Distal Tubular Acidosis Research Articles

Autoimmune Tubulopathies.

The renal tubule and collecting duct express a large number of proteins, all having putative immunoreactive motives. Therefore, all can be the target of pathogenic autoantibodies. However, autoimmune tubulopathies seem to be rare and we hypothesize that they are underdiagnosed. This review summarizes the current knowledge on autoimmune tubulopathies. We elected to classify tubulopathies according to the segment that is targeted, because this determines, at least in part, the phenotypic presentation. In the proximal tubule, autoantibodies can cause anti-brush border antibody disease, renal Fanconi syndrome, renal proximal tubular acidosis or tubulointerstitial nephritis and uveitis syndrome. Autoantibodies targeting the thick ascending limb of the loop of Henle can cause either acquired Bartter's syndrome or hypomagnesemia with hypercalciuria, whereas autoantibodies targeting the distal convoluted tubule can cause acquired Gitelman's syndrome. Finally, renal distal tubular acidosis or nephrogenic diabetes insipidus can be caused by autoantibodies targeting the collecting duct. In most instances, the characterization of the autoantibodies remains incomplete and the pathogenesis of the disease obscure. We believe it is important to increase the awareness of the physicians regarding autoantibodies-mediated tubular diseases in order to have a better estimation of the prevalence and to improve the care to patients. A research effort to increase the understanding of the pathogenesis of autoantibodies-mediated tubular diseases is also hoped for.

Compounded medicines: tailored solution for rare diseases - the case of Urea Cycle Disorders and Primary Distal Tubular Acidosis

Introduction: Rare diseases are those with a prevalence of 1 in 2,000. These include urea cycle disorders (UCDs) and primary distal tubular metabolic acidosis (DTA). Their treatment relies on the use of oral sodium benzoate and sodium bicarbonate, respectively. The aim of this study was to formulate capsules of sodium benzoate and sodium bicarbonate of 250 mg and to demonstrate their role in the treatment of these rare diseases. Materials and Methods: A retrospective descriptive study was carried out over a 3-year period evaluating requests for compounded medicines. Formulation and quality control of sodium benzoate and sodium bicarbonate capsules dosed at 250 mg were performed according to Good Hospital Preparation Practices. Treatment efficacy and adverse effects were evaluated. Results and Discussion: A total of 10106 drugs were compounded during the study period, including 325 preparations based on drugs for metabolic disorders, i.e. 3.22% of all preparations. Sodium benzoate accounted for 12.31% and sodium bicarbonate for 10.15% of these preparations for metabolic disorders. The capsules were formulated with a consistent appearance, weight uniformity and drug content with a stability of 3 months. Treatment efficacy was followed in a population of 20 patients, 11 of whom completed the questionnaire. A male predominance was observed in patients with UCD and primary DTA, with the majority of patients with UCD and primary DTA having onset of symptoms before 1 year. Treatment efficacy was observed in 9 patients with no adverse events reported. Conclusions: The present study confirms the stability and efficacy of compounded medicines based on sodium benzoate and sodium bicarbonate in the treatment of UCD and DTA, making them an excellent alternative for their treatment.

Lithium-Induced Disruption of Intracellular Ca2+ Balance in the Collecting Duct Intercalated Cells Contributes to Metabolic Acidosis in Mice

