Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; OMIM 248250) is a rare autosomal recessive kidney disease caused by mutations in the
CLDN16
or
CLDN19
genes encoding the ...proteins claudin-16 and claudin-19, respectively. These are involved in paracellular magnesium and calcium transport in the thick ascending limb of Henle’s loop and account for most of the magnesium reabsorption in the tubules. FHHNC is characterized by hypomagnesaemia, hypercalciuria, and nephrocalcinosis, and progresses to kidney failure, requiring dialysis and kidney transplantation mainly during the second to third decades of life. Patients carrying
CLDN19
mutations frequently exhibit associated congenital ocular defects leading to variable visual impairment. Despite this severe clinical course, phenotype variability even among siblings has been described in this disease, suggesting unidentified epigenetic mechanisms or other genetic or environmental modifiers. Currently, there is no specific therapy for FHHNC. Supportive treatment with high fluid intake and dietary restrictions, as well as magnesium salts, thiazides, and citrate, are commonly used in an attempt to retard the progression of kidney failure. A kidney transplant remains the only curative option for kidney failure in these patients. In this review, we summarize the current knowledge about FHHNC and discuss the remaining open questions about this disorder.
Vitamin D is essential for the normal mineralization of bones during childhood. Although diet and adequate sun exposure should provide enough of this nutrient, there is a high prevalence of vitamin D ...deficiency rickets worldwide. Children with certain conditions that lead to decreased vitamin D production and/or absorption are at the greatest risk of nutritional rickets. In addition, several rare genetic alterations are also associated with severe forms of vitamin-D-resistant or -dependent rickets. Although vitamin D3 is the threshold nutrient for the vitamin D endocrine system (VDES), direct measurement of circulating vitamin D3 itself is not a good marker of the nutritional status of the system. Calcifediol (or 25(OH)D) serum levels are used to assess VDES status. While there is no clear consensus among the different scientific associations on calcifediol status, many clinical trials have demonstrated the benefit of ensuring normal 25(OH)D serum levels and calcium intake for the prevention or treatment of nutritional rickets in childhood. Therefore, during the first year of life, infants should receive vitamin D treatment with at least 400 IU/day. In addition, a diet should ensure a normal calcium intake. Healthy lifestyle habits to prevent vitamin D deficiency should be encouraged during childhood. In children who develop clinical signs of rickets, adequate treatment with vitamin D and calcium should be guaranteed. Children with additional risk factors for 25(OH)D deficiency and nutritional rickets should be assessed periodically and treated promptly to prevent further bone damage.
Background
Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder caused by impaired distal mechanisms of urinary acidification. Most cases are secondary to pathogenic variants in
...ATP6V0A4
,
ATP6V1B1
, and
SLC4A1
genes, which encode transporters regulating acid-base balance in the collecting duct.
Methods
Retrospective study of molecular and clinical data from diagnosis and long-term follow-up (10, 20, and 40±10 years) of 16 patients with primary dRTA diagnosed in childhood.
Results
Molecular analyses revealed nine patients had
ATP6V0A4
pathogenic variants, five in
ATP6V1B1
, and two in
SLC4A1
. A novel intragenic deletion and a common
ATP6V0A4
gene variant (c.1691 + 2dupT) in
ATP6V0A4
occurred in two-thirds of these patients, suggesting a founder effect. Median age at diagnosis was 3.25 months (IQR 1, 13.5), which was higher in the
SLC4A1
group. Median SDS height at diagnosis was −1.02 (IQR −1.79, 0.14). Delayed clinical diagnosis was significantly related to growth failure (
P
= 0.01). Median SDS height at 20 years follow-up was −1.23 (IQR −1.71, −0.48), and did not significantly improve from diagnosis (P = 0.76). Kidney function declined over time: at last follow-up, 43% had moderate to severe chronic kidney disease (CKD). Adequate metabolic control was not related to CKD development. Incidence of sensorineural hearing loss (SNHL) was high in
ATP6V1B1
patients, though not universal. Patients harboring
ATP6V0A4
variants also developed SNHL at a high rate (80%) over time.
Conclusions
Patients with dRTA can develop moderate to severe CKD over time with a high frequency despite adequate metabolic control. Early diagnosis ameliorates long-term height prognosis.
The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A ...cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by Next-Generation Sequencing (NGS). A targeted panel for disorders of calcium and phosphorus metabolism was designed to include 65 genes associated with these disorders. We observed two variants of uncertain significance (p.(Ser487Phe) and p.Asn315Asp), one likely pathogenic (p.Val382Met) and one benign variant (p.Ala393_Gln395dup) in the GCM2 gene in the heterozygous state in five families (two index cases had hypocalcemia and hypoparathyroidism, respectively, and three index cases had primary hyperparathyroidism). Our study shows the utility of NGS in unravelling the genetic origin of some disorders of the calcium and phosphorus metabolism, and confirms the GCM2 gene as an important element for the maintenance of calcium homeostasis. Importantly, a novel variant in the GCM2 gene (p.(Ser487Phe)) has been found in a patient with hypocalcemia.
