Síndrome de Gitelman: cuándo sospecharlo / Gitelman syndrome, when to suspect it

Las tubulopatías son un grupo heterogéneo de entidades definidas por anomalías de la función tubular renal. El síndrome de Gitelman, objeto de nuestro artículo, está causado por mutaciones inactivantes del gen SLC12A3, que codifica el cotransportador Na-Cl sensible a tiazidas del túbulo contorneado distal, produciendo así una pérdida urinaria de Cl-Na. Se exponen tres casos clínicos de síndrome de Gitelman, cada uno con una clínica de presentación. La finalidad de este artículo es sensibilizar al lector en esta tubulopatía y ayudar en su diagnóstico precoz (AU)

Tubulopathies are a heterogeneous group of entities defined by abnormalities of renal tubular function. Gitelman syndrome, the subject of our article, is caused by inactivating mutations of the SLC12A3 gene, which encodes the thiazide-sensitive Na-Cl cotransporter of the distal convoluted tubule, thus producing a urinary loss of Cl-Na.Three clinical cases of Gitelman syndrome are presented, each with a clinical presentation. The purpose of this article is to familiarize the reader with this tubulopathy and to help in its early diagnosis. (AU)

Gitelman syndrome, a rare cause of refractory hypokalemia. A case report / Símdrome de Gitelman, causa rara de hipopotasemia refractaria. Reporte de caso

Abstract Introduction: Gitelman syndrome is a rare hereditary primary renal tubular disorder, with a prevalence of approximately 1 to 10 cases per 40 000 people. It does not have specific symptoms, so its diagnosis depends on high clinical suspicion by the treating physical and a sequential approach to hypokalemia, especially in young patients. Thus, a diagnostic algorithm is proposed at the end of this report. Case presentation: A 23-year-old woman with a history of hospitalization due to hypokalemia presented to the emergency service with intermittent cramping in her lower limbs, which was exacerbated by gastrointestinal symptoms. Laboratory tests reported the following findings: metabolic alkalosis, elevated levels of potassium, magnesium, chloride and sodium in urine, and reduced levels of calcium in urine. Thus, potassium supplementation and eplerenone administration were started, obtaining the complete resolution of symptoms. At her last follow-up appointment, the patient was asymptomatic, and her serum electrolyte levels were normal. In addition, during her hospital stay and due to the high suspicion of Gitelman syndrome, a genetic study was performed, which reported a mutation of the SCL12A3 gene, confirming the diagnosis. Conclusion: The sequential approach to a patient with recurrent hypokalemia is very important to reach an accurate diagnosis among a wide range of differential diagnoses.

Resumen Introducción. El síndrome de Gitelman es un trastorno tubular renal primario hereditario poco frecuente, con una prevalencia aproximada de 1 a 10 casos por cada 40 000 personas; su sintomatologia es inespecífica, por lo que su diagnóstico depende de la alta sospecha clínica por parte del médico tratante y de un abordaje secuencial de la hipopotasemia, sobre todo en pacientes jóvenes, para lo cual se propone un algoritmo diagnóstico al final de este reporte. Presentación de caso. Mujer de 23 años con antecedente de hospitalización por hipopotasemia, quien consultó por calambres musculares intermitentes en miembros inferiores, los cuales se agudizaron debido a síntomas gastrointestinales. En los exámenes de laboratorio se reportaron los siguientes hallazgos: alcalosis metabólica, niveles elevados de potasio, magnesio, cloro y sodio en orina, y niveles reducidos de calcio en orina, por lo que se inició suplementación de potasio y manejo con eplerenona, obteniéndose resolución completa de los síntomas. En su último control, la paciente se encontraba asintomática y sus niveles séricos de electrolitos eran normales. Además, durante la hospitalización, y debido a la alta sospecha de síndrome de Gitelman, se solicitó estudio genético que reportó mutación del gen SCL12A3, confirmándose el diagnóstico. Conclusión. El abordaje secuencial de un paciente con hipopotasemia recurrente es de gran importancia para realizar un diagnóstico certero ante una amplia gama de diagnósticos diferenciales.

