagnóstico , Canais de Cloreto/genética , Mutação , Adulto , Masculino , Feminino , Éxons/genética , Análise Mutacional de DNA , Códon sem SentidoRESUMO
Type 1 Bartter's syndrome and Gitelman's syndrome are characterized by mutations in two key renal Na+ transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg2+) and calcium (Ca2+) transport in the kidney, significant alterations in the transport of these two electrolytes are observed in type 1 Bartter's syndrome and Gitelman's syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rats to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg2+ and Ca2+ preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter patterns, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in type 1 Bartter's syndrome, nephron adaptations prevent salt wasting and favor Mg2+ preservation but not Ca2+, whereas in Gitelman's syndrome, those adaptations favor Ca2+ preservation over Mg2+. In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males.NEW & NOTEWORTHY Although changes in Ca2+ excretion in type 1 Bartter's syndrome and Gitelman's syndrome are well understood, Mg2+ excretion displays an interesting paradox. This computational modeling study provides insights into how renal adaptations in these two disorders impact Ca2+ and Mg2+ transport along different nephron segments. Model simulations showed that nephron adaptations favor Mg2+ preservation over Ca2+ in Bartter's syndrome and Ca2+ preservation over Mg2+ in Gitelman's syndrome and are stronger in females than in males.
Assuntos
Síndrome de Bartter , Síndrome de Gitelman , Magnésio , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/genética , Síndrome de Gitelman/fisiopatologia , Magnésio/metabolismo , Síndrome de Bartter/metabolismo , Síndrome de Bartter/genética , Animais , Feminino , Masculino , Cálcio/metabolismo , Ratos , Néfrons/metabolismo , Simulação por Computador , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/genética , Fatores Sexuais , Modelos Biológicos , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Membro 1 da Família 12 de Carreador de Soluto/genéticaRESUMO
Cystic fibrosis is a multisystem disease with extremely variable onset, symptoms and course. One of the onset modality but also a complication of the disease is the pseudo-Bartter syndrome, characterized by hyponatremia, hypochloremic dehydration and metabolic alkalosis in absence of any renal disease. This syndrome occurs more frequently in the first year of life and has a peak in the summer. In this article, we describe two cases of cystic fibrosis associated with pseudo-Bartter syndrome in childhood. Excluding every possible cause of metabolic alkalosis associated with hyponatremia was crucial for our diagnostic pathway, and the experience gained with the first case helped a lot with the second one.
Assuntos
Síndrome de Bartter , Fibrose Cística , Humanos , Fibrose Cística/complicações , Fibrose Cística/genética , Fibrose Cística/diagnóstico , Síndrome de Bartter/complicações , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Masculino , Feminino , Hiponatremia/etiologia , Alcalose/etiologia , Pré-Escolar , CriançaRESUMO
PURPOSE OF REVIEW: Postnatal renal tubule development is critical to adult kidney function. Several postnatal changes regulate the differentiation and proliferation of renal tubular cells. Here, we review the literature and our efforts on thick ascending limb (TAL) development in Bartter syndrome (BS). RECENT FINDINGS: Glomerular filtrate quickly increases after birth, imposing fluid shear stress and circumferential stretch on immature renal tubules. Recent studies showed that kidney organoids under flow (superfusion) have better development of tubular structures and the expression of cilia and solute transporters. These effects are likely mediated by mechanosensors, such as cilia and the piezo1 channel. Improved renal oxygenation and sodium pump-dependent active transport can stimulate mitochondrial respiration and biogenesis. The functional coupling between transport and mitochondria ensures ATP supply for energy-demanding reactions in tubular cells, including cell cycle progression and proliferation. We recently discovered that postnatal renal medulla maturation and TAL elongation are impaired in Clc-k2-deficient BS mice. Primary cultured Clc-k2-deficient TAL cells have G1-S transition and proliferation delay. These developmental defects could be part of the early pathogenesis of BS and worsen the phenotype. SUMMARY: Understanding how tubular flow and transepithelial ion fluxes regulate renal tubule development may improve the treatment of congenital renal tubulopathies.
