Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis: clinical and molecular characteristics

Abstract

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal-recessive renal tubular disorder characterized by excessive urinary losses of magnesium and calcium, bilateral nephrocalcinosis and progressive chronic renal failure. Presentation with FHHNC symptoms generally occurs early in childhood or before adolescence. At present, the only therapeutic option is supportive and consists of oral magnesium supplementation and thiazide diuretics. However, neither treatment seems to have a significant effect on the levels of serum magnesium or urine calcium or on the decline of renal function. In end-stage renal disease patients, renal transplantation is the only effective approach. This rare disease is caused by mutations in the CLDN16 or CLDN19 genes. Patients with mutations in CLDN19 also present severe ocular abnormalities such as myopia, nystagmus and macular colobamata. CLDN16 and CLDN19 encode the tight-junction proteins claudin-16 and claudin-19, respectively, which are expressed in the thick ascending limb of Henle's loop and form an essential complex for the paracellular reabsorption of magnesium and calcium. Claudin-19 is also expressed in retinal epithelium and peripheral neurons. Research studies using mouse and cell models have generated significant advances on the understanding of the pathophysiology of FHHNC. A recent finding has established that another member of the claudin family, claudin-14, plays a key regulatory role in paracellular cation reabsorption by inhibiting the claudin-16–claudin-19 complex. Furthermore, several studies on the molecular and cellular consequences of disease-causing CLDN16 and CLDN19 mutations have provided critical information for the development of potential therapeutic strategies.

Tight junction proteins in gastrointestinal and liver disease

“…Moreover, CLDN8 contributed to regulation of paracellular Na + permeability, protecting the leakage of Na + into the intestinal lumen 40. CLDN16 is responsible for the defective absorption of Ca 2+ in the intestine causing primary hypercalciuria 41. Furthermore, the interdependence between CLDN proteins in regulating intestinal homeostasis is well demonstrated by in vivo loss-of-function studies for CLDN15.…”

Nephrocalcinosis: A Review of Monogenic Causes and Insights They Provide into This Heterogeneous Condition

“…Rapid progression of CKD in these patients may not be attributable solely to nephrocalcinosis, as their renal dysfunction is more severe/presents earlier than that observed in other tubulopathies predisposing to nephrocalcinosis such as primary distal renal tubular acidosis or Bartter syndrome [30]. CLDN19 mutations are associated with severe ocular abnormalities as claudin-19 is also expressed in the retinal epithelium [28].…”

“…The thick ascending limb (TAL) of loop of Henle, where~25% of calcium reabsorption [6] and 60% of magnesium reabsorption usually takes place [28], is the site of two rare autosomal recessive channelopathies affecting calcium and magnesium absorption. Mutations in CLDN16 and CLDN19, which encode the tight junction proteins claudin-16 and claudin-19 respectively, give rise to the condition familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) [29].…”

“…Patients are symptomatic from a young age, although initial presenting features may be non-specific such as polyuria/polydipsia, failure to thrive and vomiting. The biochemical profile of FHHNC phenotypes includes excessive loss of calcium and magnesium in the urine, with normal serum calcium levels and low serum magnesium levels [28]. Importantly, serum hypomagnesaemia is not universally present, and a fractional excretion value of magnesium (FeMg%) should be calculated using serum magnesium, serum creatinine and urinary magnesium levels to ensure diagnostic accuracy [30].…”

“…A further predisposing factor for nephrolithiasis and nephrocalcinosis in FHHNC is hypocitraturia, which removes the protective effect of urinary citrate against precipitation of calcium salts in the urine [30]. The renal prognosis for FHHNC is poor; many patients progress to ESRD during adolescence [28]. Rapid progression of CKD in these patients may not be attributable solely to nephrocalcinosis, as their renal dysfunction is more severe/presents earlier than that observed in other tubulopathies predisposing to nephrocalcinosis such as primary distal renal tubular acidosis or Bartter syndrome [30].…”