Hipokalemia de gradiente transtubular alto: una propuesta práctica para su enfoque / High transtubular gradient hypokalemia: a practical proposal for its focus

Resumen El potasio es un ion de predominio intracelular involucrado en múltiples funciones esenciales para mantener la homeostasis celular. Por lo anterior, sus concentraciones a nivel plasmático se encuentran estrechamente reguladas mediante el sistema renal y endocrino, además de estar afectado ante situaciones como la acidosis, cambios en la osmolaridad plasmática y concentración de otros electrolitos. La hipokalemia es un trastorno electrolítico común en la práctica clínica causado por el aporte inadecuado o pérdidas excesivas. Su enfoque diagnóstico requiere de una apropiada historia clínica que incluya antecedentes personales patológicos, farmacológicos, y un examen físico detallado con determinación del estado de volemia e hidratación del paciente, así como la medición de otros electrolitos a nivel plasmático y ocasionalmente en orina. El gradiente transtubular de potasio es una herramienta útil para direccionar posibles causas. Dentro de las causas de hipokalemia de gradiente transtubular elevado se encuentra el síndrome de Bartter.

Abstract Potassium is a predominantly intracellular ion involved in multiple essential functions to maintain cellular homeostasis. Therefore, its variations at the plasma level are tightly regulated by the renal and the endocrine systems; in addition to being affected by situations such as acidosis, changes in plasma osmolality and concentration of another electrolytes. Hypokalemia is a common electrolyte disorder in clinical practice affected by reporting excessive damage or loss. Its diagnostic approach requires a complete medical record that includes personal pathological and pharmacological information, a specific physical examination with certain conditions like patient's blood volume and hydration status, as well as the measurement of other electrolytes at the plasma level and occasionally in urine. The transtubular potassium gradient is a useful tool to address possible causes. Bartter syndrome is one of the causes of elevated transtubular gradient hypokalemia.

Outcome of primary tubular tubulopathies diagnosed in pediatric age.

BACKGROUND AND OBJECTIVE: Primary tubulopathies are rare and usually present at pediatric age. Recent advances in genetic diagnosis and treatment have changed its natural history. This study provides the clinical spectrum of a series of primary tubulopathies diagnosed in a Pediatric Nephrology Unit and to offer long-term follow-up data regarding growth, estimated glomerular filtration (eGFR) and intercurrent complications. PATIENTS AND METHODS: Observational study in 53 patients with primary tubulopathies and identified genetic defect: Gitelman syndrome (36%), distal renal tubular acidosis (15%), cystinuria (11%), X-linked hypophosphatemic rickets (7%), Dent-syndrome Lowe (7%), cystinosis (6%), and 1-2 cases of other tubulopathies. Demographic, analytical and clinical data were collected at diagnosis, during evolution and at the time of the study. RESULTS: The age (median and interquartile range) at diagnosis was 5.08 years (1.33-8.50). The most frequent presentation manifestations were metabolic decompensations associated with intercurrent processes (40%) and short stature (38%). Height (mean ±â€¯SD) was -1.39 ±â€¯1.49 at diagnosis and 1.07 ±â€¯1.54 after a follow-up of 18.92 (6.25-24.33) years. Sixteen (32%) developed an eGFR <90 ml/min/1.73 m2. Three patients required replacement renal replacement. Eleven patients had metabolic decompensations that required hospitalization, 9 renal colic and/or kidney stones and 10 mental problems. Six of 8 patients with distal renal tubular acidosis developed sensorineural deafness. CONCLUSIONS: Primary tubulopathies are a heterogeneous group of diseases that cause growth impairment, largely reversible with treatment, risk of eGFR reduction and significant extrarenal complications derived or associated.

Outcome of primary tubular tubulopathies diagnosed in pediatric age. / Evolución de tubulopatías renales primarias diagnosticadas en edad pediátrica.