Assuntos
Túbulos Renais , Humanos , Animais , Túbulos Renais/metabolismo , Túbulos Renais/crescimento & desenvolvimento , Síndrome de Bartter/metabolismo , Síndrome de Bartter/fisiopatologia , Síndrome de Bartter/genéticaRESUMO
BACKGROUND Bartter syndrome is a rare, inherited salt-wasting tubulopathy caused by mutations in 1 of 6 genes that express ion transport channels in the thick ascending limb of nephrons. Excessive prostaglandin E2 and associated hyperreninemic hyperaldosteronism occurs, causing polyhydramnios, polyuria, prematurity, failure to thrive, and characteristic physical features. Hypokalemia, hypochloremic metabolic alkalosis, and, depending on the affected gene, hypercalciuria and nephrocalcinosis are hallmarks of Bartter syndrome. CASE REPORT A 9-month-old male infant, born prematurely due to polyhydramnios, presented in the Emergency Department with dehydration due to incoercible vomiting and significant polyuria. A 6-year-old male infant with a previous history of prematurity due to polyhydramnios was referred to the Pediatric Endocrinology Department due to short stature and notable polydipsia and polyuria. Considering these marked symptoms, both cases triggered suspicion and started workup for arginine-vasopressin insufficiency/resistance. However, during the investigations, a broader clinical revision revealed that both had dysmorphic physical features (triangularly shaped face, prominent forehead, protruding ears, drooping mouth), poor growth, impaired weight gain, and typical biochemical findings (hypokalemic metabolic alkalosis, hypercalciuria, secondary hyperaldosteronism) of Bartter syndrome. Genetic testing confirmed the diagnosis of Bartter syndrome types 1 and type 2, respectively, and this diagnosis allowed proper treatment and significant clinical improvements, personalized follow-up, and genetic counseling for parents desiring further healthy pregnancies. CONCLUSIONS Here, we present clinical and follow-up findings of 2 patients with Bartter syndrome types 1 and 2 discovered upon a broader clinical revision of suspected arginine-vasopressin insufficiency/resistance. We also review pertinent data on diagnosis and management of this challenging syndrome.
Assuntos
Síndrome de Bartter , Humanos , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Masculino , Lactente , Criança , Arginina VasopressinaRESUMO
Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension. Given the importance of NKCC2 in salt-sensitive hypertension and the pathophysiology of prenatal BS, studying the molecular regulation of this Na-K-2Cl cotransporter has attracted great interest. Therefore, several studies have addressed various aspects of NKCC2 regulation, such as phosphorylation and post-Golgi trafficking. However, the regulation of this cotransporter at the pre-Golgi level remained unknown for years. Similar to several transmembrane proteins, export from the ER appears to be the rate-limiting step in the cotransporter's maturation and trafficking to the plasma membrane. The most compelling evidence comes from patients with type 5 BS, the most severe form of prenatal BS, in whom NKCC2 is not detectable in the apical membrane of thick ascending limb (TAL) cells due to ER retention and ER-associated degradation (ERAD) mechanisms. In addition, type 1 BS is one of the diseases linked to ERAD pathways. In recent years, several molecular determinants of NKCC2 export from the ER and protein quality control have been identified. The aim of this review is therefore to summarize recent data regarding the protein quality control of NKCC2 and to discuss their potential implications in BS and blood pressure regulation.
Assuntos
Síndrome de Bartter , Pressão Sanguínea , Membro 1 da Família 12 de Carreador de Soluto , Síndrome de Bartter/metabolismo , Síndrome de Bartter/genética , Humanos , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Animais , Degradação Associada com o Retículo EndoplasmáticoRESUMO
OBJECTIVES: To summarize the clinical characteristics and genetic variations in children with cystic fibrosis (CF) primarily presenting with pseudo-Bartter syndrome (CF-PBS), with the aim to enhance understanding of this disorder. METHODS: A retrospective analysis was performed on the clinical data of three children who were diagnosed with CF-PBS in Hunan Children's Hospital from January 2018 to August 2023, and a literature review was performed. RESULTS: All three children had the onset of the disease in infancy. Tests after admission showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, and genetic testing showed the presence of compound heterozygous mutation in the CFTR gene. All three children were diagnosed with CF. Literature review obtained 33 Chinese children with CF-PBS, with an age of onset of 1-36 months and an age of diagnosis of 3-144 months. Among these children, there were 29 children with recurrent respiratory infection or persistent pneumonia (88%), 26 with malnutrition (79%), 23 with developmental retardation (70%), and 18 with pancreatitis or extrapancreatic insufficiency (55%). Genetic testing showed that c.2909G>A was the most common mutation site of the CFTR gene, with a frequency of allelic variation of 23% (15/66). CONCLUSIONS: CF may have no typical respiratory symptoms in the early stage. The possibility of CF-PBS should be considered for infants with recurrent hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, especially those with malnutrition and developmental retardation. CFTR genetic testing should be performed as soon as possible to help with the diagnosis of CF.
