Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.

Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions

Biallelic Loss-of-Function NDUFA12 Variants Cause a Wide Phenotypic Spectrum from Leigh/Leigh-Like Syndrome to Isolated Optic Atrophy

BACKGROUND: Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. OBJECTIVES: To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease. METHODS: We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature. RESULTS: Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel. CONCLUSIONS: Our case series expands phenotype–genotype correlations in NDUFA12-associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes – particularly with dystonia – as well as isolated optic atrophy

Migrant children within Europe: a systematic review of children’s perspectives on their health experiences

Objectives: To review the extant literature in order to explore what is known about children’s own perspectives on the ir health experiences , focusing upon children and young people who have migrated into, and within, Europe. Study Design: A systematic review with narrative synthesis. Methods: A review of English language articles was performed in June 2016 using the following databases: Medline, CINAHL, Coc hrane and Web of Science. Included papers had to report data generated directly with children, up to 18 years of age, who had migrated across national borders into, or within, Europe during their own lifetimes. Extraction from articles was undertaken by a ll authors and quality assessment of included reviews was performed using the Mixed Methods Appraisal Tool ( MMAT ) . Results: The articles in the final dataset included research based on 4 broad areas: alcohol, smoking and substance use; diet, eating disorde rs and overweight; emotional, psychological and mental health issues and; children’s views and experiences of health and health services. The majority of studies were cross - sectional analytic or incidence or prevalence studies. Conclusion: There is a gene ral lack of clarity in the literature regarding the reporting of children’s own migration status. Children’s voices are often subsumed within those of their adult parents or carers. There is a need to promote more child - focussed research which gives voice to migrant children to better understand the complex and multidimensional factors that contribute to their (ill) health

Optical coherence tomography shows progressive local nerve fiber loss after disc hemorrhages in glaucoma patients.

BACKGROUND AND AIM: The aim of this work is to investigate whether optic disc hemorrhages (ODH) lead to significant loss of nerve fibers at the lesion site over time and whether such a loss is reflected by visual field defects corresponding to the affected nerve fiber bundle. METHODS: In this retrospective study of ten sequential glaucoma patients (ten eyes) with ODH, we used high-resolution OCT circular scans (Spectralis HRA + OCT, Heidelberg Engineering, Heidelberg, Germany) to determine peripapillary retinal nerve fiber layer (RNFL) thickness at the time of ODH presentation and at follow-up visit between 3 and 6 months. Corresponding perimetric data were analyzed for global (mean defect, MD) and localized progression of visual field defects. RESULTS: ODH were mostly located in the inferior quadrant as determined clinically and from fundus photographs. Iterative OCT imaging revealed a significant RNFL reduction in the affected quadrant relative to the respective quadrant in the fellow eye (RNFL change = -2.25 ± 2.69 μm vs. 0.75 ± 2.78 μm, p = 0.01) within 120 ± 43 days. However, only three cases presented with new/progressive nerve fiber bundle defects corresponding to the lesion site within the given follow-up period. CONCLUSIONS: ODH lead to a significantly higher RNFL loss at the lesion site relative to the overall structural progression in glaucoma patients. However, this focal change is not generally reflected by respective nerve fiber bundle defects in the time frame investigated

“The Buoy”: Utilization of a low-threshold ambulatory setting for traumatized children and adolescents in Austria

Grundlagen Diese Untersuchung hatte zum Ziel, die Inanspruchnahme einer Ambulanz, welche niedrigschwellige, Trauma-fokussierte Kurzpsychotherapie für Kinder und Jugendliche anbietet, während der ersten sechs Jahre ihres Bestehens zu untersuchen. Methodik Wir führten eine retrospektive Analyse der Krankengeschichten aller zwischen 2001 und 2007 behandelten Patienten (n=2510) durch und dokumentierten demographische Daten, Gründe für die Behandlung, zuweisende Institution, Obsorge berechtigte Person oder Institution, die Anzahl der Kontakte, psychische oder körperliche Erkrankung eines Elternteils und verschriebene Medikation. Ergebnisse Die behandelten Patienten waren zwischen 1 und 17 Jahre alt, die Geschlechterverteilung war gleichmäßig. Häufigster Anlass für eine Kontaktaufnahme waren der Tod eines Verwandten, die Tatsache, Zeuge eines gewaltsamen Todes geworden zu sein oder andere Gewalterfahrungen. Die Inanspruchnahme durch Migranten stieg während des Untersuchungszeitraumes laufend an. Kinder aus Pflegefamilien suchten die Institution seltener als erwartet auf. Medikation wurde kaum verschrieben. Schlussfolgerungen Die intensive Nutzung dieser Institution zeigt deutlich den großen Bedarf an kurzfristiger akuter Traumatherapie für Kinder und Jugendliche. Bemühungen, leicht zugängliche Institutionen für traumatisierte Kinder und Jugendliche zur Verfügung zu stellen, sollten intensiviert werden.Background This investigation intended to assess the use of an outpatient clinic providing low-threshold, short-term trauma therapy for children and adolescents across the first 6 years of its existence. Methods A retrospective analysis of the records of all patients undergoing treatment in this institution between 2001 and 2007 (n=2510) has been performed. We evaluated demographic data, reason for contacting the unit, the referring person or institution, the person or institution in charge of the care and custody of the child, the number of contacts with the clinic, presence of physical or psychiatric illness of a parent, and medications prescribed. Results Ages of patients ranged from 1 to 17. Gender distribution was even. Having experienced the death of a relative, experienced violence, or having witnessed traumatic death were the main reasons for presentation. The utilization rates of immigrants rose throughout the observation period. Children from foster care were seen less frequently than expected. Medication was hardly prescribed. Conclusions Ample utilization of this institution clearly demonstrates the need for short-term acute outpatient trauma therapy for children and adolescents. Efforts to provide easily accessible institutions for youth who experience traumatic events should be stepped up.(VLID)342645

Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of human ARH3, the first eukaryotic protein-ADP-ribosylhydrolase

ADP-ribosylhydrolases catalyze the release of ADP-ribose from ADP-ribosylated proteins via hydrolysis of the glycosidic bond between ADP-ribose and a specific amino-acid residue in a target protein. Human ADP-ribosylhydrolase 3, consisting of 347 amino-acid residues, has been cloned and heterologously expressed in Escherichia coli, purified and crystallized in two different space groups. Preliminary X-ray diffraction studies yielded excellent diffraction data to a resolution of 1.6 A

Structure of Mouse ADP-ribosylhydrolase 3 (mARH3)

ADP-ribosylation is a reversible and covalent post-translational modification in which the attachment of ADP-ribose is catalyzed by ADP-ribosyltransferases and the removal of ADP-ribose is catalyzed by ADP-ribosylhydrolases. ADP-ribosylhydrolase 3 from mouse, consisting of 347 amino-acid residues, has been cloned, purified and crystallized. The three-dimensional structure has been resolved at a resolution of 1.8 A. The structure constitutes a compact all-alpha-helical protein with two Mg(2+) ions located in the active-site crevice. A structural comparison of mouse ADP-ribosylhydrolase 3 with its human orthologue shows a high degree of structural similarity. Furthermore, four prokaryotic proteins deposited in the PDB could be identified as being structurally related