BACKGROUND AND OBJECTIVE: Primary tubulopathies are rare and usually present at pediatric age. Recent advances in genetic diagnosis and treatment have changed its natural history. This study provides the clinical spectrum of a series of primary tubulopathies diagnosed in a Pediatric Nephrology Unit and to offer long-term follow-up data regarding growth, estimated glomerular filtration and intercurrent complications. PATIENTS AND METHODS: Observational study in 53 patients with primary tubulopathies and identified genetic defect: Gitelman syndrome (36%), distal renal tubular acidosis (15%), cystinuria (11%), X-linked hypophosphatemic rickets (7%), Dent-syndrome Lowe (7%), cystinosis (6%), and 1-2 cases of other tubulopathies. Demographic, analytical and clinical data were collected at diagnosis, during evolution and at the time of the study. RESULTS: The age (median and interquartile range) at diagnosis was 5.08 years (1.33-8.50). The most frequent presentation manifestations were metabolic decompensations associated with intercurrent processes (40%) and short stature (38%). Height (mean±SD) was -1.39±1.49 at diagnosis and 1.07±1.54 after a follow-up of 18.92 (6.25-24.33) years. Sixteen (32%) developed an estimated glomerular filtration<90ml / min / 1.73m2. Three patients required replacement renal replacement. Eleven patients had metabolic decompensations that required hospitalization, 9 renal colic and / or kidney stones and 10 mental problems. Six of 8 patients with distal renal tubular acidosis developed sensorineural deafness. CONCLUSIONS: Primary tubulopathies are a heterogeneous group of diseases that cause growth impairment, largely reversible with treatment, risk of estimated glomerular filtration reduction and significant extrarenal complications derived or associated.

Diagnóstico de síndrome de Gitelman en paciente con condrocalcinosis / Diagnosis of gitelman syndrome in patient with condrocalcinosis

RESUMEN Introducción: El síndrome de Gitelman es una tubulopatía caracterizada por alcalosis metabólica hipopotasémica, hipomagnesemia e hipocalciuria. Sus efectos musculoesqueléticos son comunes, pudiendo provocar desarrollo de condrocalcinosis. Caso clínico: Paciente con condrocalcinosis de larga data asociada a hipomagnesemia crónica en tratamiento con calcio y magnesio. Tras la suspensión del tratamiento debido a una intervención quirúrgica presentó debilidad generalizada, alcalosis metabólica, hipopotasemia, hipomagnesemia e hipocalciuria con diagnóstico final de síndrome de Gitelman. Tras la instauración de tratamiento, mejoró clínica y analíticamente manteniendo cifras iónicas estables. Discusión y conclusiones: Resulta fundamental un adecuado diagnóstico de este tipo de tubulopatías, ya que un tratamiento adecuado evita complicaciones asociadas.

ABSTRACT Introduction: Gitelman syndrome is a renal tubule disease that involves hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria. The musculoskeletal effects of Gitelman syndrome are common, including the development of chondrocalcinosis. Clinical case: A female patient with long-standing chondrocalcinosis associated with chronic hypomagnesaemia on treatment with calcium and magnesium. After the suspension of the treatment due to surgery, she presented with a generalised weakness, metabolic alkalosis, hypokalaemia, hypomagnesaemia and hypocalciuria, with final diagnosis of Gitelman syndrome. After re-introducing the treatment, she improved clinically, with electrolytes remaining stable. Discussion and conclusions: A proper diagnosis of this type of tubular diseases is essential because an adequate treatment avoids associated complications.

Síndrome de Gitelman / Gitelman syndrome

El síndrome de Gitelman forma parte de las denominadas tubulopatías perdedoras de sal. El bloqueo parcial de la reabsorción de sodio en el túbulo contorneado distal determina la aparición de hipokalemia e hipomagnesemia. Se realizó un estudio descriptivo de una serie de cinco casos de síndrome de Gitelman (4 mujeres, de 28 a 85 años de edad) atendidos en nuestra institución entre los años 2004 y 2015. La forma de diagnóstico más frecuente en nuestra serie fue por hallazgo de laboratorio. El único síntoma clínico manifestado en forma espontánea fue astenia. En cuanto a los valores de laboratorio, la potasemia fue 2.5 ± 0.5 mmol/l, con un valor mínimo de 2.1. Adicionalmente, el valor de magnesio en sangre fue 1.3 ± 0.3 mg/dl. Como conclusión, observamos que las formas de presentación consisten en alteraciones bioquímicas con o sin manifestaciones inespecíficas, lo que representa actualmente la mayor dificultad diagnóstica y refuerza la importancia de lograr un diagnóstico oportuno, en especial en pacientes jóvenes y con valores críticos de potasio sérico.