Assuntos
Síndrome de Bartter , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Mutação , Humanos , Fibrose Cística/genética , Fibrose Cística/complicações , Masculino , Feminino , Lactente , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Síndrome de Bartter/genética , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/complicações , Pré-Escolar , Criança , Estudos RetrospectivosRESUMO
Bartter syndrome (BS) is a rare, inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism, hypokalemia, hypochloremia, metabolic alkalosis, and low-to-normal blood pressure. Classic BS, or BS Type 3, the most common subtype in the Asian population, is caused by a molecular defect in ClC-Kb, a voltage-gated chloride channel in renal tubules, due to CLCNKB gene mutation. Because the onset of BS is more common in children than in adults, the diagnosis, treatment outcomes, genotype/phenotype association, and follow-up of adult-onset BS Type 3 are limited. This case report describes the findings in a 20-year-old man who was admitted with hypokalemic paralysis, with clinical manifestations were similar to those of Gitelman syndrome (GS); however, the patient was later diagnosed to have BS Type 3 through genetic testing (NM_000085.4 (CLCNKB): c.1052G>T). A literature review showed that no homozygous mutations have been reported to date. After 5 years of treatment and follow-up, we found that this genotype requires high levels of potassium and is prone to urinary protein and metabolic syndrome. Distinguishing adult-onset BS from GS is challenging in clinical practice. However, genetic diagnosis can help solve this problem effectively, and genotypes play a guiding role in treatment planning.
Assuntos
Síndrome de Bartter , Canais de Cloreto , Humanos , Masculino , Adulto Jovem , Síndrome de Bartter/genética , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/complicações , Canais de Cloreto/genética , Seguimentos , Síndrome de Gitelman/genética , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/complicações , MutaçãoRESUMO
Inactivating mutations of kidney Na-K-2Cl cotransporter NKCC2 lead to antenatal Bartter syndrome (BS) type 1, a life-threatening salt-losing tubulopathy. We previously reported that this serious inherited renal disease is linked to the endoplasmic reticulum-associated degradation (ERAD) pathway. The purpose of this work is to characterize further the ERAD machinery of NKCC2. Here, we report the identification of ancient ubiquitous protein 1 (AUP1) as a novel interactor of NKCC2 ER-resident form in renal cells. AUP1 is also an interactor of the ER lectin OS9, a key player in the ERAD of NKCC2. Similar to OS9, AUP1 co-expression decreased the amount of total NKCC2 protein by enhancing the ER retention and associated protein degradation of the cotransporter. Blocking the ERAD pathway with the proteasome inhibitor MG132 or the α-mannosidase inhibitor kifunensine fully abolished the AUP1 effect on NKCC2. Importantly, AUP1 knock-down or inhibition by overexpressing its dominant negative form strikingly decreased NKCC2 polyubiquitination and increased the protein level of the cotransporter. Interestingly, AUP1 co-expression produced a more profound impact on NKCC2 folding mutants. Moreover, AUP1 also interacted with the related kidney cotransporter NCC and downregulated its expression, strongly indicating that AUP1 is a common regulator of sodium-dependent chloride cotransporters. In conclusion, our data reveal the presence of an AUP1-mediated pathway enhancing the polyubiquitination and ERAD of NKCC2. The characterization and selective regulation of specific ERAD constituents of NKCC2 and its pathogenic mutants could open new avenues in the therapeutic strategies for type 1 BS treatment.
