CNNM2, encoding a basolateral protein required for renal Mg2+ handling, is mutated in dominant hypomagnesemia.

Familial hypomagnesemia is a rare human disorder caused by renal or intestinal magnesium (Mg(2+)) wasting, which may lead to symptoms of Mg(2+) depletion such as tetany, seizures, and cardiac arrhythmias. Our knowledge of the physiology of Mg(2+) (re)absorption, particularly the luminal uptake of Mg(2+) along the nephron, has benefitted from positional cloning approaches in families with Mg(2+) reabsorption disorders; however, basolateral Mg(2+) transport and its regulation are still poorly understood. Here, by using a candidate screening approach, we identified CNNM2 as a gene involved in renal Mg(2+) handling in patients of two unrelated families with unexplained dominant hypomagnesemia. In the kidney, CNNM2 was predominantly found along the basolateral membrane of distal tubular segments involved in Mg(2+) reabsorption. The basolateral localization of endogenous and recombinant CNNM2 was confirmed in epithelial kidney cell lines. Electrophysiological analysis showed that CNNM2 mediated Mg(2+)-sensitive Na(+) currents that were significantly diminished in mutant protein and were blocked by increased extracellular Mg(2+) concentrations. Our data support the findings of a recent genome-wide association study showing the CNNM2 locus to be associated with serum Mg(2+) concentrations. The mutations found in CNNM2, its observed sensitivity to extracellular Mg(2+), and its basolateral localization signify a critical role for CNNM2 in epithelial Mg(2+) transport.

Serum homocysteine levels in Czech children and adolescents.

AIM: The principal aim was to establish reference paediatric data for the serum homocysteine levels in Czech children and adolescents. METHODS AND RESULTS: 144 children either healthy or not sufferig from acute or chronic inflammation, autoimmune disorders including rheumatic diseases, inflammatory musculoskeletal disorders, inflammatory bowel disease, diabetes mellitus, hypercholesterolemia, epilepsy, chronic renal failure, aged 0-19.9 years (0-6.9 years, n = 40; 7-10.9 y, n = 28; 11-15.9 y, n = 45; 16-19.9 y, n = 31) had their blood samples collected and the serum homocysteine level (S-homocysteine) was evaluated by chemiluminescence. A significant age dependence of the S-homocysteine levels was observed (R = 0.35, p < 0.01); with highest values of upper reference range in the 11-15.9 and 16-19.9 years' group, respectively. CONCLUSION: The establishment of S-homocysteine reference Czech pediatric values is a potentially useful tool for proper evaluation of elevated homocysteine levels and corresponding risks in childhood.

Elevated serum homocysteine levels in paediatric patients with primary Raynaud's phenomenon.

INTRODUCTION: Raynaud's phenomenon (RP) is a paroxysmal and recurrent acral ischemia resulting from an abnormal arterial vasospastic response to cold or emotional stress. Homocysteine, a sulphured amino acid, has been linked to cardiovascular and neurodegenerative diseases, diabetes, thrombosis, and bone fragility. Homocysteine has been also linked to the pathogenesis of RP, as increased serum homocysteine (S-homocysteine) levels were observed in patients with RP. OBJECTIVE: As all publications concerning S-homocysteine in RP involved only adult patients, our aim was to evaluate S-homocysteine in children and adolescents with RP. METHODS: Nineteen patients (two boys and 17 girls; mean age 16.1 ± 2.2 SD) with primary RP were enrolled. The controls were 51 children and adolescents (21 boys and 30 girls; mean age 15.1 ± 1.8 SD). RESULTS: The S-homocysteine level was significantly higher in the RP group in comparison with controls (11.2 ± 2.4 vs. 8.0 ± 2.0 µmol/L; P = 0.00001). S-homocysteine levels in RP were not age-dependent. CONCLUSION: Paediatric patients with RP have increased S-homocysteine levels, suggesting that homocysteine plays an important role in the development of vascular dysfunction, even at an early age.

Normal bone turnover in transient hyperphosphatasemia.

Transient hyperphosphatasemia of infancy and early childhood (THI) is characterized by a temporary isolated elevation of serum alkaline phosphatase activity (ALP), predominantly its bone or liver isoform, in either sick or healthy children under 5 years of age. Return to normal ALP levels usually occurs within four months. Spontaneous rise of ALP might concern the physician, especially when treating seriously ill children. However, THI is considered a benign biochemical disorder with no clinical consequences. Some existing reports support the hypothesis that THI is a result of increased bone turnover. We present evidence of normal bone turnover in two children with THI. In a one-year-old girl and a boy of the same age, high ALP levels (31 and 109 µkat/L, respectively) were accidentally detected. The children had no signs of metabolic bone disease or of liver disease. The high ALP levels returned to normal in two months, thus fulfilling the diagnosis of THI. In both patients, serum parathyroid hormone and bone turnover markers, serum CrossLaps, and serum osteocalcin were neither elevated, nor did these markers follow the ALP dynamics, thus reflecting normal bone turnover in THI. Children with THI should be spared from extensive investigations and unnecessary vitamin D treatment.

