RMND1-related leukoencephalopathy with temporal lobe cysts and hearing loss—another mendelian mimicker of congenital cytomegalovirus infection

Background Leukoencephalopathy with temporal lobe cysts may be associated with monogenetic conditions such as Aicardi–Goutières syndrome or RNASET2 mutations and with congenital infections such as cytomegalovirus. In view of the fact that congenital cytomegalovirus is difficult to confirm outside the neonatal period, excluding a Mendelian disorder is extremely relevant, changing family planning and medical management in affected families. We performed diagnostic testing in individuals with leukoencephalopathy with temporal lobe cysts without a definitive diagnosis of congenital cytomegalovirus infection. Methods We reviewed a large-scale biorepository of patients with unsolved leukodystrophies and identified two individuals with required for meiotic nuclear division 1 (RMND1) mutations and similar magnetic resonance imaging (MRI) features, including temporal lobe cysts. Ten additional subjects with confirmed RMND1 mutations were identified as part of a separate disease specific cohort. Brain MRIs from all 12 individuals were reviewed for common neuroradiological features. Results MRI features in RMND1 mutations included temporal lobe swelling, with rarefaction and cystic evolution, enlarged tips of the temporal lobes, and multifocal subcortical white matter changes with confluent periatrial T2 signal hyperintensity. A combination of these features was present in ten of the 12 individuals reviewed. Conclusions Despite the small number of reported individuals with RMND1 mutations, a clinically recognizable phenotype of leukoencephalopathy with temporal lobe swelling, rarefaction, and cystic changes has emerged in a subset of individuals. Careful clinical phenotyping, including for lactic acidosis, deafness, and severe muscle involvement seen in RMND1 mutation positive individuals, and MRI pattern recognition will be important in differentiating these patients from children with congenital infections like cytomegalovirus

Role of Decreased Levels of Fis Histone-Like Protein in Crohn's Disease-Associated Adherent Invasive Escherichia coli LF82 Bacteria Interacting with Intestinal Epithelial Cells▿

The interaction of Crohn's disease (CD)-associated adherent-invasive Escherichia coli (AIEC) strain LF82 with intestinal epithelial cells depends on surface appendages, such as type 1 pili and flagella. Histone-like proteins operate as global regulators to control the expression of these virulence factors. We evaluated the role of histone-like proteins in AIEC reference strain LF82 during infection of intestinal epithelial cells, Intestine-407, and observed that the fis mRNA level was decreased. The role of Fis in AIEC LF82 was determined by studying the phenotype of an LF82 fis::Km mutant. This was the first mutant of strain LF82 that has been described thus far that is unable to express flagellin but still able to produce type 1 pili. The cyclic-di-GMP pathway linking flagella and type 1 pilus expression is not involved in Fis-mediated regulation, and we identified in the present study Fis-binding sites located upstream of the fimE gene and in the intergenic region between fimB and nanC of the fim operon encoding type 1 pili. The major consequence of decreased Fis expression in AIEC bacteria in contact with host cells is a direct downregulation of fimE expression, leading to the preferential ON phase of the fimS element. Thus, by maintaining type 1 pilus expression, AIEC bacteria, which interact with the gut mucosa, have greater ability to colonize and to induce inflammation in CD patients

Mutation in the AGK gene in two siblings with unusual Sengers syndrome

International audienc

Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1.

BackgroundDystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association.MethodsWe used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and immunolabelling on cultured fibroblasts to demonstrate the lower expression and the mislocalization of the protein.ResultsWe report on a boy born from consanguineous healthy parents, who presented at three years of age with rapidly progressing dystonia, progressive cerebellar atrophy, and dilated cardiomyopathy. We identified regions of homozygosity and performed whole exome sequencing that revealed a homozygous missense mutation in TOR1AIP1. The mutation, absent in controls, results in a change of a highly conserved glutamic acid to alanine. TOR1AIP1 encodes lamina-associated polypeptide 1 (LAP1), a transmembrane protein ubiquitously expressed in the inner nuclear membrane. LAP1 interacts with torsinA, the protein mutated in DYT1-dystonia. In vitro studies in fibroblasts of the patient revealed reduced expression of LAP1 and its mislocalization and aggregation in the endoplasmic reticulum as underlying pathogenic mechanisms.Conclusions and relevanceThe pathogenic role of TOR1AIP1 mutation is supported by a) the involvement of a highly conserved amino acid, b) the absence of the mutation in controls, c) the functional interaction of LAP1 with torsinA, and d) mislocalization of LAP1 in patient cells. Of note, cardiomyopathy has been reported in LAP1-null mice and in patients with the TOR1AIP1 nonsense mutation. Other cases will help delineate the clinical spectrum of LAP1-related mutations

