Two heterozygous mutations of CLDN16 in a Japanese patient with FHHNC

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC, MIN 248250) is a rare autosomal recessive tubular disorder that eventually progresses to renal failure. However, the progression to end-stage renal failure can vary from patient to patient. A primary defect is related to impaired tubular resorption of magnesium and calcium in the thick ascending limb of Henles loop. Recently, paracellin-1 was identified as a renal tight junction protein predominantly expressed in TAL. Mutations of its gene (CLDN16) have been shown to cause FHHNC. We describe a sporadic Japanese case of FHHNC. The male patient showed hematuria, hypercalciuria, and nephrocalcinosis at 5 years of age. Hypomagnesemia was also noticed at this time. As renal function gradually deteriorated, further evaluation was performed at 14 years of age and a diagnosis of FHHNC was made. Despite several medications (magnesium supplementation, citrate, and hydrochlorothiazide), he eventually progressed to renal insufficiency at 19 years of age. Analysis of the CLDN16 gene demonstrated two heterozygous mutations (R149Q and R216C). Mutations of the same amino acids have already been described in FHHNC and thus these mutations might be the cause of the disease in our patient. Hence, we confirm the genetic impairment of the CLDN16 gene in a Japanese patient with FHHNC.     

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis associated with CLDN16 mutations

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), an autosomal recessive renal tubular disorder, is characterized by the impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of the loop of Henle and an eventual progression to end-stage renal disease. Recent studies have reported that this disease is caused by mutations in the CLDN16 gene, which encodes the tight junction protein, paracellin-1. Paracellin-1 belongs to the claudin family and regulates the paracellular transport of magnesium and calcium. Here, we report on two Korean siblings with typical clinical features of FHHNC in association with compound heterozygous mutations, G233C and 800delG, in CLDN16. Their parents were asymptomatic heterozygous carriers of the single mutations. This is the first report of FHHNC in Korea, and the mutations reported are novel.     

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: report of three Turkish siblings

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), an autosomal recessive renal tubular disorder is characterized by the impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of the loop of Henle. This disease is caused by mutations in the claudin-16 gene (CLDN16), which encodes the tight junction protein, claudin-16. Claudin-16 belongs to the claudin family and regulates the paracellular transport of magnesium and calcium. Here, we report on three Turkish siblings with typical clinical features of FHHNC in association with the homozygous mutation Leu151Phe.     

Hypomagnesemia and nephrocalcinosis in a patient with two heterozygous mutations in the CLDN16 gene

We report the case of a 20-year-old male Caucasian patient with diagnosed nephrocalcinosis and a medical history of seizures and recurrent urinary tract infections. Laboratory investigations revealed clinical and biochemical abnormalities characteristic of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Since FHHNC is caused by mutations in the CLDN16 gene encoding a renal tight junction protein, we sequenced the complete coding region of this gene and detected two heterozygous mutations, the known Leu151Phe (+453G-->T) mutation and a novel Cys120Arg (+358T-->C) mutation. Due to their location within the primary structure of Claudin-16, both mutations are suggested to interfere with renal paracellular magnesium conductance.     

Paracellin-1 gene mutation with multiple congenital abnormalities

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive renal tubular disorder characterized by renal magnesium wasting, hypercalciuria, advanced nephrocalcinosis and progressive renal failure. Mutations in the paracellin-1 (CLDN16) gene have been defined as the underlying genetic defect. The tubular disorders and progression in renal failure are usually resistant to magnesium substitution and hydrochlorothiazide therapy, but hypomagnesemia may improve with advanced renal insufficiency. We present a patient with a homozygous truncating CLDN16 gene mutation (W237X) who had early onset of renal insufficiency despite early diagnosis at 2 months. He also had additional abnormalities including horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia and hypertrichosis. To the best of our knowledge, this is the youngest case diagnosed as familial hypomagnesemia with hypercalciuria and nephrocalcinosis and the first case having such additional congenital abnormalities independent of the disease itself.     

Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis, the GFR was already decreased to <60 ml/min per 1.73 m(2) for 11 patients. Twelve patients exhibited progression to end-stage renal disease, at a median age of 14.5 yr. Treatment with magnesium salts and thiazides seemed to have no effect on the progression of the disease. Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%). Fifteen different mutations were observed, including eight novel mutations. The accumulation of mutations affecting the first extracellular loop was striking, with 48% of all mutant alleles exhibiting a Leu151Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or eastern European countries. In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.     

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

Background  Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder that eventually progresses to renal failure, depending upon the extent of nephrocalcinosis. Its basic pathogenesis is impaired tubular resorption of magnesium and calcium in the thick ascending limb of the loop of Henle (TAL) due to a genetic defect in paracellin-1 (a tight junction protein expressed in TAL). Mutations of the claudin16 gene (CLDN16), formerly called paracellin-1 gene (PCLN-1), have been linked to FHHNC. Methods  An extended Egyptian family with more than one member affection by nephrocalcionsis was included and thoroughly investigated in the current study after giving informed consent. Thorough history was taken for polyuria, polydipsia and hypocalcemia symptoms, as well as clinical examination with stress on anthropometric measurements and radiological evaluation for kidneys and bones. Laboratory workup for the differential diagnosis of nephrocalcinosis was done: complete urinalysis, including urinary calcium excretion, urine pH and electrolytes, arterial blood gas (ABG), serum electrolytes (sodium, potassium, calcium, magnesium and phosphorous), renal function tests as well as parathyroid and gonadotropin-sex hormone assay. DNA extraction from peripheral blood leukocytes was done followed by amplification using primers previously described, purification and finally sequencing to analyze each exon of the CLDN16 gene. Results  Two sibs for a consanguineous couple were affected by nephrocalcinosis and showed persistent hypocalcemia, hypercalciuria, nephrocalcinosis with persistently alkaline urine and ocular manifestations in the form of congenital cataracts, high myopia and retinal abnormalities. The elder sib showed genitourinary abnormalities in the form of hypospadias and cryptorchidism. These two sibs had a homozygous two-base deletion in exon 1 of the CLDN16 gene (C. 233_234 del GG; Ins C), causing a frame shift mutation (Arg55 fs); however, their parents were heterozygote carriers for that mutation. Conclusion  The above-mentioned clinical data in the two affected sibs together with the family history of end-stage renal disease associated with nephrocalcinosis and high myopia suggested a diagnosis of FHHNC, which was confirmed for the first time in an Egyptian family by a novel mutation in exon 1 of the CLDN16 gene. Genitourinary associations with FHHNC have not yet been reported in the literature. Here, we will try to highlight the principles of mutation detection based on sequencing with the use of the online NCBI databases, statistics and other search tools.     

A novel <Emphasis Type="Italic">PCLN-1</Emphasis> gene mutation in familial hypomagnesemia with hypercalciuria and atypical phenotype

Familial hypomagnesemic hypercalciuria and nephrocalcinosis (FHHNC [MIM 248250]) is a rare renal tubular disorder characterized by impaired reabsorption of magnesium and calcium in the thick ascending limb of Henle’s loop (tALH), causing renal magnesium wasting and hypercalciuria. Patients with FHHNC usually present with recurrent urinary tract infections, polyuria, nephrolithiasis (NL) and nephrocalcinosis (NC) with many progressing to chronic renal failure (CRF). We have shown recently that loss of function mutations in paracellin-1 PCLN-1/claudin-16, a renal tight junction protein located in the TAL, are causative of FHHNC. We present clinical and molecular studies on a highly inbred family with FHHNC in association with an unusual phenotype in that all affected members were extremely short. Affected individuals were found to be homozygous for marker D3S1314 on chromosome 3q. Sequencing of the PCLN-1/claudin-16 gene revealed a previously unknown point mutation at S235Y on exon 4 on the 4th transmembrane domain, providing additional evidence that inactivating mutations in the PCLN-1/claudin-16 gene result in FHHNC.     

