Osnat Konen

Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome

Ubiquitination plays a crucial role in neurodevelopment as exemplified by Angelman syndrome, which is caused by genetic alterations of the ubiquitin ligase-encoding UBE3A gene. Although the function of UBE3A has been widely studied, little is known about its paralog UBE3B. By using exome and capillary sequencing, we here identify biallelic UBE3B mutations in four patients from three unrelated families presenting an autosomal-recessive blepharophimosis-ptosis-intellectual-disability syndrome characterized by developmental delay, growth retardation with a small head circumference, facial dysmorphisms, and low cholesterol levels. UBE3B encodes an uncharacterized E3 ubiquitin ligase. The identified UBE3B variants include one frameshift and two splice-site mutations as well as a missense substitution affecting the highly conserved HECT domain. Disruption of mouse Ube3b leads to reduced viability and recapitulates key aspects of the human disorder, such as reduced weight and brain size and a downregulation of cholesterol synthesis. We establish that the probable Caenorhabditis elegans ortholog of UBE3B, oxi-1, functions in the ubiquitin/proteasome system in vivo and is especially required under oxidative stress conditions. Our data reveal the pleiotropic effects of UBE3B deficiency and reinforce the physiological importance of ubiquitination in neuronal development and function in mammals.

Infantile Cerebral and Cerebellar Atrophy Is Associated with a Mutation in the MED17 Subunit of the Transcription Preinitiation Mediator Complex

Primary microcephaly of postnatal onset is a feature of many neurological disorders, mostly associated with mental retardation, seizures, and spasticity, and it typically carries a grave prognosis. Five infants from four unrelated families of Caucasus Jewish origin presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined, and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect. A search for a common homozygous region revealed a 2.28 Mb genomic segment on chromosome 11 that encompassed 16 protein-coding genes. A missense mutation in one of them, MED17, segregated with the disease state in the families and was carried by four of 79 anonymous Caucasus Jews. A corresponding mutation in the homologous S.cerevisiae gene SRB4 inactivated the protein, according to complementation assays. Screening of MED17 in additional patients with similar clinical and radiologic findings revealed four more patients, all homozygous for the p.L371P mutation and all originating from Caucasus Jewish families. We conclude that the p. L371P mutation in MED17 is a founder mutation in the Caucasus Jewish community and that homozygosity for this mutation is associated with infantile cerebral and cerebellar atrophy with poor myelination.

Clinical and molecular variability in congenital dyserythropoietic anaemia type I

Congenital dyserythropoietic anaemia (CDA) type I is a rare, inherited disorder characterised by ineffective erythropoiesis and macrocytic anaemia. Complex bone disease has only occasionally been associated with this disease. CDA I is caused by mutations in the CDAN1 gene encoding for codanin‐1. Our aim was to characterise the CDAN1 mutation in eight unrelated patients with sporadic CDA I, three of whom had complex bone disease. Six novel mutations in the CDAN1 gene were identified. In two patients, one mutation and in another, both mutations were elusive. No patient was homozygous for a null‐type mutation. However, one patient with complex bone disease was homozygous for a splice‐site mutation (IVS‐12+5G > A). Western blotting revealed that codanin‐1 synthesis was 65% less than the control. Five single nucleotide polymorphisms (SNPs) previously unreported in the literature or the SNP database were also identified. Although the absence of codanin‐1 is probably lethal, the presence of 35% of the protein was compatible with life but was associated with severe clinical manifestations. However, in most patients studied, no correlation could be established between the expected levels of codanin‐1 or the nature of the mutation and the severity of the clinical manifestations.

Volvulus of the stomach in childhood: The spectrum of the disease

Introduction During a 5-year time frame, five cases of symptomatic gastric volvulus were diagnosed and treated in our department. Four presented with the acute form of gastric volvulus and underwent emergency surgery. The fifth suffered the chronic variant of the syndrome and was benefited by nonoperative management. The cases serve to remind emergency physicians of the spectrum of gastric volvulus. The report supplements the sparse clinical description in the emergency literature. Results In the operated patients, there were no postoperative complications. The outcome, to the time of publication, has been good in every instance. The history, etiology, presentation, and treatment of the disease are discussed in detail. Conclusions Not infrequently, gastric volvulus in children fails to exhibit the full gamut of signs and symptoms such as abdominal distension, vomiting, pain, and retching. For this, as well as for other stated reasons, symptomatic gastric volvulus in infancy and childhood may not be as rare as is commonly assumed.

eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation.

Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. Here, we show that a human X-chromosomal neurological disorder characterized by intellectual disability and microcephaly is caused by a missense mutation in eIF2γ (encoded by EIF2S3), the core subunit of the heterotrimeric eIF2 complex. Biochemical studies of human cells overexpressing the eIF2γ mutant and of yeast eIF2γ with the analogous mutation revealed a defect in binding the eIF2β subunit to eIF2γ. Consistent with this loss of eIF2 integrity, the yeast eIF2γ mutation impaired translation start codon selection and eIF2 function in vivo in a manner that was suppressed by overexpressing eIF2β. These findings directly link intellectual disability to impaired translation initiation, and provide a mechanistic basis for the human disease due to partial loss of eIF2 function.

Transient colocolic intussusception

We present the CT findings of a transient colocolic intussusception, related to an underlying colonic tumor, but remote from it. The resolving nature of intussusception was clearly demonstrated on delayed images and may explain the characteristic chronic clinical symptoms of intussusception in adult.

Post-transplantation lymphoproliferative disorder in pediatric kidney-transplant recipients - A national study

Cleper R, Ben Shalom E, Landau D, Weissman I, Krause I, Konen O, Rahamimov R, Mor E, Bar‐Nathan N, Frishberg Y, Davidovits M. Post‐transplantation lymphoproliferative disorder in pediatric kidney‐transplant recipients – A national study.

C1-2 vertebral anomalies in 22q11.2 microdeletion syndrome

BackgroundChromosome 22q11.2 microdeletion syndrome (22q11DS) is characterized by cleft palate, cardiac anomalies, characteristic facies, high prevalence of skeletal anomalies and learning disability.ObjectiveTo evaluate the prevalence of craniovertebral junction anomalies in children with 22q11DS and compare these findings to those in nonsyndromic children with velopharyngeal insufficiency (VPI).Materials and methodsSequential CT scans performed for presurgical carotid assessment in 76 children (45 children positive for chromosome 22q11.2 deletion and 31 negative for the deletion) with VPI were retrospectively evaluated for assessment of C1-2 anomalies.ResultsC1-2 vertebral anomalies, specifically midline C1 defects, uptilted or upswept posterior elements of C2 and fusions of C2-3, were nearly universal in our cohort of 22q11DS patients with VPI. They were strikingly absent in the majority of non-22q11DS patients with VPI.ConclusionC1-2 vertebral anomalies, particularly those listed above, are important radiographic markers for 22q11DS.

A urethral catheter knot: A rare complication of cystourethrography

Complications of voiding cystourethrography are infrequent. We report a rare complication of knotting of the catheter within the bladder, necessitating surgical removal of the catheter through the urethra.

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

The mitochondrial inner membrane possesses distinct subdomains including cristae, which are lamellar structures invaginated into the mitochondrial matrix and contain the respiratory complexes. Generation of inner membrane domains requires the complex interplay between the respiratory complexes, mitochondrial lipids and the recently identified mitochondrial contact site and cristae organizing system (MICOS) complex. Proper organization of the mitochondrial inner membrane has recently been shown to be important for respiratory function in yeast. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with a neurodegenerative disorder accompanied by hyperlactatemia, 3-methylglutaconic aciduria, disturbed hepatocellular function with abnormal cristae morphology in liver and cerebellar and vermis atrophy, which suggest mitochondrial dysfunction. Using homozygosity mapping and exome sequencing the patients were found to be homozygous for the p.(Gly15Glufs*75) variant in the QIL1/MIC13 (C19orf70) gene. QIL1/MIC13 is a constituent of MICOS, a six subunit complex that helps to form and/or stabilize cristae junctions and determine the placement, distribution and number of cristae within mitochondria. In patient fibroblasts both MICOS subunits QIL1/MIC13 and MIC10 were absent whereas MIC60 was present in a comparable abundance to that of the control. We conclude that QIL1/MIC13 deficiency in human, is associated with disassembly of the MICOS complex, with the associated aberration of cristae morphology and mitochondrial respiratory dysfunction. 3-Methylglutaconic aciduria is associated with variants in genes encoding mitochondrial inner membrane organizing determinants, including TAZ, DNAJC19, SERAC1 and QIL1/MIC13.