Assuntos
Síndrome de Bartter , Degradação Associada com o Retículo Endoplasmático , Feminino , Gravidez , Humanos , Retículo Endoplasmático/metabolismo , Síndrome de Bartter/genética , Síndrome de Bartter/metabolismo , Ubiquitinação , Proteínas de Membrana/metabolismo , Membro 1 da Família 12 de Carreador de SolutoRESUMO
BACKGROUND: Antenatal Bartter syndrome is a life-threatening disease caused by a mutation in the MAGED2 gene located on chromosome Xp11. It is characterized by severe polyhydramnios and extreme prematurity. While most reported mutations are located in the exon region, variations in the intron region are rarely reported. METHODS: In our study, we employed whole exome sequencing and Sanger sequencing to genotype members of this family. Additionally, a minigene assay was conducted to evaluate the impact of genetic variants on splicing. RESULTS: Our findings reveal a novel intronic variant (NM_177433.3:c.1271 + 4_1271 + 7delAGTA) in intron 10 of the MAGED2 gene. Further analysis using the minigene assay demonstrated that this variant activated an intronic cryptic splice site, resulting in a 96 bp insertion in mature mRNA. CONCLUSIONS: Our results indicate that the novel intronic variant (c.1271 + 4_1271 + 7delAGTA) in intron 10 of the MAGED2 gene is pathogenic. This expands the mutation spectrum of MAGED2 and highlights the significance of intronic sequence analysis.
Assuntos
Síndrome de Bartter , Humanos , Feminino , Gravidez , Síndrome de Bartter/genética , Íntrons , Mutação , Splicing de RNA , China , Antígenos de Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
Type 1 Bartter syndrome causes hypokalaemia and metabolic alkalosis owing to mutation in the SLC12A1 gene. Meanwhile, hypocalcaemia is rare in Bartter syndrome, except in type 5 Bartter syndrome. Herein, we describe two siblings with type 1 Bartter syndrome with recurrent transient severe hypocalcaemia. They each visited our hospital several times with chief complaints of numbness in the limbs, shortness of breath and tetany after stresses such as exercise or fever. Severe hypocalcaemia was also observed with a serum calcium level of approximately 6.0 mg/dL at each visit. The clinical symptoms and abnormalities in laboratory findings quickly improved with rest and intravenous treatment. In a steady state, no severe hypocalcaemia was evident, but serum intact parathyroid hormone (PTH) levels were high. In recent years, a large-scale study has revealed that type 1 and type 2 Bartter syndrome have high PTH values. In addition, there are reports that these patients develop hypocalcaemia due to PTH resistance. Therefore, our patient was also in a PTH-resistant state, and hypocalcaemia was thought to be exacerbated by physical stress. It is not well known that Bartter syndrome patients other than those with type 5 suffer from hypocalcaemia. And hypocalcaemia was not detected in normal examinations under steady-state conditions. Therefore, in patients with type 1 and type 2 Bartter syndrome, severe hypocalcaemia may occur, but may go unnoticed. When following up these patients, the attending physician must keep in mind that such patients are in a PTH-resistant state and that physical stress can cause severe hypocalcaemia.
Assuntos
Síndrome de Bartter , Hipocalcemia , Humanos , Hipocalcemia/etiologia , Hipocalcemia/genética , Síndrome de Bartter/complicações , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Irmãos , Hormônio Paratireóideo , Membro 1 da Família 12 de Carreador de SolutoRESUMO
The ClC-K channels CLCNKA and CLCNKB are crucial for the transepithelial transport processes required for sufficient urinary concentrations and sensory mechanoelectrical transduction in the cochlea. Loss-of-function alleles in these channels are associated with various clinical phenotypes, ranging from hypokalemic alkalosis to sensorineural hearing loss (SNHL) accompanied by severe renal conditions, i.e., Bartter's syndrome. Using a stepwise genetic approach encompassing whole-genome sequencing (WGS), we identified one family with compound heterozygous variants in the ClC-K channels, specifically a truncating variant in CLCNKA in trans with a contiguous deletion of CLCNKA and CLCNKB. Breakpoint PCR and Sanger sequencing elucidated the breakpoint junctions derived from WGS, and allele-specific droplet digital PCR confirmed one copy loss of the CLCNKA_CLCNKB contiguous deletion. The proband that harbors the CLCNKA_CLCNKB variants is characterized by SNHL without hypokalemic alkalosis and renal anomalies, suggesting a distinct phenotype in the ClC-K channels in whom SNHL predominantly occurs. These results expanded genotypes and phenotypes associated with ClC-K channels, including the disease entities associated with non-syndromic hearing loss. Repeated identification of deletions across various extents of CLCNKA_CLCNKB suggests a mutational hotspot allele, highlighting the need for an in-depth analysis of the CLCNKA_CLCNKB intergenic region, especially in undiagnosed SNHL patients with a single hit in CLCNKA.