A novel mutation in the ABCD1 gene of a Moroccan patient with X-linked adrenoleukodystrophy: case report

International audienceAbstractBackgroundX-linked adrenoleukodystrophy (X-ALD; OMIM: 300100) is the most common peroxisomal disease caused by mutations in the ATP-binding cassette, sub-family D member 1 gene or ABCD1 (geneID: 215), the coding gene for the adrenoleukodystrophy protein (ALDP), which is an ATP-binding transport protein associated to an active transport of very long chain fatty acids (VLCFAs). Dysfunction of ALDP induces an accumulation of VLCFAs in all tissues leading to a neurodegenerative disorder that involves the nervous system white matter.Case presentationIn our case report, magnetic resonance imaging (MRI) as well as the high levels of VLCFAs prompted the diagnosis the X-ALD. Molecular analysis of ABCD1 gene have shown a pathogenic homozygous nonsense mutation (c.1677C > G; p.(Tyr559*)) in exon 7.ConclusionThus, we identified here a novel mutation in the ABCD1 gene in a Moroccan patient causing X-linked adrenoleukodystrophy

Identification of a new Arylsulfatase A (ARSA) gene mutation in Tunisian patients with metachromatic leukodystrophy (MLD)

International audienceMetachromatic leukodystrophy (WILD) is an autosomal recessive, lysosomal storage disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). The aim of the present study was to identify the molecular basis of MILD in Tunisian population. Two Tunisian patients with late infantile MILD were studied. Both patients were homozygous for a new missense mutation that causes a substitution of Trp in Gly p.W124G. This is the first mutation of ARSA gene described in Tunisian population. (C) 2009 Elsevier B.V. All rights reserved

Philosophie, Phänomenologie und Psychologie. Husserl und der “zeitgemäße Anachronismus” der Phänomenologie der Gestaltpsychologie

Often there has been seen connections and continuity between the phenomenology of Husserl and the epistemological orientation of representatives of Gestalt psychology. In fact the two methodological procedures are quite different. In the era of Weimarer Republic the Berlin School used a combination of empirical research, philosophical reflexion, phenomenology and physiology, those conceptions – derived from the work of Stumpf – were their methodological guidelines until World War II. Compared to the ‘pure’ phenomenology and epistemology in times of the Weimarer Republic the gestalt phenomenology can be seen as ‘impure’ and ‘anachronistic’. In this paper the characteristics and the actuality of this ‘anachronism’ are discussed

Transient neonatal renal failure and massive polyuria in MEGDEL syndrome.

MEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome) syndrome is a mitochondrial disorder associated with recessive mutations in SERAC1

Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

International audienceNeuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis. Here, we report a patient with a neuro-ichthyotic syndrome associated with deleterious mutations in the ALDH1L2 (aldehyde dehydrogenase 1 family member L2) gene encoding for mitochondrial 10-formyltetrahydrofolate dehydrogenase. Using fibroblast culture established from the ALDH1L2-deficient patient, we demonstrated that the enzyme loss impaired mitochondrial function affecting both mitochondrial morphology and the pool of metabolites relevant to β-oxidation of fatty acids. Cells lacking the enzyme had distorted mitochondria, accumulated acylcarnitine derivatives and Krebs cycle intermediates, and had lower ATP and increased ADP/AMP indicative of a low energy index. Re-expression of functional ALDH1L2 enzyme in deficient cells restored the mitochondrial morphology and the metabolic profile of fibroblasts from healthy individuals. Our study underscores the role of ALDH1L2 in the maintenance of mitochondrial integrity and energy balance of the cell, and suggests the loss of the enzyme as the cause of neuro-cutaneous disease. npj Genomic Medicine (2019) 4:17 ; https://doi