Inherited hypercalciuric syndromes: Dent's disease (CLC-5) and familial hypomagnesemia with hypercalciuria (paracellin-1)

Dent's disease and familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) are inherited diseases in which hypercalciuria, nephrocalcinosis, and renal failure are prominent features. Dent's disease resembles a Fanconi syndrome, with impaired reabsorption in the proximal tubule; FHHNC, with urinary loss of magnesium and calcium, is associated with impaired cation transport in the thick ascending limb of Henle's loop. Gene mapping in families and positional cloning led in both cases to identification of the responsible gene. Dent's disease is associated with mutations that disrupt function of a voltage-gated chloride channel, CLC-5, expressed in subapical endosomes of the proximal tubule and in other nephron segments. Impaired function of this channel disturbs reabsorption of filtered proteins, as well as other transport functions of the proximal tubule, and leads, apparently indirectly, to hypercalciuria and renal failure. FHHNC results from mutations in paracellin-1, a tight-junction protein that appears to be important in conducting or regulating paracellular cation transport. Impaired function of paracellin-1 leads specifically to urinary losses of magnesium and calcium, but because transcellular transport is intact these patients do not have hypokalemia or salt wasting. Identification of both genes represent triumphs of a genetic approach to solving problems of pathophysiology.     

Claudin‐16 Deficiency Impairs Tight Junction Function in Ameloblasts,Leading to Abnormal Enamel Formation

Claudin‐16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin‐16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow‐up for these patients. © 2015 American Society for Bone and Mineral Research.     

Follow-up of five patients with FHHNC due to mutations in the Paracellin-1 gene

Familial hypomagnesemia, hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive inherited disorder that has recently been attributed to a defect in the paracellin-1 ( PCLN-1)gene, encoding for a protein responsible for the tubular reabsorption of magnesium and calcium. Limited information is available on clinical course, therapy and prognosis. We provide information on five patients with FHHNC and their follow-up at our institution. Polyuria, nephrocalcinosis and hyperuricemia were the main clinical findings of a diagnosis at a median age of 4.4 years. The clinical course of PCLN-1 mutations as presented in this study is highly variable, ranging from compensated renal failure to end-stage renal failure - as happened in two of our patients. The progression to renal failure cannot be deduced from the initial presentation. Medical treatment does not appear to influence the progression of the disease. Despite calcium and magnesium substitution, normal values could not be achieved in these patients. Early treatment with vitamin D and calcium was essential to maintain growth. Adequate treatment allows for a normal height and pubertal development.     

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: variable phenotypic expression in three affected sisters from Mexican ancestry

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease caused by mutations in genes for the tight junction transmembrane proteins Claudin-16 (CLDN16) and Claudin-19 (CLDN19). We present the first case report of a Mexican family with three affected sisters carrying a p.Gly20Asp mutation in CLDN19 whose heterozygous mother showed evident hypercalciuria and normal low magnesemia without any other clinical, laboratory, and radiological symptoms of renal disease making of her an unsuitable donor. The affected sisters showed variable phenotypic expression including age of first symptoms, renal urinary tract infections, nephrolithiasis, nephrocalcinosis, and eye symptoms consisting in retinochoroiditis, strabismus, macular scars, bilateral anisocoria, and severe myopia and astigmatism. End stage renal disease due to renal failure needed kidney transplantation in the three of them. Interesting findings were a heterozygous mother with asymptomatic hypercalciuria warning on the need of carefully explore clinical, laboratory, kidney ultrasonograpy, and mutation status in first degree asymptomatic relatives to avoid inappropriate kidney donors; an evident variable phenotypic expression among patients; the identification of a mutation almost confined to Spanish cases and a 3.5?Mb block of genomic homozygosis strongly suggesting a common remote parental ancestor for the gene mutation reported.     

Report of a family with two different hereditary diseases leading to early nephrocalcinosis

The etiologies of early onset nephrocalcinosis in consanguineous families include five major inherited recessive disorders: primary hyperoxaluria (PH), familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), distal renal tubular acidosis (dRTA), hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and antenatal Bartter syndrome. In this paper, we describe two girls from consanguineous parents with early onset nephrocalcinosis. Based on both clinical and biochemical assessment in combination with molecular genetics, we have shown that the etiology of nephrocalcinosis is different in each girl: one had FHHNC and her sister had dRTA.     

CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder caused by CLDN16 mutations. CLDN16 encodes the renal tight junction protein claudin-16, which is important for the paracellular reabsorption of calcium and magnesium in the thick ascending limb of Henle''s loop. That FHHNC is frequently associated with progressive renal failure suggests additional roles for claudin-16 in the maintenance of tight junction integrity. An investigation of 32 patients with FHHNC and 17 different mutations was previously reported; here, the analysis is expanded to 39 additional patients and 12 new mutations. Expression studies revealed that five of the 12 new mutations led to partial loss of claudin-16 function and the remaining seven led to complete loss of function. The 23 patients who had mutations resulting in complete loss of function of both alleles were significantly younger at the onset of symptoms than the 46 patients who had at least one mutant allele providing partial function (2.2 versus 5.6 years; P < 0.01). In addition, those with complete loss of function had a more rapid decline in GFR (7.3 versus 2.9 ml/min per 1.72 m²/y; P < 0.01), leading to 54% requiring renal replacement therapy by age 15 compared with 20% of those with residual function (P < 0.05). These data suggest that residual function of claudin-16 may delay the progression of renal failure in FHHNC.Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; OMIM *248250) is a rare autosomal recessive tubular disorder. It is characterized by massive urinary losses of magnesium (Mg) and calcium (Ca) leading to hypomagnesemia and bilateral nephrocalcinosis. The disease usually presents with recurrent urinary tract infections and polyuria/polydipsia. Additional symptoms include rickets, nephrolithiasis, hematuria, muscular tetanies, seizures, failure to thrive, vomiting, and abdominal pain.^1,2 Ocular abnormalities and hearing impairment have been described in a subset of patients with FHHNC.^3,4 Additional biochemical abnormalities include signs of incomplete distal renal tubular acidosis, hypocitraturia, increased parathyroid hormone (PTH) levels (independent of GFR), and hyperuricemia.^3,5–8 Unlike most other inherited tubular diseases affecting electrolyte homeostasis, FHHNC is generally complicated by progressive renal failure during childhood or adolescence, but the pathogenesis of chronic renal failure remains a matter of debate.Clearance studies in patients with FHHNC localized the site of disturbed handling of Mg and Ca to the thick ascending limb (TAL) of Henle''s loop.⁶ The TAL plays an important role in the tubular reabsorption of Mg and Ca, which occurs by paracellular flux, a process driven by the lumen-positive transepithelial potential in this nephron segment.In 1999, Simon et al.⁹ identified a new gene (CLDN16, formerly PCLN1) and characterized mutations in this gene as the underlying molecular defect in FHHNC. Since then, approximately 30 additional families with FHHNC as a result of CLDN16 defects have been described.^2,10–13 Hypercalciuria and nephrolithiasis have also been observed in heterozygous FHHNC mutation carriers.^2,3 FHHNC is a genetically heterogeneous disease because recently CLDN19 mutations have been identified in a cohort of patients mainly originating from Spain.¹⁴ The renal phenotype of these patients is very similar to patients exhibiting CLDN16 mutations; however, patients with CLDN19 mutations also have severe ocular abnormalities in most cases.CLDN16 and CLDN19 encode the tight junction (TJ) proteins claudin-16 (paracellin-1) and claudin-19, both being members of the claudin multigene family. Claudins are important components of the TJ strands in various tissues.¹⁵ They are part of a complex protein network built up by a variety of different proteins, and there is clear evidence that claudins confer ion selectivity to the paracellular pathway.^16–18In the kidney, claudin-16 expression is restricted to the TAL of Henle''s loop. It was speculated that claudin-16 constitutes the core of an intercellular pore, allowing paracellular reabsorption of Mg and Ca ions.^9,19 Following the observation that a naturally occurring knockout model in Japanese black cattle shows early-onset renal failure with diffuse interstitial nephritis,²⁰ it was recently speculated that claudin-16, like other claudins, may also be involved in the regulation of cell growth, proliferation, differentiation, and dedifferentiation.²¹ Hou et al.²² described the functional analysis of claudin-16 in polarized cell lines. They demonstrated that in LLC-PK1 cells, claudin-16 modulated the ion selectivity of the TJ by selectively increasing the permeability of Na⁺ with no effects on Cl⁻, resulting in a high permeability ratio of Na⁺ to Cl⁻. Instead, Mg flux across cell monolayers showed a far less pronounced change after claudin-16 expression. From these data, it might be concluded that claudin-16 defects lead to a loss of cation selectivity with a subsequent decrease in lumen-positive potential that is the driving force for the paracellular flux of cations. This hypothesis of a nonselective paracellular cation channel is supported by a mouse model using transgenic RNAi depletion of claudin-16. Loss of CLDN16 in this model caused TJ in TAL to lose the cation selectivity.²³ Hou et al.²² also analyzed the consequences of most of the reported human CLDN16 mutations by heterologous expression in vitro. Whereas most mutations resulted in a complete loss of function, some mutations retained a substantial residual function. One of these mutations (L151F) is by far the most frequent FHHNC mutation, occurring in almost 50% of the patients described so far.²Combining this information with additional functional analysis of new mutations using the same expression system, we present a genotype/phenotype correlation with a special focus on the progression of renal failure in a large cohort of patients with FHHNC. We provide clinical data indicating that homozygous or compound heterozygous patients who carry at least one CLDN16 mutation with residual function have a much more benign course of the disease than patients with a complete loss of function.     