INTRODUCTION. Lithium (Li+) is an effective mood stabilizer that continues to be widely used in modern psychiatric practice. One of the most common adverse effects of Li+ therapy is nephrogenic diabetes insipidus manifesting in reduced urinary concentrating ability due to impaired vasopressin (AVP) signaling in the collecting duct principal cells. While distal tubular acidosis has also been reported in patients receiving Li+, molecular determinants underlying the pathophysiological effects of Li+ on the collecting duct intercalated cells and renal acid-base transport remain to be fully elucidated. Activation of Gq-coupled vasopressin 1a receptors (V1aR) in A-intercalated cells reportedly induces intracellular Ca2+ ([Ca2+]i) mobilization and stimulates luminal H+ secretion, resulting in urine acidification. OBJECTIVE. The objective of this study was to test if Li+ impaired V1aR-induced [Ca2+]i response in the intercalated cells of murine collecting ducts. HYPOTHESIS. We hypothesized that Li+ markedly impaired V1aR-dependent [Ca2+]i signaling in A-intercalated cells causing the reduction of luminal proton secretion in the collecting duct. METHODS. We combined immunofluorescent imaging in freshly isolated collecting duct segments with metabolic cage studies in C57BL/6NJ (Jackson Labotatory) mice receiving a regular Teklad 2918 chow (control) or a Teklad 2918-based diet containing 0.3% lithium carbonate (Li+-treated) to evaluate how Li+ affects V1aR-mediated [Ca2+]i signal, H+ transport by intercalated cells, as well as urinary pH and ammonia excretion. RESULTS. We found that AVP elicited a transient [Ca2+]i response in the aquaporin-2 (AQP2) negative cells from collecting duct segments isolated from control mice. The response was mediated by Ca2+ release from the endoplasmic reticulum (ER), as it was inhibited by pretreatment of collecting duct segments with thapsigargin, a SERCA pump inhibitor. The amplitude of the AVP-induced calcium transient was 4 times lower in the AQP2-negative cells isolated from Li+-treated mice. Li+ intake remarkably facilitated store-operated calcium entry (SOCE) in the collecting duct cells, indicating chronic ER depletion and stress. At the systemic level Li+-treated mice exhibited urine alkalinization (by 0.8 pH units) and a 6-fold elevation in urinary ammonium excretion, when compared to controls. CONCLUSIONS. Intracellular Ca2+ signaling in the intercalated cells is an essential determinant of acid-base handling in the collecting duct. Our findings reveal that Li+ markedly alters [Ca2+]i signaling in the intercalated cells, causing urine alkalinization and elevated ammonium excretion, likely, to compensate for ensuing metabolic acidosis. NIDDK R01DK125464. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The molecular spectrum of Turkish osteopetrosis and related osteoclast disorders with natural history (including a candidate gene, CCDC120).

Osteopetrosis and related osteoclastic disorders are a heterogeneous group of inherited diseases characterized by increased bone density. The aim of this study is to investigate the molecular spectrum and natural history of the clinical and radiological features of these disorders. 28 patients and 20 families were enrolled in the study; 20 of them were followed for a period of 1-16 years. Targeted gene analysis and whole-exome sequencing (WES) were performed. Biallelic mutations in CLCN7 or TCIRG1 were detected in three families, in TNFRSF11A or CA2 in two families, and in SNX10 in one family in the osteopetrosis group. A heterozygous variant of CLCN7 was also found in one family. In the osteopetrosis and related osteoclast disorders group, three different variants of CTSK were detected in five families with pycnodysostosis and the SLC29A3 variant causing dysosteosclerosis was detected in one family. In autosomal recessive osteopetrosis (ARO), a malignant infantile form, four patients died during follow-up, two of whom had undergone hematopoietic stem cell transplantation. Interestingly, all patients had osteopetrorachia of the long bone metaphyses in infancy, typical skeletal features such as Erlenmeyer flask deformity and bone-in-bone appearance that developed toward the end of early childhood. Two siblings with a biallelic missense mutation in CLCN7 and one patient with the compound heterozygous intronic TCIRG1 variant corresponded to the intermediate form of ARO (IARO); there was intrafamilial clinical heterogeneity in the family with the CLCN7 variant. One of two patients with IARO and distal tubular acidosis was found to have a large deletion in CA2. In one family, two siblings with a heterozygous mutation in CLCN7 were affected, whereas the father with the same mutation was asymptomatic. In WES analysis of three brothers from a family without mutations in osteopetrosis genes, a hemizygous missense variant in CCDC120, a novel gene, was found to be associated with high bone mass. This study extended the natural history of the different types of osteopetrosis and also introduced a candidate gene potentially causing osteopetrosis.

Kidney manifestations of pediatric Sjögren's syndrome.

