Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: unusual clinical associations and novel claudin16 mutation in an Egyptian family

Al-Haggar, Mohammad; Bakr, Ashraf; Tajima, Toshihiro; Fukui, Kenji; Hammad, Ayman; Soliman, Othman E.; Darwish, Ahmad; Alsaid, Afaf; Yahia, Sohier; Abdel-Hady, Dina

doi:10.1007/s10157-008-0126-6

Cited by 13 publications

(7 citation statements)

References 17 publications

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“…Although there are no studies focusing on the possible association of primary hypomagnesemia in humans and cataract, indirect evidence from human and animal studies do suggest the possibility of such an association. An association between congenital cataract and a rare autosomal recessive tubular disorder characterized by hypomagnesemia with hypercalciuria and nephrocalcinosis has been reported [20]. Studies have also demonstrated an association of early onset cataract in uncontrolled diabetes and hypomagnesemia [21,22].…”

Section: Association Of Magnesium Deficiency and Cataractmentioning

confidence: 94%

Mechanisms of cataractogenesis in the presence of magnesium deficiency

Agarwal¹,

Iezhitsa²,

Agarwal³

et al. 2013

Magnesium Research

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Senile cataract is the most common cause of bilateral blindness and results from the loss of transparency of the lens. Maintenance of the unique tissue architecture of the lens is vital for keeping the lens transparent. Membrane transport mechanisms utilizing several magnesium (Mg)-dependent ATPases, play an important role in maintaining lens homeostasis. Therefore, in Mgdeficiency states, ATPase dysfunctions lead to intracellular depletion of K + and accumulation of Na + and Ca 2+. High intracellular Ca 2+ causes activation of the enzyme calpain II, which leads to the denaturation of crystallin, the soluble lens protein required for maintaining the transparency of the lens. Mg deficiency also interferes with ATPase functions by causing cellular ATP depletion. Furthermore, Mg deficiency enhances lenticular oxidative stress by increased production of free radicals and depletion of antioxidant defenses. Therefore, Mg supplementation may be of therapeutic value in preventing the onset and progression of cataracts in conditions associated with Mg deficiency.

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Section: Association Of Magnesium Deficiency and Cataractmentioning

confidence: 94%

Mechanisms of cataractogenesis in the presence of magnesium deficiency

Agarwal¹,

Iezhitsa²,

Agarwal³

et al. 2013

Magnesium Research

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“…Additional findings include nephrolithiasis, abdominal pain, vomiting, convulsions, muscular twitches, failure to thrive, incomplete distal renal tubular acidosis, and hypocitraturia. 4 The conventional therapy for patients with FHHNC includes magnesium supplements and thiazides to reduce the hypercalciuria, although these medications may improve some biochemical abnormalities, such improvements do not always result in delayed progression of renal dysfunction. 5 Zimmermann et al studied the efficacy of hydrochlorothiazide (HCT) in FHHNC patients in a clinical trial, and concluded that HCT is effective in reducing hypercalciuria due to CLDN16 mutation on a shortterm basis; however, the efficacy of HCT to attenuate disease progression remains to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

“…1 To date, 54 different CLDN16 mutations have been identified, 3 most of these mutations (67%) were missense mutations, although deletions and frameshift mutations were also reported. 4 Here, we describe a novel missense mutation in the CLDN16 gene in a Palestinian family with FHHNC.…”

Section: Introductionmentioning

confidence: 89%

A Novel Mutation in the CLDN16 Gene in a Palestinian Family with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Abu-Libdeh

Abu‐Libdeh

Abdulhag

2017

JCS

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Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive renal disorder characterized by excessive renal magnesium and calcium loss, bilateral nephrocalcinosis, and progressive renal failure, due to impaired tubular reabsorption in the thick ascending loop of Henle. FHHNC is caused by loss of function mutations in the claudin-16 gene (CLDN16) and claudin-19 gene (CLDN19). A 2-month-old male infant presented with convulsions during hypomagnesemia, hypocalcemia, and hypophosphatemia, biochemical findings were consistent with FHHNC. There is a positive family history of the death of a 12 years old sibling due to renal failure. Gene sequencing of the CLDN16 revealed a novel missense mutation with the replacement of T by C in codon 120 located in exon 2, predicting cysteine to arginine substitution p.Cys120Arg. This is the first description of this missense mutation and the first confirmation of FHHNC by molecular testing in a Palestinian family which enables genetic counseling and future prenatal diagnosis.