Níveis séricos elevados de homocisteína em pacientes pediátricos com fenômeno de Raynaud primário / Elevated serum homocysteine levels in paediatric patients with primary Raynaud's phenomenon

INTRODUÇÃO: O fenômeno de Raynaud (FR) é uma isquemia acral recorrente resultante de resposta vasoespástica arterial anormal ao frio ou ao estresse emocional. A homocisteína, um aminoácido sulfurado, foi relacionada a doenças cardiovasculares e neurodegenerativas, diabetes mellitus, trombose e fragilidade óssea. Também foi relacionada à patogênese do FR, por terem sido observadas elevações nos níveis séricos de homocisteína (S-homocisteína) em pacientes com FR. OBJETIVO: Considerando que todas as publicações concernentes à S-homocisteína em casos de FR envolviam apenas pacientes adultos, o objetivo deste estudo foi avaliar a S-homocisteína em crianças e adolescentes com FR. MÉTODOS: Foram recrutados 19 pacientes (dois meninos e 17 meninas; idade média 16,1 ± 2,2 DP) com FR primário. Como controles, foram recrutados 51 crianças e adolescentes (21 meninos e 30 meninas; idade média 15,1 ± 1,8 DP). RESULTADOS: O nível de S-homocisteína estava significativamente mais elevado no grupo FR, em comparação com os controles (11,2 ± 2,4 vs. 8,0 ± 2,0 µmol/L; P = 0,00001). Os níveis de S-homocisteína nos participantes com FR não dependeram da idade. CONCLUSÃO: Pacientes pediátricos com FR apresentam níveis elevados de S-homocisteína, sugerindo que a homocisteína desempenha papel importante no desenvolvimento da disfunção vascular, mesmo em pacientes muito jovens.

INTRODUCTION: Raynaud's phenomenon (RP) is a paroxysmal and recurrent acral ischemia resulting from an abnormal arterial vasospastic response to cold or emotional stress. Homocysteine, a sulphured amino acid, has been linked to cardiovascular and neurodegenerative diseases, diabetes, thrombosis, and bone fragility. Homocysteine has been also linked to the pathogenesis of RP, as increased serum homocysteine (S-homocysteine) levels were observed in patients with RP. OBJECTIVE: As all publications concerning S-homocysteine in RP involved only adult patients, our aim was to evaluate S-homocysteine in children and adolescents with RP. METHODS: Nineteen patients (two boys and 17 girls; mean age 16.1 ± 2.2 SD) with primary RP were enrolled. The controls were 51 children and adolescents (21 boys and 30 girls; mean age 15.1 ± 1.8 SD). RESULTS: The S-homocysteine level was significantly higher in the RP group in comparison with controls (11.2 ± 2.4 vs. 8.0 ± 2.0 µmol/L; P = 0.00001). S-homocysteine levels in RP were not age-dependent. CONCLUSION: Paediatric patients with RP have increased S-homocysteine levels, suggesting that homocysteine plays an important role in the development of vascular dysfunction, even at an early age.

Mild course of Puumala nephropathy in children in an area with sporadic occurrence Hantavirus infection.

The first three children with Puumala virus nephropathy diagnosis in the Czech Republic are reported on. A boy and two girls were admitted with symptoms of interstitial nephritis. The medical history in all children revealed flu-like symptoms. All patients were mildly pyrexial and had elevated erythrocytes sedimentation rate, C-reactive protein and low hemoglobin levels. Serum creatinine levels were elevated and proteinuria exceeded 700 mg/L in all children. Tubular proteinuria, glycosuria, high urinary N-acetyl-beta-D-glucosaminidase levels and alpha-1-microglobulin levels confirmed the tubular lesion. Renal biopsies revealed a uniform pattern and showed non-purulent interstitial nephritis in all patients. Puumala virus antigen antibodies were detected in the plasma. All patients were treated with steroids and urine abnormalities and renal function returned to normal within 4 weeks. Hantavirus infection should be considered as one of possible causes of interstitial nephritis with decreased GFR in children even in areas with a low incidence of this infection.