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Very few patients with familial hypomagnesemia, hypercalciuria and nephrocalcinosis have been described. Information about clinical course, familial studies or evolution after renal transplantation is very scant. We have studied eight patients with this syndrome who belong to five different families. The mean age at diagnosis was 15 +/- 7 years (5...
Citations
... . The importance of these genes to paracellular divalent cation permeability is best appreciated in the syndrome of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a condition caused by mutations in either gene.110,111 FHHNC patients present with a severe phenotype characterized by substantial urinary wasting of calcium and magnesium, resulting in the development of hypomagnesemia and nephrocalcinosis, the latter often associated with renal insufficiency.[110][111][112][113] Transplantation of a healthy unaffected kidney into an FHHNC patient prevents urinary calcium and magnesium losses, highlighting that the disease occurs as a consequence of a primary renal defect.113 ...
... FHHNC patients present with a severe phenotype characterized by substantial urinary wasting of calcium and magnesium, resulting in the development of hypomagnesemia and nephrocalcinosis, the latter often associated with renal insufficiency.[110][111][112][113] Transplantation of a healthy unaffected kidney into an FHHNC patient prevents urinary calcium and magnesium losses, highlighting that the disease occurs as a consequence of a primary renal defect.113 ...
Calcium and magnesium are the most abundant divalent cations in the body. The plasma level is controlled by coordinated interaction between intestinal absorption, reabsorption in the kidney, and, for calcium at least, bone storage and exchange. The kidney adjusts urinary excretion of these ions in response to alterations in their systemic concentration. Free ionized and anion‐complexed calcium and magnesium are filtered at the glomerulus. The majority (i.e., >85%) of filtered divalent cations are reabsorbed via paracellular pathways from the proximal tubule and thick ascending limb (TAL) of the loop of Henle. Interestingly, the largest fraction of filtered calcium is reabsorbed from the proximal tubule (65%), while the largest fraction of filtered magnesium is reclaimed from the TAL (60%). The paracellular pathways mediating these fluxes are composed of tight junctional pores formed by claudins. In the proximal tubule, claudin‐2 and claudin‐12 confer calcium permeability, while the exact identity of the magnesium pore remains to be determined. Claudin‐16 and claudin‐19 contribute to the calcium and magnesium permeable pathway in the TAL. In this review, we discuss the data supporting these conclusions and speculate as to why there is greater fractional calcium reabsorption from the proximal tubule and greater fractional magnesium reabsorption from the TAL.
... Given that total serum magnesium levels are primarily controlled by magnesium excretion in the urine, analysis of magnesium in the urine provides an alternative to total serum magnesium measurements [3]. Measuring creatinine in the 24hr sample is also helpful given that volume assessment can be done to assess for polyuria, which is evident with renal wasting of magnesium (consequent to drug or disease such as diabetes [42,43]) and ensures the completeness of the 24hr sample collection. However, this method of magnesium collection is rendered inconvenient by the circadian pattern of renal magnesium excretion, requiring a 24-hour urine specimen for accurate measurements [2,3,12]. ...
Magnesium is the fourth most abundant cation in the human body, essential for physiological processes and is the electrolyte with levels most deranged in critically ill patients. These derangements of Magnesium imbalance can go unnoticed and result in poor clinical outcomes, requiring both worthy attention to abnormal values and accurate tools and methods to measure Magnesium reliably. At present, clinical laboratories employ various methodologies for measuring Magnesium in blood and urine. This review aims to address the role of Magnesium from not only physiological and pathophysiological perspectives, but importantly to review the methods for measuring Magnesium with relevant analytical considerations. Given the role of Magnesium and drugs for various treatments, measuring Magnesium has become more relevant as drugs can lead to Magnesium imbalances. Clinical manifestations and etiology of Magnesium imbalance as divided into hypomagnesemia and hypermagnesemia is also reviewed.
... Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder characterized by renal calcium and magnesium loss, medullary nephrocalcinosis, and progressive chronic kidney disease (CKD) [1]. Patients with FHHNC usually present with recurrent urinary tract infections (UTI), polyuria, polydipsia, and failure to thrive. ...
... diuretics plausibly delays the progression of end-stage CKD [2]. Current treatment for end-stage renal dysfunction in this disease is renal transplantation [1]. Increased parathyroid hormone (PTH) concentrations, regardless of GFR, have been described in most cases [3]. ...
