Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis

Michelis, Michael F.; Drash, Allan L.; Linarelli, Louie G.; Rubertis, Frederick R. De; Davis, Bernard B.

doi:10.1016/0026-0495(72)90025-x

Cited by 85 publications

(42 citation statements)

References 32 publications

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“…In 1972, Michelis et al (27) first described a hypomagnesemic disorder characterized by excessive renal magnesium and calcium wasting. In addition, affected individuals had bilateral nephrocalcinosis and developed progressive renal failure.…”

Section: Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinmentioning

confidence: 99%

Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders

Konrad¹,

Weber²

2003

Journal of the American Society of Nephrology

111

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Abstract. Recent advances in molecular genetics in hereditary hypomagnesemia substantiated the role of a variety of genes and their encoded proteins in human magnesium transport mechanisms. This knowledge on underlying genetic defects helps to distinguish different clinical subtypes and gives first insight into molecular components involved in magnesium transport. By mutation analysis and functional protein studies, novel pathophysiologic aspects were elucidated. For some of these disorders, transgenic animal models were generated to study genotype-phenotype relations and disease pathology. This review will discuss genetic and clinical aspects of familial disorders associated with magnesium wasting and focuses on the recent progress that has been made in molecular genetics. Besides isolated renal forms of hereditary hypomagnesemia, the following disorders will also be presented: familial hypomagnesemia with hypercalciuria and nephrocalcinosis, hypomagnesemia with secondary hypocalcemia, Ca 2ϩ /Mg 2ϩ -sensing receptor-associated disorders, and disorders associated with renal salt-wasting and hypokalemic metabolic alkalosis, comprising the Gitelman syndrome and the Bartter-like syndromes.

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Section: Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinmentioning

confidence: 99%

Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders

Konrad¹,

Weber²

2003

Journal of the American Society of Nephrology

111

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“…Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; Online Mendelian Inheritance in Man 248250) is a rare autosomal recessive disease first described as Michelis-Castrillo syndrome (1). Only 87 patients (51 families) have been described to date in international publications (2,3).…”

Section: Introductionmentioning

confidence: 99%

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Godron¹,

Harambat²,

Boccio³

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal tubular disease. It is caused by mutations in CLDN16 and CLDN19, encoding claudin-16 and -19, respectively. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is usually complicated by progressive CKD. The objectives of this study were to describe the clinical and genetic features of familial hypomagnesemia with hypercalciuria and nephrocalcinosis and analyze phenotype-genotype associations in patients with CLDN16 or CLDN19 mutations.Design, setting, participants, & measurements Data from 32 genetically confirmed patients (9 patients with CLDN16 and 23 patients with CLDN19 mutations) from 26 unrelated families were retrospectively reviewed.Results Diagnosis was based on clinical criteria at a median age of 9.5 years and confirmed by genetic testing at a median age of 15.5 years. In total, 13 CLDN16 or CLDN19 mutations were identified, including 8 novel mutations. A founder effect was detected for the recurrent CLDN16 p.Ala139Val mutation in North African families and the CLDN19 p.Gly20Asp mutation in Spanish and French families. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age in CLDN19 versus 100% in CLDN16 mutations (log rank P,0.01). Ocular abnormalities were observed in 91% of patients with CLDN19 mutations and none of the patients with CLDN16 mutations (P,0.01). Treatments seem to have no effect on hypercalciuria and CKD progression.Conclusions Patients with CLDN19 mutations may display more severe renal impairment than patients with CLDN16 mutations. Ocular abnormalities were observed only in patients with CLDN19 mutations.

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“…[1][2][3][4][5][6] The mode of inheritance is autosomal recessive. Besides marked hypomagnesaemia the affected individuals present with polyuria, hyposthenuria, hypercalciuria, advanced nephrocalcinosis, low citrate excretion and impaired glomerular filtration rate (GFR).…”

Section: Introductionmentioning

confidence: 99%

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene

et al. 2000

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Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC, MIM 248250) is a complex renal tubular disorder characterised by hypomagnesaemia, hypercalciuria, advanced nephrocalcinosis, hyposthenuria and progressive renal failure. The mode of inheritance is autosomal recessive. A primary defect in the reabsorption of magnesium in the medullary thick ascending limb of the loop of Henle (mTAL) has been proposed to be essential in FHHNC pathophysiology. To identify the underlying genetic defect we performed linkage analysis in eight families, including three with consanguineous marriages. We found linkage to microsatellite markers on chromosome 3q27 with a maximum two-point lod score (Z max ) of 5.208 for D3S3530 without evidence for genetic heterogeneity. Haplotype analysis revealed crucial recombination events reducing the critical interval to 6.6 cM. Recently, mutations in the gene PCLN-1, mapping to 3q27 and coding for paracellin-1, were identified by Simon et al (1999) as the underlying genetic defect in FHHNC. Paracellin-1 represents a renal tight junction protein predominantly expressed in the TAL. Mutational analysis in our patient cohort revealed eight different mutations in the PCLN-1 gene, within six novel mutations. In seven of 13 mutant alleles we detected a Leu151 substitution without evidence for a founder effect. Leu151 is a residue of the first extracellular loop of paracellin-1, the part of the protein expected to bridge the intercellular space and to be important for paracellular conductance. This study confirms the implication of paracellin-1 defects in FHHNC and points to a predominant role of this protein in the paracellular reabsorption of divalent cations in the TAL.

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Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis

Cited by 85 publications

References 32 publications

Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders

Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene

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