Incidence and prevalence of urolithiasis is apparently increasing worldwide, also among children and adolescents. Nevertheless, robust data have only been obtained in a few countries. In Spain, a ...voluntary Registry for Pediatric Renal Lithiasis has been active since 2015. Irregular participation limits its applicability, as well as its limitation to patients with a stone available for morphocompositional study, to obtain data about incidence and prevalence. On the other hand, findings about typology of stones and clinical and analytical characteristics of these subjects have been communicated in several meetings. Other valuable efforts in this field are the elaboration of guidelines for the collection and processing of urine samples for the study of urolithiasis in pediatric patients with the consensus of the Spanish Society for Pediatric Nephrology (AENP) as well as the Spanish Society for Laboratory Medicine (SEQC), the collaborative network RenalTube for the diagnosis of primary tubulopathies and the registry of patients with Primary Hyperoxaluria (OxalSpain). In many hospitals from the public healthcare system, pediatric nephrologists are the specialists in charge of the management of children with kidney stones, but there is no formal regulation on this competence. Other specialists, such as urologists, pediatric surgeons or pediatric urologists, in many cases do not offer a complete insight into the etiopathogenic mechanisms and the consequent medical treatment. Access to medication according to standards of treatment is warranted, provided a correct diagnosis is achieved, but criteria for the reimbursement of certain therapies, such as RNAi drugs for primary hyperoxaluria, are arguable.
The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be ...involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in the CNNM2 gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p.(Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype-phenotype ...relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg
transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca
homeostasis.
Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The ...clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy.
This study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy.
This study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family.
Our results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.
La acidosis tubular renal distal (ATRD) es una enfermedad rara que se debe al fallo del proceso normal de acidificación de la orina a nivel tubular distal y colector. Se caracteriza por una acidosis ...metabólica hiperclorémica persistente, con anión gap normal en plasma, en presencia de un pH urinario elevado y baja excreción urinaria de amonio.
Se han descrito hasta el momento 5 genes cuyas mutaciones dan lugar a ATRD primaria. Las alteraciones de los genes ATP6V1B1 y ATP6V0A4 se heredan de forma recesiva y están asociadas a formas de inicio más precoces y con sordera neurosensorial en muchos casos. Las variantes patogénicas en el gen SLC4A1 se heredan habitualmente de forma dominante y dan lugar a cuadros más leves, con un diagnóstico más tardío y alteraciones electrolíticas menores. Sin embargo, la evolución a nefrocalcinosis y litiasis, y el desarrollo de enfermedad renal crónica a medio-largo plazo se ha descrito de forma similar en estos 3grupos. Por último, se han descrito también formas recesivas de ATRD asociadas a mutaciones en los genes FOXI1 y WDR72.
El manejo clínico de la ATRD se basa en sales de bicarbonato o citrato, que no logran corregir en todos los casos las alteraciones metabólicas descritas y, por lo tanto, las consecuencias asociadas a ellas. Recientemente, un nuevo tratamiento basado en sales de bicarbonato y citrato de liberación prolongada ha recibido la denominación de medicamento huérfano en Europa para el tratamiento de la ATRD.
Distal renal tubular acidosis (DRTA) is a rare disease resulting from a failure in the normal urine acidification process at the distal tubule and collecting duct level. It is characterised by persistent hyperchloremic metabolic acidosis, with a normal anion gap in plasma, in the presence of high urinary pH and low urinary excretion of ammonium.
To date, 5 genes whose mutations give rise to primary DRTA have been described. Alterations in the ATP6V1B1 and ATP6V0A4 genes are inherited recessively and are associated with forms of early onset and, in many cases, with neurosensorial deafness. Pathogenic variants in the SLC4A1 gene are habitually inherited dominantly and give rise to milder symptoms, with a later diagnosis and milder electrolytic alterations. Nonetheless, evolution to nephrocalcinosis and lithiasis, and the development of chronic kidney disease in the medium to long term has been described in a similar manner in all 3groups. Lastly, recessive forms of DTRA associated to mutations in the FOXI1 and WDR72 genes have also been described.
The clinical management of DTRA is based on bicarbonate or citrate salts, which do not succeed in correcting all cases of the metabolic alterations described and, thus, the consequences associated with them. Recently, a new treatment based on slow-release bicarbonate and citrate salts has received the designation of orphan drug in Europe for the treatment of DTRA.
Type III Bartter syndrome (BS) is an autosomal recessive renal tubule disorder caused by loss-of-function mutations in the CLCNKB gene, which encodes the chloride channel protein ClC-Kb. In this ...study, we carried out a complete clinical and genetic characterization in a cohort of 30 patients, one of the largest series described. By comparing with other published populations, and considering that 80% of our patients presented the p.Ala204Thr Spanish founder mutation presumably associated with a common phenotype, we aimed to test the hypothesis that allelic differences could explain the wide phenotypic variability observed in patients with type III BS.
Clinical data were retrieved from the referral centers. The exon regions and flanking intronic sequences of the CLCNKB gene were screened for mutations by polymerase chain reaction (PCR) followed by direct Sanger sequencing. Presence of gross deletions or duplications in the region was checked for by MLPA and QMPSF analyses.
Polyuria, polydipsia and dehydration were the main common symptoms. Metabolic alkalosis and hypokalemia of renal origin were detected in all patients at diagnosis. Calciuria levels were variable: hypercalciuria was detected in 31% of patients, while 23% had hypocalciuria. Nephrocalcinosis was diagnosed in 20% of the cohort. Two novel CLCNKB mutations were identified: a small homozygous deletion (c.753delG) in one patient and a small deletion (c.1026delC) in another. The latter was present in compound heterozygosis with the already previously described p.Glu442Gly mutation. No phenotypic association was obtained regarding the genotype.
A poor correlation was found between a specific type of mutation in the CLCNKB gene and type III BS phenotype. Importantly, two CLCNKB mutations not previously described were found in our cohort.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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