Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.

Schimke immuno-osseous dysplasia is a multi-system autosomal recessive disorder with variable expression that affects the skeletal, renal, immune, vascular, and haematopoietic systems. Medical therapy is limited especially for more severely affected individuals.

The aim of this study was to develop a population pharmacokinetic model of tacrolimus in pediatric kidney transplant patients, identify factors that explain variability, and determine dosage regimens. Pharmacokinetic samples were collected from 50 de novo pediatric kidney transplant patients (age 2-18 years) who were on tacrolimus treatment. Population pharmacokinetic analysis of tacrolimus was performed using NONMEM, and the impact of variables (demographic and clinical factors, and CYP3A4-A5, ABCB1, and ABCC2 polymorphisms) was tested. The pharmacokinetic data were described by a two-compartment model that incorporated first-order absorption and lag time. The apparent oral clearance (CL/F) was significantly related to body weight (allometric scaling); in addition, it was higher in patients with low hematocrit levels and lower in patients with CYP3A5*3/*3. The population pharmacokinetic-pharmacogenetic model developed in de novo pediatric kidney transplant patients demonstrated that, in children, tacrolimus dosage should be based on weight, hematocrit levels, and CYP3A5 polymorphism. Individualization of therapy will enable the optimization of tacrolimus exposure, with resultant beneficial effects on kidney function in the initial post-transplantation period.

The objective was to develop a population pharmacokinetic-pharmacogenetic model of mycophenolic acid following administration of mycophenolate mofetil (MMF) in de novo pediatric renal-transplant patients and identify factors that explain variability. The pharmacokinetic samples were collected from 89 de novo pediatric renal-transplant patients treated with MMF and studied during the first 60 postoperative days. All patients were genotyped for UGT1A8-A9, UGT2B7, and ABCC2. Population pharmacokinetic analysis was performed with the NONMEM and was validated using bootstrap visual predictive check. The pharmacokinetic data were best described by a 2-compartment model with Erlang distribution to describe the absorption phase. The covariate analysis identified body weight as an individual factor influencing central volume of distribution and concomitant immunosuppressive medication and identified body weight and UGT2B7 802C>T genotype as individual factors influencing apparent oral clearance (CL/F) of MMF. CL/F in cyclosporine-MMF-treated patients was 33% higher than in tacrolimus-MMF-treated patients. The CL/F was significantly lower in patients with UGT2B7 802 C/C genotype compared with patients with UGT2B7 802 C/T and 802T/T genotypes, and this effect was independent of concomitant immunosuppressive medication or body weight. The population pharmacokinetic-pharmacogenetic model of mycophenolic acid was validated. Body weight, concomitant medication, and UGT2B7 genotype contribute significantly to the interindividual variability of MMF disposition in pediatric renal-transplant patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• MMF has been proposed as a treatment of steroid-dependent nephrotic syndrome and in the recent years, several studies have suggested its positive effect in preventing relapses. WHAT THIS PAPER ADDS• The population pharmacokinetics of MPA was first evaluated in children with idiopathic nephrotic syndrome and data fitted well with a two-compartment model with first-order absorption and lag time.• Body weight and serum albumin had a significant impact on oral clearance. • A three-point (T0, T1 and T4h) Bayesian estimator of AUC0-12 was developed. AIMSTo develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration-time curve over 12 h (AUC0-12). METHODSThe pharmacokinetic model of MMF was described from 23 patients aged 7.4 Ϯ 3.9 years (range 2.9-14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag-time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method. RESULTSThe population pharmacokinetic parameters were apparent oral clearance 9.7 l h , lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC0-12 was obtained using the combination of three MPA concentrations measured just before (T0), 1 and 4 h (T1 and T4) after drug intake with a small error of 0.298 mg h -1 ml -1 between estimated and reference AUC0-12. CONCLUSIONSThe population pharmacokinetic model of MPA was developed in children with INS. A three-point (T0, T1 and T4h) Bayesian estimator of AUC0-12 was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Renal failure, proteinuria, leukocyturia, haematuria, and concentration defect are the prominent features of renal granulomatous sarcoidosis in children. Steroid therapy, adjusted according to disease activity, may prevent end-stage renal failure.

Schimke immuno-osseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia, nephropathy, and T-cell deficiency. SIOD is caused by mutations in the putative chromatin remodeling protein SMARCAL1. We report an 8-year-old boy with SIOD and recurrent, severe, refractory migraine-like headaches. Through a retrospective questionnaire-based study, we found that refractory and severely disabling migraine-like headaches occur in nearly half of SIOD patients. We have also found that the vasodilator minoxidil provided symptomatic relief for one patient. We hypothesize that these headaches may arise from an intrinsic vascular, neuroimmune, or neurovascular defect resulting from loss of SMARCAL1 function.