SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement.

Ionic calcium (Ca) is a key messenger in signal transduction and its mitochondrial uptake plays an important role in cell physiology. This uptake is mediated by the mitochondrial Ca uniporter (MCU), which is regulated by EMRE (essential MCU regulator) encoded by the SMDT1 (single-pass membrane protein with aspartate rich tail 1) gene. This work presents the genetic, clinical and cellular characterization of two patients harbouring SMDT1 variants and presenting with muscle problems.

Outcome of infantile nephropathic cystinosis depends on early intervention, not genotype: A multicenter sibling cohort study.

Infantile nephropathic cystinosis (INC) is an inheritable lysosomal storage disorder characterized by lysosomal cystine accumulation, progressive kidney disease, and multiple extrarenal complications (ERCs). Cysteamine postpones the onset of end-stage kidney disease (ESKD) and reduces the incidence of ERCs; however, cysteamine is generally initiated upon establishment of the renal Fanconi syndrome (FS) and partial loss of kidney function, whereas data on long-term effects of cysteamine administered from neonatal age are lacking. An international multicenter retrospective cohort study of siblings with INC was set up to investigate the outcome in relation to age at initiation of cysteamine versus CTNS genotype, with attention to patients treated with cysteamine from neonatal age.

Functional Hemolytic Test for Complement Alternative Pathway Convertase Activity.

The complement system is a key part of innate immunity. However, if the system becomes dysregulated, damage to healthy host cells can occur, especially to the glomerular cells of the kidney. The convertases of the alternative pathway of the complement system play a crucial role in complement activation.

Parenteral hydroxocobalamin dose intensification in five patients with different types of early onset intracellular cobalamin defects: Clinical and biochemical responses.

Intracellular cobalamin metabolism (ICM) defects can be present as autosomal recessive or X-linked disorders. Parenteral hydroxocobalamin (P-OHCbl) is the mainstay of therapy, but the optimal dose has not been determined. Despite early treatment, long-term complications may develop.

Molecular Basis of Cystinosis: Geographic Distribution, Functional Consequences of Mutations in the CTNS Gene, and Potential for Repair.

Mutations in the CTNS gene encoding the lysosomal membrane cystine transporter cystinosin are the cause of cystinosis, an autosomal recessive lysosomal storage disease. More than 140 CTNS mutations have been reported worldwide. Recent studies have discovered that cystinosin exerts other key cellular functions beyond cystine transport such as regulation of oxidative state, lysosomal dynamics and autophagy.

18F-FDG-PET/CT for the detection of disease in patients with head and neck cancer treated with radiotherapy.

Objective: The aim of this study is to evaluate the diagnostic performance of FDG-PET/CT for the detection of residual disease after (chemo)radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) and to evaluate the prognostic value of the FDG-PET/CT findings.

Methods: Patients with HNSCC who underwent FDG-PET/CT after (chemo)radiotherapy were studied retrospectively.

Results: 104 FDG-PET/CT-scans were performed at a median of 13.

Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory.

TMPRSS6 variants that affect protein function result in impaired matriptase-2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype-phenotype correlation, and optimal clinical management.

Recovery of renal function after long-term dialysis and resolution of cardiomyopathy in a patient with aHUS receiving eculizumab.

We present the case of a 18-month-old girl with renal and cardiac manifestations of atypical haemolytic uraemic syndrome (aHUS), and a novel complement factor H mutation. Transient haematological remission was achieved with intensive plasmapheresis, but cardiac function deteriorated and renal function was not restored. Initiation of eculizumab after 6 months of dialysis significantly improved organ function.

Long-acting octreotide as secondary prevention of chemotherapy-induced diarrhea: proof of concept.

Background: The aim of this study is to investigate the role of Octreotide LAR in secondary prevention in patients with chemotherapy-induced diarrhea.

