Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Abstract

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.

Magnesium in Man: Implications for Health and Disease

“…Patients suffer from nonspecific symptoms such as depression, tiredness, muscle spasms, and muscle weakness, and diagnosis therefore may take years (TABLE 3) (177,523). Only severe Mg 2ϩ depletion (Ͻ0.4 mM) may lead to cardiac arrhythmias, tetany, and seizures.…”

Clinical utility gene card for: familial hypomagnesemia with hypercalciuria and nephrocalcinosis with/without severe ocular involvement

“…4 A founder effect has been also detected for the recurrent disease-causing c.416C4T (p.A139V) variant in North African families. 10 Only 17 CLDN19 disease-causing variants are known, 2,3,10,15-18 including missense variants (12), nonsense variants (3), one large deletion and one small deletion. Two missense variants affect the last nucleotide of exon 1 and are also predicted to disrupt a donor splice site.…”

“…A founder effect has been shown for the recurrent disease-causing variant c.59G4A (p.G20D) in Spanish and French families. 2,10,17 The GeneBank accession numbers for CLDN16 and CLDN19 are NG_008149.1, NM_006580.3 and NG_008993.1, NM_148960.2, respectively. Reference CLDN16 (ENSG00000113946) and CLDN19 (ENSG00000164007) sequences can also be found in the Ensembl database (http://www.ensembl.org).…”

“…However, these treatments do not seem to have a considerable effect on the levels of urinary calcium or serum magnesium. 10,17 Severe myopia can be corrected with glasses, contact lenses, laser surgery or implanting artificial lenses. There is currently no cure for nystagmus or for coloboma.…”

Working Out Nephronophthisis Genetics One Family at a Time

“…For example, recessive mutations in Claudin-16 (CLDN16) and CLDN19 cause familial hypercalciuric hypomagnesemia with nephrocalcinosis. 15 Mutations in CLDN19 additionally cause macular coloboma or pigmentary retinitis, similar to some NPNH-RC cases. 15 However, in Japanese black cattle, recessive mutations of the CLDN16 gene only cause renal tubular dysplasia without hypomagnesemia and nephrocalcinosis, 16 suggesting that phenotypic manifestations of Mg 21 transport defect may be species-dependent.…”