Gitelman syndrome is one of the salt losing tubulopathies. Hypokalemia and hypomagnesemia appear in the setting of the partial blockade of salt absorption in the distal tubule. We conducted a descriptive study of a case series of five patients with Gitelman syndrome (4 women, from 28 to 85 years) in our institution, between the years 2004 and 2015. The most frequent form of diagnosis in our series was by laboratory finding. The only acknowledged clinical symptom was malaise. Regarding laboratory findings, the mean potassemia was of 2.5 ± 0.5 mmol/l, with a minimum value of 2.1 mmol/l. Additionally, the serum magnesium value was of 1.3 ± 0.3 mg/dl. In conclusion, we observed that the forms of presentation consist of biochemical alterations with or without nonspecific manifestations, which currently represents the greatest diagnostic difficulty and reinforces the importance to achieve a timely diagnosis, especially in young patients with critical serum potassium values.

Persistent severe hypokalemia: Gitelman syndrome and differential diagnosis / Hipocalemia grave persistente: Síndrome de Gitelman e diagnósticos diferenciais

Abstract The main causes of hypokalemia are usually evident in the clinical history of patients, with previous episodes of vomiting, diarrhea or diuretic use. However, in some patients the cause of hypokalemia can become a challenge. In such cases, two major components of the investigation must be performed: assessment of urinary excretion potassium and the acid-base status. This article presents a case report of a patient with severe persistent hypokalemia, complementary laboratory tests indicated that's it was hypomagnesaemia and hypocalciuria associated with metabolic alkalosis, and increase of thyroid hormones. Thyrotoxic periodic paralysis was included in the differential diagnosis, but evolved into euthyroid state, persisting with severe hypokalemia, which led to be diagnosed as Gitelman syndrome.

Resumo As principais causas de hipocalemia normalmente são evidentes na história clínica dos pacientes em investigação etiológica, com episódios prévios de vômitos, diarréia ou uso de diuréticos. Entretanto, em alguns pacientes, a causa da hipocalemia pode se tornar um desafio. Em tais casos, dois principais componentes da investigação devem ser realizados: avaliação da excreção do potássio urinário e do "status" ácido-básico. Este artigo traz um relato de caso de uma paciente portadora de hipocalemia grave persistente, com investigação laboratorial complementar caracterizada por hipomagnesemia e hipocalciúria, associada à alcalose metabólica e elevação dos hormômios tireoideanos. A apresen- tação inicial do quadro incluiu paralisia periódica tireotóxica como um dos principais diagnósticos diferenciais, porém, a paciente evoluiu para um es- tado eutireoideo e persistiu com grave hipocalemia, sendo, por fim, realizado diagnóstico clínico de Síndrome de Gitelman.

A new SLC12A3 founder mutation (p.Val647Met) in Gitelman's syndrome patients of Roma ancestry.

BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive disorder caused by mutations in the SLC12A3 gene. GS is characterized by hypokalaemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Most of the reported patients of Roma ancestry are homozygous for an SLC12A3 intron 9 frameshifting mutation (c.1180+1G>T). Some forms of Bartter's syndrome result from mutations in the CLNCKB gene and clinically overlap with GS. OBJECTIVES: To characterize a second SLC12A3 mutation in Roma patients negative for the intron 9 variant. METHODS: SLC12A3 and CLNCKB genes were analyzed by next-generation sequencing in two Spanish and Greek gypsy patients who were negative for the intron 9 splicing mutation. Sanger sequencing was performed to confirm the putative mutations in patients and family members. RESULTS: We identified a missense variant (p.Val647Met, c.1939G>A) in both cases, and both were homozygous for Met. This mutation was also found in three additional patients; two homozygous and one heterozygous compound with the intron 9 splicing mutation. This new SLC12A3 mutation seems to be characteristic of gipsy GS patients and was linked to the same haplotype in all cases, supporting a founder origin. All the patients showed biochemical features characteristic of GS. CONCLUSION: We report a second founder mutation among GS patients of Roma ethnic background. The direct screening of this mutation would facilitate the characterization of patients who are negative for the more common intron 9 +1G>T mutation.

Transient hyperphosphatemia: a benign laboratory disorder in a boy with Gitelman syndrome / Hiperfosfatemia transitória: uma alteração laboratorial benigna em um menino com síndrome de Gitelman

Abstract Transient hyperphosphatasemia of infancy and early childhood (THI) is characterized by transiently increased activity of serum alkaline phosphatase (S-ALP), predominantly its bone or liver isoform, in children under five years of age. There are no signs of metabolic bone disease or hepatopathy corresponding with the increased S-ALP. THI is benign disorder, rather laboratory than clinical disorder, which is usually accidentally detected in both healthy and sick children. When encountered in a child with either chronic bone, liver or kidney disease, it might concern the physician. We present a three year old boy with genetically confirmed Gitelman syndrome where THI was detected accidentally during periodic check-up. S-ALP peaked to 41.8 µkat/L, there were neither laboratory or clinical signs of liver or bone disease; the S-ALP dropped to normal value of 4 µkat/L 60 days later. Therefore, the patient fulfilled the criteria for THI. There were no further increases in S-ALP.

Resumo A hiperfosfatasemia transitória benigna da infância (HTBI) é caracterizada por elevação transitória da atividade da fosfatase alcalina sérica (S-ALP), predominantemente em sua isoforma óssea ou hepática, em crianças com menos de cinco anos de idade. Não há sinais de patologia óssea metabólica ou hepatopatia correspondentes ao aumento da S-ALP. A HTBI é um distúrbio benigno, mais laboratorial que clínico, normalmente detectado acidentalmente em crianças saudáveis e acometidas por alguma patologia. Quando encontrada em crianças com doença crônica óssea, hepática ou renal, maiores preocupações são justificadas. O presente relato descreve o caso de um menino de três anos de idade com síndrome de Gitelman geneticamente confirmada, em que a HTBI foi detectada acidentalmente durante um exame periódico. A S-ALP atingiu o pico de 41,8 µkat/L, sem sinais laboratoriais ou clínicos de doença hepática ou óssea. O valor de S-ALP caiu para o nível normal de 4 µkat/L 60 dias mais tarde. Portanto, o paciente satisfazia os critérios para HTBI. Não houve outros aumentos na S-ALP.

Aspectos clínicos, fisiopatológicos e genéticos das tubulopatias hereditárias na infância / Clinical, pathophysiological and genetic aspects of inherited tubular disorders in childhood

ResumoNesta revisão, descrevemos a função tubular de cada segmento do néfron seguida das descrições das principais alterações moleculares que possam ocorrer nos transportadores expressos nestes locais. Assim, o conhecimento das modificações na função tubular renal permite o entendimento e o reconhecimento clínico das doenças tubulares renais que podem causar a morte fetal, neonatal ou infantil. Além disso, as crianças com tubulopatias podem evoluir para doença renal crônica terminal numa fase precoce da vida e também podem apresentar distúrbios do crescimento e do desenvolvimento acompanhados ou não de alterações neurológicas. Então, nós utilizamos o unitermo "inherited tubular disorders" a fim de selecionar na base de dados do PubMed os estudos publicados desde 2006. Esperamos que a leitura desta revisão auxilie no rápido diagnóstico dos pacientes com tubulopatias, o que poderá permitir o tratamento especializado e a possível melhora do prognóstico e qualidade de vida destes indivíduos.