... Mg +2 has little or no effect on calcitonin secretion. In addition to medullary nephrocalcinosis and associated inflammation, abnormalities during kidney development caused by claudin mutations are responsible mechanisms for progressive renal failure [1]. While the nonsense, truncating, splice-site, and missense mutations with resulting in a complete loss of function (CLOF), missense mutations displaying substantial residual function > 40% as compared with wild-type claudin-16 function (PLOF). ...
Biallelic loss of function mutations in the CLDN16 gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of CLDN16 variants (c.715G>A, p.G239R; and novel c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in CLDN16. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.
... In fact, its definitive name comes from an article published by Manuel Praga et al. in 1995. 17 Cesar Loris, a paediatric nephrologist at the Hospital Infantil Universitario Miguel Servet in Zaragoza, confirmed with his colleagues that in the Spanish patients, the rate of eye disorders was unusually high (81% vs. 24% in patients from other countries). 18 The fact that, except for a very few, the Spanish patients with FHHNC did not have mutations in that gene was striking. ...
Las tubulopatías primarias son enfermedades raras. La mayoría de ellas tienen una herencia autosómica recesiva. La posibilidad de disponer, en la actualidad, de las técnicas de biología molecular ha permitido conocer la causa íntima genética de estas enfermedades y descubrir que esos trastornos son más frecuentes en los territorios en los que en el pasado existió un mayor o menor grado de consanguinidad. Por otra parte, los desplazamientos poblacionales que son tan antiguos como la humanidad, son la causa de la difusión de algunas enfermedades de origen genético. Su conocimiento, permite a los investigadores perseguir los pasos que han seguido determinadas mutaciones cromosómicas desde el lugar de origen del “ancestro fundador” hasta otros lugares radicados, muchas veces, en lugares del planeta muy distantes.
En el presente artículo, revisamos a partir de resultados propios y ajenos, algunos hallazgos disponibles sobre las bases moleculares de ciertas tubulopatias y de dos trastornos renales causantes de cálculos renales, en relación con la endogamia y los desplazamientos poblacionales.
... 40 In humans, some renal tubular disorders associ ated with the development of nephrocalcinosis and/or nephrolithiasis (eg, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, distal renal tubular acidosis) may cause changes in serum levels or urinary fractional excretion of magnesium along other electrolyte disturbances. [10][11][12]41 However, to the best of our knowl edge, magnesium and concurrent electrolytes abnormali ties in association with such tubular disorders were not reported in cats. Further investigations are needed to elu cidate whether cats may also have similar illness. ...
Objectives:
Magnesium has been 'the forgotten ion' for many years. Over the past decade, however, the role of magnesium in essential physiological functions and several illness conditions have been elucidated. Nevertheless, the investigation of magnesium in cats with chronic kidney disease (CKD) and nephrolithiasis is yet to be determined. The purpose of this study was to investigate whether CKD cats with nephrolithiasis have changes in total serum magnesium concentrations, and whether magnesium disorders may be associated with other electrolyte disturbances, as well as with prognosis. We also aimed to evaluate whether total serum magnesium concentration differs between CKD cats with and without nephrolithiasis.
Methods:
Total serum magnesium concentrations were assessed in 42 cats with CKD with stage 1-4 nephrolithiasis. The correlation between magnesium and other electrolytes, as well as Kaplan-Meier survival analysis, were performed. We also selected 14 control cats with CKD without nephrolithiasis age-matched with 14 cats with CKD with nephrolithiasis.
Results:
Hypermagnesemia was observed in 16/42 (38.1%) and hypomagnesemia in 6/42 (14.3%) cats. Serum magnesium abnormalities were observed in cats of all stages, and marked hypermagnesemia was noted in cats with stage 4 CKD with nephrolithiasis (P <0.001). There was a negative correlation between total serum magnesium and ionized calcium (r = -0.64; P <0.01), and a positive correlation between total serum magnesium and serum phosphorus (r = 0.58, P = 0.01). Cats with CKD with nephrolithiasis and hypomagnesemia or hypermagnesemia had higher mortality than those with normal total serum magnesium concentration (P <0.01), regardless of CKD stage. There was no difference in total serum magnesium concentration between CKD cats with and without nephrolithiasis.
Conclusions and relevance:
Cats with CKD with nephrolithiasis have magnesium abnormalities. Hypomagnesemia and hypermagnesemia were associated with an increase in mortality, and thus total serum magnesium abnormalities may be used as prognostic factors in these cases.