Approximately 1% of all patients with Sjögren's syndrome (SS) are children. Unlike the adult form, in which sicca syndrome is the main presentation, in children, the most common clinical finding is recurrent enlargement of the salivary glands. In pediatric SS, extraglandular manifestations represent a significant feature and, among these, kidney manifestations are relevant. Kidney involvement is observed in 5-20.5% of children with SS, most frequently tubulointerstitial nephritis. This injury can lead to serious phenotypes, including distal kidney tubular acidosis with the development of severe hypokalemia, which can lead to ECG abnormalities, weakness, and hypokalemic periodic paralysis. Kidney implications in pediatric SS also include nephrolithiasis, nephrocalcinosis, and various types of glomerular damage, which often require immunosuppressive therapies. Laboratory findings are usually comparable to adults, including hyperglobulinemia and high rates of antinuclear antibodies (ANA, 63.6-96.2%), and anti-Ro/SSA (36.4-84.6%). The current classification criteria for SS are inaccurate for the pediatric population, and more specific criteria are needed to improve the diagnostic rate. Due to the rarity of the disease, strong recommendations for treatment are lacking, and several therapeutic strategies have been reported, mostly based on glucocorticoids and disease-modifying antirheumatic drugs, with different outcomes. The aim of this paper is to provide an overview of the kidney implications of pediatric SS based on the latest evidence of the medical literature.

Acute Hypokalemic Paralysis Secondary to Distal Renal Tubular Acidosis Presenting as Guillain Barre Syndrome

A 52 year old female patient presented to emergency casualty with Acute onset quadriparesis with respiratory muscle involvement in. During initial work up Serum electrolytes showed severe hypokalemia. Arterial blood gas showed normal anionic gap metabolic acidosis with positive urine anion gap and urine examination showed alkaline PH in the presence of systemic acidosis. All these findings suggest Distal Tubular Acidosis. Further evaluation revealed strongly positive Anti nuclear antibodies with SS-A also being positive suggesting Sjogren’s Syndrome.

Lithiase urinaire de type IVa2 et pathologies associées : à propos de 3 cas

IntroductionUrinary lithiasis is a very common condition. The morpho-constitutional analysis of urinary stones is important for etiological diagnosis. It guides the explorations and the specific management. Type IVa2 stones are rare, have particular morphology and correspond to very targeted pathologies. We propose to report our cases of patients diagnosed with type IVa2 urinary lithiasis. MethodsOur retrospective work focused on three cases of patients with the morphological type of renal lithiasis IVa2, collected between 2008 and 2020 in the Medicine A Department of Charles Nicolle Hospital in Tunis. ResultsAll three patients were female; average age 37.6 years. The clinical symptomatology was identical marked by renal colic with recurrent episodes. The presence of a type IVa2 stone, isolated or associated with other components, guided the etiological investigation to look for a secondary or primary cause of distal renal tubular acidosis. We retained the diagnosis of a primary hyperparathyroidism in one case and a primary Gougerot-Sjögren's syndrome in the second case, and probable in the last case. ConclusionDetermination of urolithiasis nature (morphological and chemical), although carried out late, was of major interest to us and allowed us to make the diagnosis of distal tubular acidosis.

Particularités épidémiologiques, cliniques et évolutives de l’acidose tubulaire distale primitive chez l’enfant tunisien