AbstractIn this review, we described the tubular function of each nephron segment followed by the most important changes that may occur in the transporters expressed therein. Thus, knowledge of the changes in renal tubular function allows the understanding and recognition of renal tubular diseases that can cause stillbirth or death in newborns or in childhood. Moreover, children with tubular disorders may progress to chronic renal disease at an early stage of life and they may also show disturbances of growth and development associate or not with neurological dysfunction. Therefore, we used the keyword "inherited tubular disorders" to select the children studies that have been published in the PubMed database since 2006. We hope that this review may help physicians to perform an early diagnosis in patients with tubular disorders allowing a specialized treatment and an improvement in their prognosis and quality of life.

Síndrome de Gitelman: do diagnóstico ao acompanhamento na gestação / Gitelman's Syndrome: from diagnosis to follow-up during pregnancy

Resumo A síndrome de Gitelman (SG) é uma forma rara de nefropatia autossômica recessiva perdedora de sal, caracterizada classicamente por hipocalemia, hipomagnesemia, hipocalciúria, alcalose metabólica e pressão arterial baixa. Fadiga, fraqueza muscular e paralisia muscular estão entre seus sintomas mais comuns. Além dos distúrbios eletrolíticos típicos, outros achados laboratoriais incluem a hiperreninemia e o hiperaldosterismo secundário. Nefrocalcinose bilateral pode ocorrer. O tratamento consiste basicamente na reposição de potássio e uso de antagonistas da aldosterona. A melhor abordagem para gestantes portadoras de SG ainda está por ser definida. Entretanto, enfatiza-se a necessidade de suplementação dos íons, o controle do peso como ferramenta clínica de avaliação do balanço hídrico e a monitorização frequente do feto e dos níveis de líquido amniótico. O risco cirúrgico associado à cesariana em paciente com SG não está definido. Apesar dos riscos associados às crises sintomáticas de hipocalemia/hipomagnesemia, a SG apresenta bom prognóstico quando adequadamente tratada. A gravidez impõe a necessidade de controle mais intenso da doença, mas apresenta bom prognóstico para o binômio materno-fetal.

Abstract Gitelman's Syndrome (GS) is a rare autosomal recessive salt-wasting nephropathy, classically characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and low blood pressure. Fatigue, muscle weakness and muscle paralysis are common symptoms. Besides the typical electrolyte disturbances, others laboratory findings include hyperreninemia and secondary hyperaldosteronism. Bilateral nephrocalcinosis may occur. The treatment consists of potassium replacement and use of aldosterone antagonists. The best approach to pregnant women with GS is yet to be defined. However, we emphasize the need for ions supplementation, weight control as a clinical tool for assessing the water balance, and frequent monitoring of the fetus and amniotic fluid levels. The surgical risk associated with cesarean section in a patient with GS is not yet defined. Despite the risks related to symptomatic episodes of hypokalemia/hypomagnesemia, GS has a good prognosis when treated properly. Pregnancy imposes the need for more intensive control of the disease, but has a good prognosis for the mother and neonate.

[Casual diagnosis of Gitelman's syndrome]. / Diagnóstico casual de un síndrome de Gitelman.

Gitelman's syndrome is a renal tubule disease of recessive autosomal inheritance in which the fundamental alteration is found in the distal tubule, specifically at the level of the Na/Cl cotransporter, is sensitive to thiazides, and coded in chromosome 16q. It is characterised by a metabolic alkalosis with normal blood pressure, hypokalaemia, as well as hypomagnesaemia and hypocalciuria, which separate it from Bartter's syndrome. Its diagnosis can be delayed up to the adult age, as patients may remain asymptomatic for long periods of time. The treatment consists of oral supplements of potassium and magnesium, and the use of potassium-sparing diuretics and indomethacin has also been described.