... Keywords: Familial hypomagnesaemia with Hypercalciuria and Nephrocalcinosis, Claudin 16, Mutation, Highly conserved motif Background Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal-recessive renal tubular disorder characterized by excessive urinary losses of magnesium and calcium, bilateral nephrocalcinosis and progressive chronic renal failure [1]. This disease is caused by mutations in the tight junction (TJ) proteins, claudin-16 and -19, which are encoded by the CLDN16 (OMIM #248250) or CLDN19 (OMIM #248190) genes respectively [2,3]. ...
Background:
Sixty mutations of claudin 16 coding gene have been reported in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) patients. Recent investigations revealed that a highly conserved glycine-leucine-tryptophan (115G-L-W117) motif in the first extracellular segment (ESC1) of claudin 16 might be essential for stabilization of the appropriately folded ECS1 structure and conservation of normal claudin 16 function. However, neither missense nor nonsense mutation has ever been described in this motif. Our study aimed at identifying mutations in a Chinese patient with FHHNC and exploring the association between genotype and phenotype.
Case presentation:
A 33-year-old female presented with 4 years history of recurrent acute pyelonephritis without other notable past medical history. Her healthy parents, who aged 56 and 53 respectively, were second cousins, and her only sibling died from renal failure without definite cause at age 25. Renal ultrasound imaging demonstrated atrophic kidneys and bilateral nephrocalcinosis. The laboratory workup revealed impaired renal function (Stage CKD IV), hypocalcemia and mild hypomagnesemia, accompanied with marked renal loss of magnesium and hypercalciuria. During the follow-up, treatment with calcitriol and calcium but not with magnesium was difficult to achieve normal serum calcium levels, whereas her serum magnesium concentration fluctuated within normal ranges. In the end, the patient unavoidably reached ESRD at 36 years old. The clinical features and family history suggested the diagnosis of FHHNC. To make a definite diagnosis, we use whole-exome sequencing to identify the disease-causing mutations and Sanger sequencing to confirm the mutation co-segregation in the family. As a result, a novel homozygous mutation (c.346C > G, p.Leu116Val) in 115G-L-W117 motif of claudin 16 was identified. Her parents, grandmother and one of her cousins carried heterozygous p.Leu116Val, whereas 200 unrelated controls did not carry this mutation.
Conclusions:
We described a delayed diagnosis patient with FHHNC in the Chinese population and identified a novel missense mutation in the highly conserved 115G-L-W117 motif of claudin 16 for the first time. According to the reported data and the information deduced from 3D modeling, we speculate that this mutation probably reserve partial residual function which might be related to the slight phenotype of the patient.
... SBS itself can cause diarrhea, but sometimes Mg supplementation increases intestinal motility, leading to further diarrhea, which in turn increases the loss of water and electrolytes and leads to secondary hyperaldosteronism and further renal Mg wasting (18). Familial hypomagnesemia with hypercalciuria and nephrocalcinosis, a rare autosomal recessive disorder, is characterized by severe renal Mg and calcium wasting (19). Acute CPP arthritis due to hypomagnesemia has also been described in patients with liver transplant, in whom it has been suspected to occur from a combination of Mg depletion before transplant and tacrolimus use, which induces renal Mg leakage (20). ...
Calcium pyrophosphate deposition (CPPD) disease, also known as pseudogout, is one of the most common forms of inflammatory arthritis. A variety of comorbidities and metabolic conditions have been recognized to predispose to CPPD. We describe here a patient with chronic CPP arthritis due to hypomagnesemia, which is one of the metabolic etiologies associated with CPPD, especially in younger patients. We also performed a literature search and reviewed all reported cases of CPPD disease associated with hypomagnesemia. All cases of hypomagnesemia and its etiologies leading to CPP arthropathy identified in the literature by this systematic search are summarized in this paper.
... 158,159 This syndrome is caused by autosomal recessive mutations in CLDN16 and CLDN19 genes, and it results in severe renal wasting of Ca 2+ and Mg 2+ along with hypomagnesemia and nephrocalcinosis. [158][159][160][161] Furthermore, a pore blocking claudin has been found expressed in TAL. In response to Ca 2+ sensing receptor activation, Cldn14 expression is greatly increased, [162][163][164] where it most likely interacts with CLDN16 to block divalent cation permeation. ...