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“…The hypothesis of the influence of modulators and epigenetic factors in the clinical spectrum of FHHNC is reinforced by studies that report unusual clinical findings in FHHNC patients with CLDN16 mutations [ 27 – 29 ] and different clinical courses in siblings with the same CLDN16 mutation [ 17 , 30 ]. One case report presented a boy with a truncating mutation in claudin-16 (p.W237X) with early-onset renal insufficiency, horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities, umbilical hernia, and hypertrichosis [ 27 ].…”

Section: Case Presentationmentioning

confidence: 99%

“…Another study reported a female patient who experienced recurrent passages of kidney stones and urinary tract infections as of 4 years old, and only developed nephrocalcinosis when she was 19 [ 28 ]. In another case, genitourinary abnormalities (hypospadias and cryptorchidism) were observed in one of the proband’s siblings [ 29 ]. A rare case report described a patient who, in addition to the classical symptoms of FHHNC, was diagnosed with smaller kidneys, severe bone disease, severe metabolic acidosis, and persistent hypocalcemia.…”

Section: Case Presentationmentioning

confidence: 99%

Identification of the first large deletion in the CLDN16 gene in a patient with FHHNC and late-onset of chronic kidney disease: case report

et al. 2015

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BackgroundFamilial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease characterized by tubular disorders at the thick ascending limb of Henle’s loop. It is caused by mutations in the tight junction structural proteins claudin-16 or claudin-19, which are encoded by the CLDN16 and CLDN19 genes, respectively. Patients exhibit excessive wasting of calcium and magnesium, nephrocalcinosis, chronic kidney disease, and early progression to end-stage renal failure during infancy.Case presentationWe here report the phenotype and molecular analysis of a female Brazilian patient with a novel large homozygous deletion in the CLDN16 gene. The proband, born from consanguineous parents, presented the first symptoms at age 20. Clinical examination revealed hypocalcemia, hypomagnesemia, nephrocalcinosis, mild myopia, high serum levels of uric acid and intact parathyroid hormone, and moderate chronic kidney disease (stage 3). She and her mother were subjected to CLDN16 and CLDN19 mutational analysis. In addition, the multiplex ligation-dependent probe amplification method was used to confirm a CLDN16 multi-exon deletion. Direct sequencing revealed a normal CLDN19 sequence and suggested a large deletion in the CLDN16 gene. Multiplex ligation-dependent probe amplification showed a homozygous CLDN16 multi-exon deletion (E2_E5del). The patient initiated conventional treatment for familial hypomagnesemia with hypercalciuria and nephrocalcinosis and progressed to end-stage kidney disease after five years.ConclusionsThis study provides the first report of a large homozygous deletion in the CLDN16 gene causing familial hypomagnesemia with hypercalciuria and nephrocalcinosis with late onset of the first symptoms. This description expands the phenotypic and genotypic characterization of the disease. The late-onset chronic kidney disease in the presence of a homozygous deletion in the CLDN16 gene reinforces the great variability of genotype-phenotype manifestation in patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

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Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: unusual clinical associations and novel claudin16 mutation in an Egyptian family

Cited by 13 publications

References 17 publications

Mechanisms of cataractogenesis in the presence of magnesium deficiency

Mechanisms of cataractogenesis in the presence of magnesium deficiency

A Novel Mutation in the CLDN16 Gene in a Palestinian Family with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Identification of the first large deletion in the CLDN16 gene in a patient with FHHNC and late-onset of chronic kidney disease: case report

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