Síndromes de Bartter y Gitelman: revisión de los aspectos genéticos, fisiopatológicos y clínicos / Bartter and Gitelman syndromes: a review of genetic, physiopathological and clinical aspects

Los síndromes de Bartter y Gitelman son trastornos hereditarios caracterizados por una reducción marcada del transporte de sales por el asa ascendente gruesa de Henle. Los pacientes con el síndrome de Bartter presentan grandes pérdidas renales de agua, hipotensión arterial, alcalosis metabólica, hipokalemia e hipercalciuria y tienen un riesgo alto de sufrir nefrolitiasis. Estudios recientes han permitido subdividir el síndrome de Bartter en cinco tipos de acuerdo con el defecto genético y el fenotipo. El tipo 1 es causado por una mutación en el gen que codifica para el cotransportador cloro-sodio-potasio; el tipo 2 se debe a una mutación en el gen que codifica para el canal de potasio ROMK. Estas dos variantes genéticas se denominan conjuntamente síndrome de Bartter neonatal por el comienzo temprano de los síntomas, con polihidramnios materno, prematuridad, poliuria grave y nivel elevado de prostaglandina E2. El tipo 3, conocido como síndrome de Bartter clásico, es causado por mutaciones en el gen que codifica para el canal de cloro CLC-Kb; se detecta desde la niñez con retardo del crecimiento, poliuria, polidipsia y anorexia. El tipo 4 se asocia a sordera neurosensorial y se caracteriza por una mutación en el gen que codifica para la proteína Barttin la cual hace parte de los canales de cloro CLC-Kb y CLC-Ka; el tipo 5 se debe a una mutación en el gen que codifica para un receptor de calcio ubicado en la membrana basolateral del asa ascendente de Henle; estos pacientes, además de los síntomas comunes a los de otros tipos, presentan déficit de paratohormona. El síndrome de Gitelman tiene un fenotipo más leve y una presentación más tardía que el de Bartter; se diferencia de este porque los pacientes tienen hipomagnesemia e hipocalciuria; pueden ser asintomáticos o presentar debilidad muscular transitoria, parestesias, parálisis e incluso alteraciones del ritmo cardíaco. Los avances en genética molecular han permitido la clasificación adecuada de estos síndromes y han abierto puertas para diferentes opciones terapéuticas. Esta revisión incluye aspectos genéticos, fisiopatológicos y clínicos de estos síndromes.

Bartter and Gitelman syndromes are hereditary disorders characterized by a remarkable reduction of salt transportation by the thick ascending limb of the Henle‘s loop. Consequently, patients suffering from Bartter syndrome present with renal salt wasting, low blood pressure, hypokalemic metabolic alkalosis and hypercalciuria, and are at risk of developing renal stones. Based on recent studies, the Bartter syndrome has been subdivided into five types according to the genetic defect involved and the phenotype: type 1 is caused by a mutation in the gene coding for the chloride, sodium, and potassium co-transporter; type 2 is due to a mutation in the gene coding for the ROMK potassium channel. These two genetic variations are jointly denominated neonatal Bartter syndrome, because of their early clinical presentation, with maternal polyhydramnios, prematurity, severe polyuria and high levels of E2 prostaglandine. Type 3, also known as classic Bartter syndrome, is produced by mutations in the gen that codes for the chloride CLC-Kb channel; this type is detected since childhood with growth delay, polyuria, polydipsia and anorexia. Type 4, which is associated with neurosensorial deafness, is characterized by a mutation in the gen that codes for the Barttin protein which is a part of the CLC-Kb and CLC-Ka chloride channels. Type 5 appears because of a mutation in the gene that codes for a calcium receptor located at the basolateral membrane of the ascending limb of Henle‘s loop; patients with this type develop parathormone deficit, as well as the symptoms that are common to all types of the syndrome. The phenotype of Gitelman syndrome is less severe and its clinical presentation is delayed; it differs from the Bartter syndrome in that patients have hypomagnesemia and hipocalciuria. They may be asymptomatic or show transitory muscular weakness, paresthesias, paralysis and even cardiac rhythm alterations. Recent advances in molecular genetics have made it possible to distinguish between the different clinical types and are the basis for several therapeutic options. This review includes genetic, physiopathological and clinical aspects of the Bartter and Gitelman syndromes.