The thick ascending limb (TAL) extends from the border of the inner medulla to the renal cortex, thus ascending through regions with wide differences in tissue solute and electrolyte concentrations. Structural and functional differences between TAL cells in the medulla (mTAL) and the cortex (cTAL) would therefore be useful to adapt TAL transport function to a changing external fluid composition. While mechanisms common to all TAL cells play a central role in the reclamation of about 25% of the NaCl filtered by the kidney, morphological features, Na⁺/ K⁺-ATPase activity, NKCC2 splicing and phosphorylation does vary between segments and cells. The TAL contributes to K⁺ homeostasis and TAL cells with high or low basolateral K⁺ conductances have been identified which may be involved in K⁺ reabsorption and secretion, respectively. Although transport rates for HCO3⁻ do not differ between mTAL and cTAL, divergent axial and cellular expression of H⁺ transport proteins in TAL have been documented. The reabsorption of the divalent cations Ca²⁺ and Mg²⁺ is highest in cTAL and paralleled by differences in divalent cation permeability and the expression of select claudins. Morphologically, two cell types with different cell surface phenotypes have been described that still need to be linked to specific functional characteristics. The unique external environment and its change along the longitudinal axis require an axial functional heterogeneity for the TAL to optimally participate in conserving electrolyte homeostasis. Despite substantial progress in understanding TAL function there are still considerable knowledge gaps that are just beginning to become bridged.
... Nephrocalcinosis in FHHNC is characterized by the deposition of calcium oxalate/phosphate in the kidney parenchyma and tubules. [3] It was described in 1972 by Michelis et al. [8] (historically known as Michelis-Gutmo syndrome) and designated as FHHNC by Praga et al. in 1995 [9] and is a rare inherited renal tubular disease with nephrocalcinosis frequently complicated by progressive renal failure during childhood or adolescence. ...
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder that is caused by mutation in genes coding for tight junction proteins claudin-16 and claudin-19. It is characterized by renal wasting of magnesium and calcium associated with the development of nephrocalcinosis and renal stones by early childhood. Most of them progress to end-stage renal failure by the second or third decade. Here, we report two siblings with FHHNC, who presented with nephrocalcinosis without any extrarenal manifestations, one of them having novel homozygous nonsense mutation in claudin-16 (CLDN16) (c.620G>A, p. Trp207Ter). Both were treated with dietary changes, hydrochlorothiazide, potassium citrate, and magnesium supplementation. FHHNC is a rare cause of nephrocalcinosis, and we believe that it should be considered in the presence of nephrocalcinosis with hypercalciuria and hypomagnesemia.
... 39 Two children <3 years had hypomagnesemia with hypercalciuria and UL without NC. 64 As shown in Table 2, oliguria was found in 14 children (8.6%). Children with UL are known to have low urine volumes. ...
... Hypomagnesemia was found in 11 children (7%) and was associated with hypocitraturia and hypomagnesuria. 64 Hyperuricosemia was observed in 11 children (7%), and hypercalcemia in 10 (6%); all with normal PTHi values and two or more risk factors associated. Hyperoxaluria was observed in three children (2%) without clinical evidence of any metabolic defect, two of which had moderate inflammatory bowel disease history. ...
Background
The prevalence of pediatric urolithiasis varies from 0.01–0.03%. Urolithiasis may be caused by anatomical, metabolic and environmental factors. Recurrence varies between 16 to 67%, and it is frequently associated with metabolic abnormalities. The objective of the present work was the identification of risk factors that promote urolithiasis in a child population.
Methods
This study included 162 children with urolithiasis and normal renal function (mean age 7.5 years). Risk factors were investigated in two stages. In the first stage, 24-hour urine, and blood samples were analyzed to assess metabolic parameters and urinary tract infection. During the second stage, the effect of calcium restriction and a calcium load on renal Ca excretion were evaluated. Data were statistically analyzed.
Results
Urolithiasis was observed in 0.02% of children, 50% of them with family history of urinary stones. There were multiple risk factors for urolithiasis including hypocitraturia (70%), hypomagnesuria (42%), hypercalciuria (37%; in 11/102 was by intestinal hyperabsorption, in 13/102 was unclassified. Ca resorption or renal Ca leak were not detected). We also detected alkaline urine (21%), systemic metabolic acidosis (20%), urinary infections (16%), nephrocalcinosis with urolithiasis (11%), oliguria (8%), urinary tract anomalies, hyperuricosemia and hypermagnesemia (7% each one), hypercalcemia (6%), hyperoxaluria (2%) and hypercystinuria (0.61%).
Conclusions
Hypocitraturia and hypomagnesuria were the most frequent risk factors associated with urolithiasis, followed by hypercalciuria. High PTH values were excluded. Children presented two or more risk factors for urolithiasis.