Assuntos
Alcalose , Síndrome de Bartter , Surdez , Perda Auditiva Neurossensorial , Humanos , Síndrome de Bartter/genética , Canais de Cloreto/genética , Estudos de Associação Genética , Genótipo , Perda Auditiva Neurossensorial/genética , MutaçãoRESUMO
BACKGROUND Gitelman syndrome (GS) is a rare inherited autosomal recessive salt-losing renal tubulopathy. Early-onset GS is difficult to differentiate from Bartter syndrome (BS). It has been reported in some cases that cyclooxygenase (COX) inhibitors, which pharmacologically reduce prostaglandin E2(PGE2) synthesis, are helpful for GS patients, especially in children, but the long-term therapeutic effect has not yet been revealed. CASE REPORT A 4-year-old boy was first brought to our hospital for the chief concern of short stature and growth retardation. Biochemical tests demonstrated severe hypokalemia, hyponatremia, and hypochloremic metabolic alkalosis. The patient's serum magnesium was normal. He was diagnosed with BS and treated with potassium supplementation and indomethacin and achieved stable serum potassium levels and slow catch-up growth. At 11.8 years of age, the patient showed hypomagnesemia and a genetic test confirmed that he had GS with compound heterozygous mutations in the SLC12A3 gene. At the age of 14.8 years, when indomethacin had been taken for nearly 10 years, the boy reported having chronic stomachache, while his renal function remained normal. After proton pump inhibitor and acid inhibitor therapy, the patient's symptoms were ameliorated, and he continued to take a low dose of indomethacin (37.5 mg/d divided tid) with good tolerance. CONCLUSIONS Early-onset GS in childhood can be initially misdiagnosed as BS, and gene detection can confirm the final diagnosis. COX inhibitors, such as indomethacin, might be tolerated by pediatric patients, and long-term therapy can improve the hypokalemia and growth retardation without significant adverse effects.
Assuntos
Síndrome de Bartter , Síndrome de Gitelman , Hipopotassemia , Adolescente , Criança , Pré-Escolar , Humanos , Masculino , Síndrome de Bartter/genética , China , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/tratamento farmacológico , Síndrome de Gitelman/genética , Transtornos do Crescimento/complicações , Hipopotassemia/tratamento farmacológico , Hipopotassemia/etiologia , Indometacina/uso terapêutico , Potássio , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismoRESUMO
Bartter syndrome is a group of rare genetic disorders that compromise kidney function by impairing electrolyte reabsorption. Left untreated, the resulting hyponatremia, hypokalemia, and dehydration can be fatal, and there is currently no cure. Bartter syndrome type II specifically arises from mutations in KCNJ1, which encodes the renal outer medullary potassium channel, ROMK. Over 40 Bartter syndrome-associated mutations in KCNJ1 have been identified, yet their molecular defects are mostly uncharacterized. Nevertheless, a subset of disease-linked mutations compromise ROMK folding in the endoplasmic reticulum (ER), which in turn results in premature degradation via the ER associated degradation (ERAD) pathway. To identify uncharacterized human variants that might similarly lead to premature degradation and thus disease, we mined three genomic databases. First, phenotypic data in the UK Biobank were analyzed using a recently developed computational platform to identify individuals carrying KCNJ1 variants with clinical features consistent with Bartter syndrome type II. In parallel, we examined genomic data in both the NIH TOPMed and ClinVar databases with the aid of Rhapsody, a verified computational algorithm that predicts mutation pathogenicity and disease severity. Subsequent phenotypic studies using a yeast screen to assess ROMK function-and analyses of ROMK biogenesis in yeast and human cells-identified four previously uncharacterized mutations. Among these, one mutation uncovered from the two parallel approaches (G228E) destabilized ROMK and targeted it for ERAD, resulting in reduced cell surface expression. Another mutation (T300R) was ERAD-resistant, but defects in channel activity were apparent based on two-electrode voltage clamp measurements in X. laevis oocytes. Together, our results outline a new computational and experimental pipeline that can be applied to identify disease-associated alleles linked to a range of other potassium channels, and further our understanding of the ROMK structure-function relationship that may aid future therapeutic strategies to advance precision medicine.
