A new mutation in the gene encoding mitochondrial seryl-tRNA synthetase as a cause of HUPRA syndrome.

BACKGROUND: HUPRA syndrome is a rare mitochondrial disease characterized by hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis. This syndrome was previously described in three patients with a homozygous mutation c.1169A > G (p.D390G) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. CASE PRESENTATION: Here we report the clinical and genetic findings in a girl and her brother. Both patients were clinically diagnosed with the HUPRA syndrome. Analysis of the pedigree identified a new homozygous mutation c.1205G > A (p.R402H) in SARS2 gene. This mutation is very rare in the population and it is located at the C-terminal globular domain of the homodimeric enzyme very close to p.D390G. CONCLUSION: Several data support that p.R402H mutation in SARS2 is a new cause of HUPRA syndrome.

Claudin-19 mutations and clinical phenotype in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsorption in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease.

Dent's disease: Identification of seven new pathogenic mutations in the CLCN5 gene.

Dent's disease is an X-linked proximal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. This disorder is frequently caused by mutations in the CLCN5 gene encoding the electrogenic chloride/proton exchanger ClC-5. Occasionally, Dent's disease has been associated to atypical cases of asymptomatic proteinuria with focal glomerulosclerosis. Twelve unrelated patients with Dent's disease, including two who presented with asymptomatic proteinuria and developed glomerulosclerosis, were studied. Mutational analysis of the CLCN5 gene was performed by DNA sequencing. We identified thirteen distinct CLCN5 mutations in the twelve patients. Seven of these mutations, p.P416fsX(*)17, p.[H107P, V108fs(*)27], p.G466D, p.G65R, p.G462S, p.Y164(*) and c.723+1G >T, were novel and possibly pathogenic. In one family, the patient's mother was not a carrier of the respective mutation. Our results increased the spectrum of CLCN5 disease causing defects with seven new pathogenic mutations and established a de novo origin in one of them. Remarkably, three new missense mutations, p.G466D, p.G65R and p.G462S, affect highly conserved glycine residues located in transmembrane α-helix GxxxG packing motifs. The two atypical cases further support that the diagnosis of Dent's disease should be considered in children with asymptomatic proteinuria and focal glomerulosclerosis and without evidence of primary glomerular disease.

Improvement in growth after 1 year of growth hormone therapy in well-nourished infants with growth retardation secondary to chronic renal failure: results of a multicenter, controlled, randomized, open clinical trial.

BACKGROUND AND OBJECTIVES: Our aim was to evaluate the growth-promoting effect of growth hormone (GH) treatment in infants with chronic renal failure (CRF) and persistent growth retardation despite adequate nutritional and metabolic management. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study design included randomized, parallel groups in an open, multicenter trial comparing GH (0.33 mg/kg per wk) with nontreatment with GH during 12 months. Sixteen infants who had growth retardation, were aged 12+/-3 months, had CRF (GFR

Renal pathology in children with mitochondrial diseases.

We studied renal involvement in 42 children with mitochondrial diseases (MDs). The diagnosis of MD was established by morphological, biochemical, and molecular genetic criteria. Renal disease was considered when patients had renal failure, nephrotic syndrome, Fanconi's syndrome or any symptomatic renal alteration. Mild tubular disorder was established if they had abnormal laboratory findings with no apparent clinical symptom. Renal involvement was found in 21 children (50%), of whom 8 had an apparent clinical picture and 13 a mild tubular disorder. Five patients with renal disease showed Debré-Toni-Fanconi's syndrome, 2 of them with decreased glomerular filtration rate (GFR). One case had nephrotic syndrome, another one presented decreased GFR, and the last one had a neurogenic bladder and bilateral hydronephrosis. Patients with mild renal disease showed tubular dysfunction with normal GFR. Renal involvement is frequent and present in about half of the children with MD. Thus, studies for evaluating kidney function should be performed on children with MD. Conversely, patients with tubulopathy of unknown origin or progressive renal disease should be investigated for the existence of MD, especially if associated with involvement of other organs or tissues. Southern blot analysis to search for large-scale mitochondrial DNA (mtDNA) rearrangements should be performed for patients with MD and kidney involvement.