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. 2012 May;7(5):801-9.
doi: 10.2215/CJN.12841211. Epub 2012 Mar 15.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations

Astrid Godron  1 , Jérôme Harambat, Valérie Boccio, Anne Mensire, Adrien May, Claire Rigothier, Lionel Couzi, Benoit Barrou, Michel Godin, Dominique Chauveau, Stanislas Faguer, Marion Vallet, Pierre Cochat, Philippe Eckart, Geneviève Guest, Vincent Guigonis, Pascal Houillier, Anne Blanchard, Xavier Jeunemaitre, Rosa Vargas-Poussou
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Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations

Astrid Godron et al. Clin J Am Soc Nephrol. 2012 May.

Abstract

Background 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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Figures

Figure 1.
Figure 1.
Haplotypes of three North African families carrying the p.Ala139Val mutation. Families 2 and 5 were consanguineous; family 6 has no history of consanguinity, but the mutation was homozygous.
Figure 2.
Figure 2.
Haplotypes of 14 nonconsanguineous French and Spanish families carrying the p.Gly20Asp mutation. In probands of families 17 and 25, this mutation was heterozygous and associated with a second mutation; the probands of all the other families were homozygous.
Figure 3.
Figure 3.
Survival without reaching CKD stage 3 by genotype.
See this image and copyright information in PMC

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