IntroductionThe distal renal tubular acidosis of children is characterized by hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria and nephrocalcinosis. It is secondary to the inability of alpha intercalar cells of the distal tubule to acidify urine of genetic origin. ObjectiveTo analyse the epidemiological aspects of distal tubular acidosis in Tunisia and study its evolutionary profile. Patients and methodsWe conducted a retrospective descriptive study involving 44 patients followed at the paediatrics department of the Charles Nicolle Hospital in Tunis for 28 years (1991–2018). ResultsThe most common discovery circumstances were growth retardation (88.6%), dehydration (56.8%), ployuro-polydipsic syndrome (47.7%), vomiting (40.9%) and nephrocalcinosis (38.6%). Growth retardation was found in 52.3% of patients. Dehydration was diagnosed in 59.1% of patients on the first exam. Polyuria was constant with an average diuresis of 8 cc/kg/h. All patients had the complete form of distal renal tubular acidosis with an average alkaline reserve of 11.1 mmol/L. Nephocalcinosis was found in 77.3% associated with nepholithiasis in 22.7%. Twenty-four patients had sensorineural deafness, nine of whom had ATP6V1B1/2p13 mutation. The ATP6V0A4/7q33-34 mutation was present in two patients. We used a high alkaline treatment dose with an average maintenance dose of 8.17 mmol/kg/24 hours. In the long term, stunting persisted in 34% of patients. The mean of creatinine's clearance at the last evaluation was 89.38 mL/min/1.73 m2 SC with stage 2 of chronic kidney disease in 50% of patients. ConclusionDistal renal tubular acidosis has long been considered a benign pathology but is responsible for a progressive decline in GFD. Adequate metabolic control is needed to stabilize kidney function.

Mechanistic insights into the primary and secondary alterations of renal ion and water transport in the distal nephron.

The kidneys, by equilibrating the outputs to the inputs, are essential for maintaining the constant volume, pH, and electrolyte composition of the internal milieu. Inability to do so, either because of internal kidney dysfunction (primary alteration) or because of some external factors (secondary alteration), leads to pathologies of varying severity, leading to modification of these parameters and affecting the functions of other organs. Alterations of the functions of the collecting duct (CD), the most distal part of the nephron, have been extensively studied and have led to a better diagnosis, better management of the related diseases, and the development of therapeutic tools. Thus, dysfunctions of principal cell-specific transporters such as ENaC or AQP2 or its receptors (mineralocorticoid or vasopressin receptors) caused by mutations or by compounds present in the environment (lithium, antibiotics, etc.) have been demonstrated in a variety of syndromes (Liddle, pseudohypoaldosteronism type-1, diabetes insipidus, etc.) affecting salt, potassium, and water balance. In parallel, studies on specific transporters (H+ -ATPase, anion exchanger 1) in intercalated cells have revealed the mechanisms of related tubulopathies like distal renal distal tubular acidosis or Sjögren syndrome. In this review, we will recapitulate the mechanisms of most of the primary and secondary alteration of the ion transport system of the CD to provide a better understanding of these diseases and highlight how a targeted perturbation may affect many different pathways due to the strong crosstalk and entanglements between the different actors (transporters, cell types).

Molecular Aspects of Distal Kidney Tubular Acidosis in Children, Its Long-Term Outcome, and Relationship with Hyperammonemia.

Objective:We aimed to present the characteristics, genetic analysis results, long-term prognosis of our patients with distal kidney tubular acidosis, and the relationship between hyperammonemia and distal kidney tubular acidosis.Materials and Methods:Biochemical, clinical, and imaging findings were collected at presentation and the last clinic visit, and results of the genetic analysis were recorded.Results:Our study included 9 patients (3 female, 33%). The median age at diagnosis was 3 months, and the median follow-up period was 111 months. Height standard deviation scores were less than −2 in 4 (44%) patients at presentation and in 3 (33%) at the last clinic visit. The median estimated glomerular filtration rate was 98 mL/min/1.73 m2 at presentation and 126 mL/min/1.73 m2 at the last clinic visit. We have found 8 different types of mutations of 2 genes, including 6 in the ATP6V0A4 gene, 2 in the SLCA4A1 gene, and 2 of them were novel. At the time of presentation, nephrocalcinosis and hypercalciuria were present in all our patients, but at the last visit, only 1 patient had hypercalciuria. Sensorineural hearing loss was found in 4 of our patients with a mutation in the ATP6V0A4 gene. Serum ammonia levels were found to be high in 3 patients with mutations in the ATP6V0A4 gene.Conclusion:Adequate metabolic control is essential for optimal growth and preserved kidney function in distal kidney tubular acidosis patients. Distal kidney tubular acidosis may be associated with hyperammonemia. We recommend keeping potassium levels at high-normal levels to reduce ammonia levels, especially in the absence of acidosis.

Long-term complications of primary distal renal tubular acidosis.