Hydrochlorothiazide in CLDN16 mutation.

BACKGROUND: Hydrochlorothiazide (HCT) is applied in the therapy of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) caused by claudin-16 (CLDN16) mutation. However, the short-term efficacy of HCT to reduce hypercalciuria in FHHNC has not yet been demonstrated in a clinical trial. METHODS: Four male and four female patients with FHHNC and CLDN16 mutation, under long-standing HCT therapy (0.4-1.2 mg/kg, median 0.9 mg/kg, dose according to calciuria), aged 0.7-22.4 years, were included in a clinical study to investigate the effect of HCT on calciuria. The study design consisted of three periods: continued therapy for 4 weeks, HCT withdrawal for 6 weeks and restart of therapy at the same dose for 4 weeks. Calciuria and magnesiuria were assessed weekly as Ca/creat and Mg/creat ratio, every 2 weeks in 24 h urine, and serum Mg, K and kaliuria (s-Mg, s-K and K/creat) at weeks 0, 6, 10 and 14. The data of each study period were averaged and analysed by Friedman and Wilcoxon test. RESULTS: Ca/creat was significantly reduced by HCT (median before/at/after withdrawal 0.76/1.24/0.77 mol/mol creat; n = 8, P<0.05). The reduction of Ca/24 h by HCT was not statistically significant (0.13/0.19/0.13 mmol/kg x 24 h; n = 5). Serum Mg (0.51/0.64/0.56 mmol/l; n = 8, P<0.05) and Serum K (3.65/4.35/3.65 mmol/l; n = 8, P<0.05) were significantly higher during withdrawal. However, Mg/creat (0.98/0.90/0.90 mol/mol creat; n = 8), Mg/24 h (0.14/0.12/0.18 mmol/kg x 24h; n = 5) and K/creat (6.3/8.4/6.2 mol/mol creat; n = 8) remained statistically unchanged during withdrawal. CONCLUSIONS: We demonstrated that HCT is effective in reducing hypercalciuria due to CLDN16 mutation on a short-term basis. However, the efficacy of HCT to attenuate disease progression remains to be elucidated.     