Assuntos
Síndrome de Bartter , Biologia Computacional , Humanos , Síndrome de Bartter/genética , Síndrome de Bartter/metabolismo , Degradação Associada com o Retículo Endoplasmático , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Saccharomyces cerevisiae/metabolismo , Biologia Computacional/métodos , Bases de Dados GenéticasRESUMO
BACKGROUND: Hereditary renal tubular disorders (HRTD) represent a group of genetic diseases characterized by disturbances in fluid, electrolyte, and acid-base homeostasis. There is a paucity of studies on pediatric HRTD in Egypt. In this study, we aimed to study the pattern, characteristics, and growth outcome of HRTD at an Egyptian medical center. METHODS: This study included children from one month to < 18-years of age with HRTD who were diagnosed and followed up at the Pediatric Nephrology Unit of Sohag University Hospital from January 2015 to December 2021. Data on patients` demographics, clinical features, growth profiles, and laboratory characteristics were collected. RESULTS: Fifty-eight children (57% males; 72% parental consanguinity; 60% positive family history) were diagnosed with seven HRTD types. The most commonly encountered disorders were distal renal tubular acidosis (distal renal tubular acidosis [RTA] 27 cases, 46.6%) and Bartter syndrome (16 cases 27.6%). Other identified disorders were Fanconi syndrome (6 cases with cystinosis), isolated proximal RTA (4 cases), nephrogenic diabetes insipidus (3 cases), and one case for each RTA type IV and Gitelman syndrome. The median age at diagnosis was 17 months with a variable diagnostic delay. The most common presenting features were failure to thrive (91.4%), developmental delay (79.3%), and dehydration episodes (72.4%). Most children showed marked improvement in growth parameters in response to appropriate management, except for cases with Fanconi syndrome. Last, only one case (with cystinosis) developed end-stage kidney disease. CONCLUSIONS: HRTD (most commonly distal RTA and Bartter syndrome) could be relatively common among Egyptian children, and the diagnosis seems challenging and often delayed.
Assuntos
Acidose Tubular Renal , Síndrome de Bartter , Cistinose , Anemia de Fanconi , Síndrome de Fanconi , Masculino , Humanos , Criança , Lactente , Feminino , Acidose Tubular Renal/diagnóstico , Acidose Tubular Renal/epidemiologia , Acidose Tubular Renal/genética , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/epidemiologia , Síndrome de Bartter/genética , Egito/epidemiologia , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/epidemiologia , Síndrome de Fanconi/genética , Diagnóstico TardioRESUMO
Bartter syndrome (BS) is a salt-losing hereditary tubulopathy characterized by hypokalemic metabolic alkalosis with secondary hyperaldosteronism. Confirmatory molecular diagnosis may be difficult due to genetic heterogeneity and overlapping of clinical symptoms. The aim of our study was to describe the different molecular findings in patients with a clinical diagnosis of classic BS. We included 27 patients (26 families) with no identified pathogenic variants in CLCNKB. We used a customized Ion AmpliSeq Next-Generation Sequencing panel including 44 genes related to renal tubulopathies. We detected pathogenic or likely pathogenic variants in 12 patients (44%), reaching a conclusive genetic diagnosis. Variants in SLC12A3 were found in 6 (Gitelman syndrome). Median age at diagnosis was 14.6 years (range 0.1-31), with no history of prematurity or polyhydramnios. Serum magnesium level was low in 2 patients (33%) but urinary calcium excretion was normal or low in all, with no nephrocalcinosis. Variants in SLC12A1 were found in 3 (BS type 1); and in KCNJ1 in 1 (BS type 2). These patients had a history of polyhydramnios in 3 (75%), and the mean gestational age was 34.2 weeks (SD 1.7). The median age at diagnosis was 1.8 years (range 0.1-6). Chronic kidney disease and nephrocalcinosis were present in 1 (25%) and 3 (75%) patients, respectively. A variant in CLCN5 was found in one patient (Dent disease), and in NR3C2 in another patient (Geller syndrome). Genetic diagnosis of BS is heterogeneous as different tubulopathies can present with a similar clinical picture. The use of gene panels in these diseases becomes more efficient than the study gene by gene with Sanger sequencing.