The clinical manifestations of primary distal renal tubular acidosis usually begin in childhood, but the disease is caused by a genetic defect that persists throughout life. This review focuses on the complications of distal tubular acidosis that occur or remain long-term such as nephrocalcinosis and urolithiasis, growth impairment, bone mineralization, severe hypokalemia, kidney cysts, and progressive kidney failure, as well as other persistent manifestations that occur independent of acidosis but are associated with some inherited forms of the disease. The pathogenic factors responsible for kidney failure are discussed in particular because it is a complication to which different publications have recently drawn attention and which affects a high percentage of adults with primary distal renal tubular acidosis. The need to maintain optimal metabolic control of the disease and scheduled clinical follow-up throughout life and the importance of organizing protocols for the transition of patients to adult nephrology services are emphasized.

Young Adults With Hereditary Tubular Diseases: Practical Aspects for Adult-Focused Colleagues.

Recent advances in the management of kidney tubular diseases have resulted in a significant cohort of adolescents and young adults transitioning from pediatric- to adult-focused care. Most of the patients under adult-focused care have glomerular diseases, whereas rarer tubular diseases form a considerable proportion of pediatric patients. The purpose of this review is to highlight the clinical signs and symptoms of tubular disorders, as well as their diagnostic workup, including laboratory findings and imaging, during young adulthood. We will then discuss more common disorders such as cystinosis, cystinuria, distal kidney tubular acidosis, congenital nephrogenic diabetes insipidus, Dent disease, rickets, hypercalciuria, and syndromes such as Bartter, Fanconi, Gitelman, Liddle, and Lowe. This review is a practical guide on the diagnostic and therapeutic approach of tubular conditions affecting young adults who are transitioning to adult-focused care.

Metabolic Acidosis and Hyponatremia in a Patient With Metastatic Melanoma

Metabolic Acidosis and Hyponatremia in a Patient With Metastatic Melanoma

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

Metabolic investigation of stone formers

Metabolic investigation of stone formers Abstract. Once a kidney stone has passed, patients must be carefully evaluated in order to identify the underlying cause of the disease and to guide preventive measures and treatment. General recommendations can be offered to all kidney stone formers, but personalized counseling and follow-up adaptations need to be guided by in-depth assessment. Metabolic evaluation for recurrent stone formers is based on 24 h urine collection. This allows a comprehensive understanding of the dietary habits of the patient and helps identifying treatable metabolic diseases and renal tubulopathies. Additional specific assessments may include urine acidification test (in case of suspected partial renal distal tubular acidosis), characterization of hypercalciuria or osteodensitometry. Metabolic evaluation often needs to be repeated over time to guide therapeutic interventions, both dietetic and drug-related.

POS-441 NEPHROCALCINOS IN ADULTS: EPIDIMIOLOGICAL PROFILE

Nephrocalcinosis is defined by the presence of calcium deposits in the renal tubules resulting from an imbalance between lithogenesis promoters and lithogenesis inhibitors. The diagnosis can be made with ultrasonography. We seek to study the particularities of this disorder in adults and its etiologies. This is a retrospective study of the macroscopic nephrocalcinosis cases in adults treated in our department from January 1986 to October 2020 26 cases were diagnosed at a mean age of 35.28 years old with extremes ranging from 11 to 79 years old. The sex ratio M/F was 1. More than half of the patients had a family history of urolithiasis. Nephrocalcinosis was suspected following renal colic in 13 cases, a polyuropolydipsic syndrome in 4 case, a hypokaliemia in 2 case, an urolithiasis in 2 case and a renal impairment in 2 case. In 3 case, the diagnosis was made fortuitly with an ultrasonography. The etiologies found were: familial distal tubular acidosis (6 cases), distal tubular acidosis caused by Sjögren’s syndrome (4 cases), primitive oxalosis (3 case), Cacci Ricci syndrome (3 cases), familial hypomagnesemia hypercalciuria (2 case), Dent syndrome (1 case) and no causes found (7 cases). Follow-up showed stabilization of renal function in 18 cases and the evolution into chronic kidney disease in 6 cases: 2 of them requiring renal replacement therapy after 5 years and the other died. Nephrocalcinosis is prevalent both in children and adults. Its etiologies are numerous. Most of the metabolic disorders are genetic. The diagnosis of nephrocalcinosis requires a deep investigation with a global clinical assessment, laboratory tests and radiological evaluation. The final objective is to prevent ESKD.