Methods: In this study, patients experiencing CID ≥ grade 2 received 30 mg long-acting octreotide as a monthly injection and the next chemotherapy dose was administrated with a 25% dose decrease. If no CID ≥ grade 2 occurred, subsequent chemotherapy doses were increased to the initial 100% values.

Platelet abnormalities in nephrotic syndrome.

Nephrotic syndrome (NS) is a common kidney disease associated with a significantly increased risk of thrombotic events. Alterations in plasma levels of pro- and anti-coagulant factors are involved in the pathophysiology of venous thrombosis in NS. However, the fact that the risk of both venous and arterial thrombosis is elevated in NS points to an additional role for blood platelets.

Conditionally immortalized human proximal tubular epithelial cells isolated from the urine of a healthy subject express functional calcium-sensing receptor.

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor, which plays an essential role in regulating Ca(2+) homeostasis. Here we show that conditionally immortalized proximal tubular epithelial cell line (ciPTEC) obtained by immortalizing and subcloning cells exfoliated in the urine of a healthy subject expresses functional endogenous CaSR. Immunolocalization studies of polarized ciPTEC revealed the apical localization of the receptor.

A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases.

The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene-specific phenotype traits, and the relative frequency of the involvement of specific genes.

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa.

Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms.

From gut to kidney: transporting and metabolizing calcineurin-inhibitors in solid organ transplantation.

Since their introduction circa 35 years ago, calcineurin-inhibitors (CNI) have become the cornerstone of immunosuppressive therapy in solid organ transplantation. However, CNI's possess a narrow therapeutic index with potential severe consequences of drug under- or overexposure. This demands a meticulous policy of Therapeutic Drug Monitoring (TDM) to optimize outcome.

A novel mutation in the SCO2 gene in a neonate with early-onset cardioencephalomyopathy.

Mutations in the SCO2 gene [SCO cytochrome oxidase deficient homolog 2 (yeast)] causing cytochrome c oxidase deficiency have been reported in at least in 26 patients with fatal infantile cardioencephalomyopathy. Mutation 1541G > A affecting protein stability is associated with the majority of cases, and the other 11 described mutations have more serious deleterious structural consequences for the protein product. Reported here is a novel case caused by compound heterozygosity of SCO2.

Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children.

Background And Objectives: Frequently relapsing and steroid-dependent minimal-change nephrotic syndrome (MCNS) that originates in childhood can persist after puberty in >20% of patients. These patients require immunosuppressive treatment during several decades of their life. We examined long-term adverse effects of persistent nephrotic syndrome and immunosuppressive medications, focusing on renal function, growth, obesity, osteoporosis, hypertension, ocular complications, and fertility in adult patients with biopsy-proven childhood-onset MCNS.

A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.

To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing.

Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs.

The 13 polypeptides encoded in mitochondrial DNA (mtDNA) are synthesized in the mitochondrial matrix on a dedicated protein-translation apparatus that resembles that found in prokaryotes. Here, we have investigated the genetic basis for a mitochondrial protein-synthesis defect associated with a combined oxidative phosphorylation enzyme deficiency in two patients, one of whom presented with encephalomyopathy and the other with hypertrophic cardiomyopathy. Sequencing of candidate genes revealed the same homozygous mutation (C997T) in both patients in TSFM, a gene coding for the mitochondrial translation elongation factor EFTs.

Antibody response against the glomerular basement membrane protein agrin in patients with transplant glomerulopathy.

Chronic allograft nephropathy (CAN) of renal allografts is still the most important cause of graft loss. A subset of these patients have transplant glomerulopathy (TGP), characterized by glomerular basement membrane (GBM) duplications, but of unknown etiology. Recently, a role for the immune system in the pathogenesis of TGP has been suggested.

Human mitochondrial complex I assembles through the combination of evolutionary conserved modules: a framework to interpret complex I deficiencies.

With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphorylation system. We have studied the assembly of complex I in cultured human cells. This will provide essential information about the nature of complex I deficiencies and will enhance our understanding of mitochondrial disease mechanisms.