Journal Information
Vol. 28. Issue. 6.December 2008
Pages 572-666
Vol. 28. Issue. 6.December 2008
Pages 572-666
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Compound heterozygosis for intrón 9 + 1 g > T and Leu 850pro mutations in the SLC12A3 gene in Gitelman's syndrome
Heterocigosis compuesta para las mutaciones Intron 9 + 1 g > T y Leu850pro en el gen SLC12A3 en el Síndrome de Gitelman
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Alicia García Péreza, Teresa Oleab, Carlos Carameloc, Eliecer Cotod, Fernando Santose
a Servicio de Nefrología, Fundación Jiménez Díaz-Capio, Madrid, Madrid, España,
b 3Hospital La Paz. Universidad Autónoma de Madrid, Madrid, Madrid, España,
c Servicio de Nefrología, Fundación Jiménez Díaz-Capio, Madrid, MadridMadrid, España,
d 1Unidad de Genética Molecular Hospital Central de Asturias e Instituto de Estudios Nefrológicos. Asturias Asturias España,
e Unidad de Nefrología pediátrica, Hospital Central de Asturias e Instituto de Estudios Nefrológicos. Asturias Asturias España,
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Sr Director: El síndrome de Gitelman es la patología tubular hereditaria más frecuente en Europa (1% de heterocigotos) (1), caracterizada por hipopotasemia, alcalosis metabólica, hipomagnesemia e hipocalciuria (2). La herencia es autosómica recesiva, en relación con mutaciones en el gen SLC12A3, que codifica el cotransportador Na/Cl en el túbulo distal, ocasionando un fallo en la reabsorción de sodio e hiperaldosteronismo secundario. Se han descrito más de 100 mutaciones diferentes.
To the editor: Gitelman¿s syndrome is the most frequent hereditary tubular disease in Europe (1% of heterozygous individuals),1 and is characterized by hypopotassemia, metabolic alkalosis, hypomagnesemia and hypocalciuria.2 A recessive autosomal hereditary pattern is observed, related to mutations of the SLC12A3 gene, which encodes for the Na/Cl co-transporter in the renal distal tubule, causing sodium reabsorption failure and secondary hyperaldosteronism. Over 100 different mutations have been reported.
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To the editor: Gitelman¿s syndrome is the most frequent hereditary tubular disease in Europe (1% of heterozygous

individuals),1 and is characterized by hypopotassemia, metabolic alkalosis, hypomagnesemia and hypocalciuria.2 A

recessive autosomal hereditary pattern is observed, related to mutations of the SLC12A3 gene, which encodes for the Na/Cl co-transporter in the renal distal tubule, causing sodium reabsorption failure and secondary hyperaldosteronism. Over 100 different mutations have been reported.



CLINICAL CASE



A 35-year-old male presented with a history of generalized weakness in the course of an episode of acute diarrhea. Plasma potassium concentration was 1.1 mEq/l. Upon readmission to a tertiary hospital due to the relapse of severe and symptomatic hypopotassemia, the laboratory tests revealed the presence of full Gitelman¿s syndrome (table I). A study of the family detected a similar biochemical condition only in the male sibling of the patient; both individuals had suffered scant previous repercussions in the form of carpopedal spasms in childhood, in relation to fever episodes, and occasionally also in adult life. Treatment was provided in the form of potassium and magnesium

supplements, spironolactone, amiloride and finally eplerenone, at very high doses for normalization of the plasma levels ¿ with the persistence of important potassium elimination in urine. The genetic study showed both siblings to carry the int. 9 + 1G > T mutation, present in the father, and the Leu850Pro mutation in exon 22, present in the mother. The two children of the patient carried only the Leu850Pro mutation.



DISCUSSION



The association of these two mutations is reported for the first time. The variant int. 9 + 1G > T has been found in the largest published series with a common mutation: 12 gypsy families with no relation to each other.3 In this group, the affected individuals were homozygous, while the parents and descendents were healthy heterozygous

carriers. This points to the possible reinforcing effect of the second mutation (Leu850Pro) upon the first, since ours are the first patients described with clinical involvement in which the variant int. 9 + 1G > T is present in heterozygosis. All patients with clinical manifestations in which a single mutation is detected should be regarded as compound heterozygotes in which the second mutation has not been detected, due to incomplete sequencing of the gene. The presence of compound heterozygosis suggests that the transporter alteration requires at least two variations in order to manifest, and which could determine a variety of structural changes with different effects upon transporter activity ¿ thus giving rise to clinical conditions of different degrees of severity.4



It should be pointed out that the diagnosis is established in adult life, with scant prior clinical expression. This contrast with the severity of hypopotassemia and hypomagnesemia, and the usually intense physical activity of the patients ¿ reflecting the scant correlation found in most cases between the biochemical alterations and the clinical picture.5 Therefore, this diagnosis must be considered in all cases of hypopotassemia with inappropriately high potassium elimination in urine, in the absence of arterial hypertension. The condition was initially not suspected,

despite the recording of a plasma potassium concentration of 1 mEq/l (infrequent even in severe diarrhea), because

of the lack of a urinary potassium measurement that constitutes a key element in the diagnosis.
Bibliography
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Nefrología (English Edition)

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