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Background Type I congenital disorders of glycosylation (CDG-I) are mostly complex multisystemic diseases associated with hypoglycosylated serum glycoproteins. A subgroup harbour mutations in genes necessary for the biosynthesis of the dolichol-linked oligosaccharide (DLO) precursor that is essential for protein N-glycosylation. Here, our objective was to identify the molecular origins of disease in such a CDG-Ix patient presenting with axial hypotonia, peripheral hypertonia, enlarged liver, micropenis, cryptorchidism and sensorineural deafness associated with hypo glycosylated serum glycoproteins. Results Targeted sequencing of DNA revealed a splice site mutation in intron 5 and a non-sense mutation in exon 4 of the dehydrodolichol diphosphate synthase gene (DHDDS). Skin biopsy fibroblasts derived from the patient revealed ~20 % residual DHDDS mRNA, ~35 % residual DHDDS activity, reduced dolichol-phosphate, truncated DLO and N -glycans, and an increased ratio of [2- 3 H]mannose labeled glycoprotein to [2- 3 H]mannose labeled DLO. Predicted truncated DHDDS transcripts did not complement rer2 -deficient yeast. SiRNA-mediated down-regulation of DHDDS in human hepatocellular carcinoma HepG2 cells largely mirrored the biochemical phenotype of cells from the patient. The patient also harboured the homozygous ALG6(F304S) variant, which does not cause CDG but has been reported to be more frequent in PMM2-CDG patients with severe/fatal disease than in those with moderate presentations. WES did not reveal other strong candidate causal genes. Conclusions We describe a patient presenting with severe multisystem disease associated with DHDDS deficiency. As retinitis pigmentosa is the only clinical sign in previously reported cases, this report broadens the spectrum of phenotypes associated with this condition.

ObjectiveTo identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies.Design and subjectsThe brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations.ResultsAll complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients.ConclusionA common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency.

BackgroundTorcular dural sinus malformations (tDSMs) with arteriovenous shunts are rare congenital intracranial vascular malformations that carry a high rate of neurologic impairment and death in the neonatal, infant and young pediatric population. Their impact on brain venous drainage, especially the deep venous system, is one of the key factors in the clinical prognosis and natural history of the disease. We describe our therapeutic strategy for tDSMs, disconnecting the reflux into the deep venous system by performing an endovascular straight sinus occlusion.MethodsAmong all children with dural sinus malformations seen between 2002 and 2020, we retrospectively reviewed those with tDSM in whom straight sinus occlusion had been performed.ResultsOur databank included nine patients with tDSM that were embolized. Mean age at the clinical onset was 8.9±9.6 months (min–max=0–31). Five patients presented a significant reflux in the straight sinus on digital subtraction angiography. Those patients were initially clinically worse (mean modified Rankin Scale (mRS) 3.8) than those who did not present with reflux (mean mRS 2.25), this reflux being responsible for intraventricular hemorrhage in three patients. The reflux was suppressed by transarterial embolization in one patient and by transvenous straight sinus occlusion in four patients. Staged endovascular treatment resulted in a complete cure in six patients without complications, and clinical improvement in all patients.ConclusionStraight sinus occlusion is a feasible technique that needs to be considered in the treatment strategy for tDSM with deep venous reflux in order to avoid or minimize brain damage.

Purpose To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). Methods The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6–18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. Results Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: −5.10 [95% confidence interval (CI) −7.84 to −2.37]; FA: −4.69 [95% CI −7.73 to −1.64]; L-thyroxine: −3.89 [95% CI −6.94 to −0.83]; FA+L-thyroxine: −3.86 [95% CI −6.67 to −1.06]), with no significant difference for any active treatment group versus placebo. Conclusion This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.

OBJECTIVE: To identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies. DESIGN AND SUBJECTS: The brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations. RESULTS: All complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients. CONCLUSION: A common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive, and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal, and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5 to 37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke-Fahn-Marsden Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year, and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002, and P = 0.012).

L’article analyse le pilotage pédagogique des équipes enseignantes du premier degré dans deux villes du Val-d’Oise (académie de Versailles) connues pour leurs problèmes sociaux et scolaires persistants : Goussainville et Villiers-le-Bel. La comparaison des projets des deux ZEP permet de mettre en évidence les différences dans la compréhension par les équipes de pilotage des enjeux d’une politique d’éducation prioritaire. Dès le projet initial, à Villiers-le-Bel, l’objectif de transformation des pratiques enseignantes est explicitement mis en avant. Ce choix est lié à l’influence au long cours d’un mouvement pédagogique implanté localement (le « Groupe d’Écouen »). À Goussainville, les premiers projets de zone s’attachent prioritairement à la résolution de problèmes considérés comme spécifiques (violence, différences culturelles). Mais à la fin de la période considérée, un recentrage sur les pratiques pédagogiques est visible en particulier au travers des formations continues proposées et de l’évolution des missions des enseignants supplémentaires issus du premier degré. The article analyses the educational management of primary school teaching teams in two towns in the Val-d’Oise (Versailles education authority) which are well- known for their persistent social and academic problems: Goussainville and Villiers-le-Bel. The management teams’ varying perceptions of the issues involved in a ZEP policy are highlighted by a comparison of the two ZEP projects. Right from the initial project in Villiers-le-Bel, the objective of transforming teaching practices is explicitly highlighted. This choice is linked to the long-term influence of a locally based educational movement (the “Écouen Group”). In Goussainville, the first zone projects focused primarily on solving problems which are considered specific (eg. violence, cultural differences). But at the end of the period under consideration, a refocusing on educational practices is apparent, in particular through the in-service training offered and the evolution of the responsibilities of additional primary teachers.

L’article analyse le pilotage pédagogique des équipes enseignantes du premier degré dans deux villes du Val-d’Oise (académie de Versailles) connues pour leurs problèmes sociaux et scolaires persistants : Goussainville et Villiers-le-Bel. La comparaison des projets des deux ZEP permet de mettre en évidence les différences dans la compréhension par les équipes de pilotage des enjeux d’une politique d’éducation prioritaire. Dès le projet initial, à Villiers-le-Bel, l’objectif de transformation des pratiques enseignantes est explicitement mis en avant. Ce choix est lié à l’influence au long cours d’un mouvement pédagogique implanté localement (le « Groupe d’Écouen »). À Goussainville, les premiers projets de zone s’attachent prioritairement à la résolution de problèmes considérés comme spécifiques (violence, différences culturelles). Mais à la fin de la période considérée, un recentrage sur les pratiques pédagogiques est visible en particulier au travers des formations continues proposées et de l’évolution des missions des enseignants supplémentaires issus du premier degré. ‪The article analyses the educational management of primary school teaching teams in two towns in the Val-d'Oise (Versailles education authority) which are well- known for their persistent social and academic problems: Goussainville and Villiers-le-Bel. The management teams' varying perceptions of the issues involved in a ZEP policy are highlighted by a comparison of the two ZEP projects. Right from the initial project in Villiers-le-Bel, the objective of transforming teaching practices is explicitly highlighted. This choice is linked to the long-term influence of a locally based educational movement (the \"Écouen Group\"). In Goussainville, the first zone projects focused primarily on solving problems which are considered specific (eg. violence, cultural differences). But at the end of the period under consideration, a refocusing on educational practices is apparent, in particular through the in-service training offered and the evolution of the responsibilities of additional primary teachers.‪