POS-446 SPECIFIC FEATURES AND OUTCOME OF NEPHROCALCINOSIS IN CHILDREN: ABOUT A SERIES OF 30 CASES

Nephrocalcinosis is a rare pediatric renal disease resulting in calcifications of the kidney tissue. It comes from various causes, especially genetic mutations. Management is based on symptomatic measures and treatment of the underlying condition. The aim of this study (from January 2010 to June 2020) is to underly the specific features of nephrocalcinosis in our pediatric population. For this, we gathered retrospective data of 30 children diagnosed with nephrocalcinosis. The mean age at diagnosis was of 3,5 years. One-third of our patients had first-degree consanguineous parents, while two-thirds of them were males. Similar cases in siblings and family members were absent. The majority of children presented with polyuria, polydipsia, and dehydration at diagnosis. Also, half of them had simultaneous urologic calculus. In five cases, nephrocalcinosis was discovered on routine abdominal ultrasound while the children were asymptomatic. The sonographic classification was in favor of stage III nephrocalcinosis in 23 cases. The underlying disease was represented mostly by tubulopathies in 40% of cases. Distal tubular acidosis was predominant. Nephrocalcinosis secondary to recurrent urinary tract infections was seen in 10% of our children. While, prematurity, primary hyperoxaluria, and familial hypercalciuria were rare (both seen in 10% of children). One child developed chronic kidney disease stage II after a follow up of seven years. Meanwhile, management was successful in stopping the evolution of the disease in all the remaining cases. It consisted on hyperhydration in all cases, alkalinization of urine in the case of acidosis, along with the specific treatment of the underlying disease. Early management of nephrocalcinosis in children can prevent the evolution of chronic kidney disease. Systematic screening should be implemented in high-risk children, especially those with tubulopathies. The high frequency of consanguineous marriages in our population suggests a genetic predisposition that needs to be proven by further studies.

Atteinte rénale au cours du syndrome de Sjögren

Primary Sjögren syndrome is an autoimmune disorder characterized by lymphoplasmacytic infiltration of the exocrine (salivary and lachrymal) glands resulting in sicca symptoms (dryness). Systemic complications can occur in primary Sjögren syndrome, but renal involvement is rare, affecting<10% patients. The most frequent form of nephropathy in primary Sjögren syndrome is tubulointerstitial nephritis, where infiltration of the kidney by plasma cells is a key feature and shows similarity to the lymphoplasmacytic infiltration of the salivary glands. Electrolyte disturbances may occur in primary Sjögren syndrome, such as renal distal tubular acidosis, diabetes insipidus, Gitelman syndrome, or Fanconi syndrome. Glomerular involvement is less frequently detected in patients with primary Sjögren syndrome, but can take the form of membranoproliferative glomerulonephritis secondary to cryoglobulinaemia. The renal prognosis in patients with primary Sjögren syndrome and TIN or glomerular disease is usually good, but the risk of chronic kidney disease remains significant for some patients. Appropriate screening must be performed at least once a year in patients with systemic primary Sjögren syndrome in order to facilitate the early detection of renal complications. In this Review, we discuss the epidemiology, pathophysiology, differential diagnosis, and treatment of renal disease in primary Sjögren syndrome.

Evaluation of phenotypic and genotypic features of children with distal kidney tubular acidosis.