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium (Mg) and calcium (Ca) in the thick ascending limb of Henle's loop. We have studied seven Arab patients with this syndrome who belong to four different families. The mean age at first presentation was 1.5+/-1.3 years (range 0.1-3 years) and at diagnosis 5.9+/-4.3 years (range 0.5-12 years). The presenting features were convulsions and carpopedal spasms (5 patients), polydipsia and polyuria (2 patients), rickets (2 patients), and recurrent urinary tract infections (1 patient). Bilateral nephrocalcinosis was observed in all patients. All patients had hypomagnesemia with a mean serum Mg of 0.45+/-0.09 mmol/l, an inappropriately high urine Mg of 2.07+/-0.73 mmol/24 h or fractional excretion of 15.3+/-7.1%, high urine Ca excretion of 4.1+/-1.2 mmol/24 h or urine Ca to creatinine ratio of 2.6+/-1.6, and normal serum potassium level of 4.4+/-0.34 mmol/l. All patients received Mg supplements and thiazide but exhibited slow worsening of their kidney function. After a mean follow-up of 4.4+/-3.9 years, one patient progressed to end-stage renal failure (ESRF). In conclusion, we report seven Arab patients with FHHNC syndrome. The clinical and biochemical data were similar to previous reports. However, they tend to show a slower rate of progression to ESRF.     

Hereditary causes of kidney stones and chronic kidney disease

Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and primary hyperoxaluria (PH) are rare but important causes of severe kidney stone disease and/or chronic kidney disease in children. Recurrent kidney stone disease and nephrocalcinosis, particularly in pre-pubertal children, should alert the physician to the possibility of an inborn error of metabolism as the underlying cause. Unfortunately, the lack of recognition and knowledge of the five disorders has frequently resulted in an unacceptable delay in diagnosis and treatment, sometimes with grave consequences. A high index of suspicion coupled with early diagnosis may reduce or even prevent the serious long-term complications of these diseases. In this paper, we review the epidemiology, clinical features, diagnosis, treatment, and outcome of patients with APRT deficiency, cystinuria, Dent disease, FHHNC, and PH, with an emphasis on childhood manifestations.     

Genetic causes of hypercalciuric nephrolithiasis

Renal stone disease (nephrolithiasis) affects 3–5% of the population and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in over 35% of patients and may occur as a monogenic disorder that is more likely to manifest itself in childhood. Studies of these monogenic forms of hypercalciuric nephrolithiasis in humans, e.g. Bartter syndrome, Dent’s disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal disease, is caused by mutations of the bumetanide-sensitive Na–K–Cl (NKCC2) co-transporter, the renal outer-medullary potassium (ROMK) channel, the voltage-gated chloride channel, CLC-Kb, the CLC-Kb beta subunit, barttin, or the calcium-sensing receptor (CaSR). Dent’s disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is due to mutations of the chloride/proton antiporter 5, CLC-5; ADHH is associated with activating mutations of the CaSR, which is a G-protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium–phosphate co-transporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to hypercalciuria and nephrolithiasis.     

Molecular determinants of magnesium homeostasis: insights from human disease

The past decade has witnessed multiple advances in our understanding of magnesium (Mg(2+)) homeostasis. The discovery that mutations in claudin-16/paracellin-1 or claudin-19 are responsible for familial hypomagnesemia with hypercalciuria and nephrocalcinosis provided insight into the molecular mechanisms governing paracellular transport of Mg(2+). Our understanding of the transcellular movement of Mg(2+) was similarly enhanced by the realization that defects in transient receptor potential melastatin 6 (TRPM6) cause hypomagnesemia with secondary hypocalcemia. This channel regulates the apical entry of Mg(2+) into epithelia. In so doing, TRPM6 alters whole-body Mg(2+) homeostasis by controlling urinary excretion. Consequently, investigation into the regulation of TRPM6 has increased. Acid-base status, 17beta estradiol, and the immunosuppressive agents FK506 and cyclosporine affect plasma Mg(2+) levels by altering TRPM6 expression. A mutation in epithelial growth factor is responsible for isolated autosomal recessive hypomagnesemia, and epithelial growth factor activates TRPM6. A defect in the gamma-subunit of the Na,K-ATPase causes isolated dominant hypomagnesemia by altering TRPM6 activity through a decrease in the driving force for apical Mg(2+) influx. We anticipate that the next decade will provide further detail into the control of the gatekeeper TRPM6 and, therefore, overall whole-body Mg(2+) balance.