Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter.

BACKGROUND: Agenesis of corpus callosum has been associated with several defects of the mitochondrial respiratory chain and the citric acid cycle. We now report the results of the biochemical and molecular studies of a patient with severe neurodevelopmental disease manifesting by agenesis of corpus callosum and optic nerve hypoplasia. METHODS AND RESULTS: A mitochondrial disease was suspected in this patient based on the prominent excretion of 2-hydroxyglutaric acid and Krebs cycle intermediates in urine and the finding of increased reactive oxygen species content and decreased mitochondrial membrane potential in her fibroblasts. Whole exome sequencing disclosed compound heterozygosity for two pathogenic variants in the SLC25A1 gene, encoding the mitochondrial citrate transporter. These variants, G130D and R282H, segregated in the family and were extremely rare in controls. The mutated residues were highly conserved throughout evolution and in silico modeling investigations indicated that the mutations would have a deleterious effect on protein function, affecting either substrate binding to the transporter or its translocation mechanism. These predictions were validated by the observation that a yeast strain harbouring the mutations at equivalent positions in the orthologous protein exhibited a growth defect under stress conditions and by the loss of activity of citrate transport by the mutated proteins reconstituted into liposomes. CONCLUSIONS: We report for the first time a patient with a mitochondrial citrate carrier deficiency. Our data support a role for citric acid cycle defects in agenesis of corpus callosum as already reported in patients with aconitase or fumarate hydratase deficiency.

Scalloping is a reliable endoscopic marker for celiac disease.

BACKGROUND: Scalloping of duodenal folds noted on esophagogastroduodenoscopy (EGD) has been associated with various illnesses including celiac disease (CD). The aim of the present study was to examine the frequency of scalloping in pediatric patients undergoing EGD and to assess its significance in the diagnosis of CD. We also evaluated the association of scalloping with the histopathology and celiac serology in the subgroup of celiac patients. PATIENTS AND METHODS: All children (0-18 years) who underwent EGD at Shaare Zedek Medical Center for any reason during a 2.5-year period were retrospectively included, yielding a consecutive cohort without selection bias. Relevant data were obtained from the patient files. RESULTS: During the study period, 623 children underwent EGD of whom 149 (24%) were eventually diagnosed with CD. In 74/623children (12%), scalloping was seen and had a sensitivity of 48% (95% CI 0.40-0.57), specificity of 99% (0.98-0.99) and positive predictive value of 97% (0.9-0.99) to diagnose CD. The prevalence of scalloping increased with advancing stage of the Marsh classification from 33% (7/21) in Marsh 1 to 63% (34/54) in Marsh 3c (P < 0.001). Scalloping was associated with a significantly higher median tissue transglutaminase level (153 [IQR 98-168] versus 49 [IQR 11-143]; P = 0.011). CONCLUSION: The results suggest that the diagnosis of CD is almost certain if isolated scalloping is observed during EGD done to rule out CD. Thus, attention to this finding may serve as an additional tool in the diagnosis of CD.

Disparities in assessments of asthma control between children, parents, and physicians.

OBJECTIVE: Assessment of asthma control in children by physicians, patients and their parents was compared, assuming parents may underestimate symptoms in asthmatic children and exploring whether physicians tend to agree with them. DESIGN: Asthma control perception was assessed in 4- to 11-year-old asthmatic children and their parents, using C-ACT, during 2011-2012. Pediatric pulmonologists used GINA guidelines for their assessment; pediatricians, not having spirometry, used the information given in addition to physical examination. The C-ACT scores given by the children and their parents were further analyzed separately, and compared with their physicians' assessment. Statistical methods, which also measured possible influence of different variables, included kappa, Chi-square, linear-by-linear association, McNemar test and logistic regression. PATIENT SELECTION: The study comprised 354 parents and children aged 4-11 years with moderate-severe asthma; 129 (36.4%) were treated by 23 pediatricians; 225 (63.6%) by 11 pediatric pulmonologists. RESULTS: The C-ACT was generally found valid in assessing asthma control (P < 0.001; κ 0.529; CI 0.441, 0.617) and showed that in 229/354 (53%) of children the asthma was uncontrolled. Nevertheless, of the 229 children who indicated their asthma was uncontrolled, 124 (54.1%) of their parents (κ 0.245; CI 0.15, 0.34) and 96 (41.9%) of their physicians believed it to be controlled (κ 0.331; 0.24, 0.43). Comparing the physician-child discordance vis-à-vis the parents, the significant difference was when 96/229 children (41.9%) and 34/126 parents (27.0%) indicated the asthma was uncontrolled while the physician determined it controlled (OR 1.95; 1.19, 3.24). There were no significant differences between pediatric pulmonologists and pediatricians. CONCLUSIONS: In addition to increasing awareness of parents to symptoms in their asthmatic children, physicians should question the child appropriately, as well as using the children's responses to C-ACT as an information source for properly assessing asthma control.