The present study aimed to assess genotype-phenotype correlations with long-term prognosis in children with distal kidney tubular acidosis (dKTA). The kidney function of children with dKTA could be impaired in the long-term. Thirty-one children with dKTA from 23 families were included in the present study. Demographic features, growth parameters, clinical manifestations, follow-up results, and genetic analysis results of the patients were recorded. Eighteen children (58.1%) were male. The median age at diagnosis was 3months. The median follow-up period was 77months and the longest was 23.5years. Eight (28.8%) patients had chronic kidney disease (CKD) stage 2 or 3. Three patients aged 24, 23, and 19years had CKD stage 3 with an estimated glomerular filtration rate of 54, 57, and 48mL/min/1.73m2, respectively. Thirteen patients had mutations in the ATP6V0A4 gene, eight had mutations in the ATP6V1B1 gene, and three had mutations in the SLC4A1 gene. There was no significant correlation between molecular diagnosis and CKD. Growth retardation with a height below a standard deviation (SD) score of - 2 was found in 14 patients (45.1%) at the time of diagnosis. The mean height SD score at the last visit was significantly higher in patients who had adequate metabolic control at > 75% of all visits as compared with that in patients who did not. Patients with dKTA usually have a good clinical prognosis in childhood with appropriate treatment; however, dRTA is characterized by deterioration of kidney function in adulthood, particularly after puberty.

P0084DIGENIC INHERITANCE: TWO RARE CASES OF GITELMAN SYNDROME

Abstract Background and Aims The clinical implementation of whole-exome sequencing (WES) as molecular diagnostic tool allows investigation of the pathogenic variants interplay in multiple genes resulting in complex spectrum of phenotypes in a same patient. The phenotypic complexity of genetic disease in patients with multiple molecular diagnoses is a challenge. The blending of two distinct disease phenotypes in a same patient may suggest an apparently new clinical phenotype, while molecular diagnoses with two overlapping disease phenotypes may result in phenotypic expansion of a single disease. We present two autosomal recessive Gitelman syndrome (GS) patients whose pathogenic variants in two different genes challenged us for clinical interpretation and therapeutic intervention. Method Case 1: GS diagnosis at 4 years of age, severe clinical phenotype (appearance at unusual early age, hypochloremia, borderline hypomagnesemia resembling Bartter syndrome (BS), need of more complex therapy. Case 2: The diagnosis of GS was made at the age of 45 years. The patient presented classical signs of GS, with less marked metabolic alkalosis and unusual chronic renal insufficiency (CRI). Exome sequencing panel was used for mutational screening of Bartter (BS) and GS genes. Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) were also applied. Results Case 1: We detected in the SLC12A3 gene the frameshift p.(Thr7Arfs) and the missense p.(Gly264Ala) variants, the first a known disease-causing mutation, the second associated with a severe form of GS in a patient. Another known disease-causing mutation p.(Met357Thr) was detected in the KCNJ1 gene encoding renal outer medullary K+ channel, ROMK1. It is one BS gene and was never associated with GS. The SLC12A3 p.(Gly264Ala) variant’s high frequency makes it uncommon polymorphism although functional because it alters NCC activity but makes questionable its causative effect on GS phenotype. Our patient severe GS phenotype may be determined by the mutations in either SLC12A3 and KCNJ1 genes inherited respectively from mother and father. If the hypomorphic SLC12A3 variant is causative, hence the heterozygous KCNJ1 pathogenic variant might be a modifier allele responsible of the GS severe presentation. Case 2: We detected two novel variants in the SLC12A3 gene [p.(Lys894fs):p.(Pro331Leu)]. Both are pathogenic according to ACMG guidelines. Another very rare missense variant p.(Val245Met) was identified in the SLC4A1 gene, whose mutations cause distal tubular acidosis type I (dRTA). The missense mutation, never associated with dRTA, is predicted pathogenic by in silico tools. Its presence questions on phenotype interpretation: blended phenotype due to a concomitant presence of a dual molecular diagnosis? Or an expansion of a single phenotype (GS) due to the presence of a modifier gene variant? dRTA and GS have overlapping features such as hypokalemia, hypercalciuria. In the patient the less marked metabolic alkalosis, and the presence of CRF points to the latter. Conclusion Digenic inheritance in GS was reported in only one other instance. These two cases demonstrate how our understanding of the complexity of genetic heterogeneity of rare diseases is far to be completed. It becomes essential to shed light on how combinations of variants in different genes are responsible for a disease phenotype