Detección prenatal y seguimieto postnatal de las anomalías congénitas del sistema nervioso central.

215 p.Las anomalías congénitas del Sistema Nervioso Central (ACSNC) se dan en el 1% de los nacimientos y suponen una causa importante de muerte neonatal y discapacidad a largo plazo. El diagnóstico suele realizarse a nivel prenatal, el pronóstico puede ser variable y la decisión supone continuar o terminar el embarazo. El objetivo de este estudio es describir las características clínicas, epidemiológicas y pronóstico de las ACSNC en el País Vasco y principalmente en Gipuzkoa, a través de los datos recogidos en el registro de anomalías congénitas del País Vasco (RACAV) durante los años 1990 a 2011. Se ha observado un aumento de la prevalencia de las ACSNC a lo largo de este periodo, principalmente por el aumento de los casos detectados prenatalmente. Los defectos del tubo neural (DNT) son los más prevalentes, seguidos de la hidrocefalia. La prevalencia de DTN no ha disminuido a pesar de la instauración oficial de la recomendación de la toma de ácido fólico periconcepcional en el 2001. Se conoce la etiología en el 22% de los casos, 14% son debidas a anomalías cromosómicas, 5% se engloban dentro de un síndrome concreto y 3% son secundarias a factores ambientales. De manera global, el 60% de las malformaciones acaban en interrupción voluntaria del embarazo (IVE), 38% nacen vivos y 2% nacen muertos. El factor más importante para decidir seguir o no con el embarazo es el momento de detección de la anomalía. De los casos nacidos vivos, la supervivencia depende de las anomalías asociadas en otros órganos

Detección prenatal y seguimieto postnatal de las anomalías congénitas del sistema nervioso central.

215 p.Las anomalías congénitas del Sistema Nervioso Central (ACSNC) se dan en el 1% de los nacimientos y suponen una causa importante de muerte neonatal y discapacidad a largo plazo. El diagnóstico suele realizarse a nivel prenatal, el pronóstico puede ser variable y la decisión supone continuar o terminar el embarazo. El objetivo de este estudio es describir las características clínicas, epidemiológicas y pronóstico de las ACSNC en el País Vasco y principalmente en Gipuzkoa, a través de los datos recogidos en el registro de anomalías congénitas del País Vasco (RACAV) durante los años 1990 a 2011. Se ha observado un aumento de la prevalencia de las ACSNC a lo largo de este periodo, principalmente por el aumento de los casos detectados prenatalmente. Los defectos del tubo neural (DNT) son los más prevalentes, seguidos de la hidrocefalia. La prevalencia de DTN no ha disminuido a pesar de la instauración oficial de la recomendación de la toma de ácido fólico periconcepcional en el 2001. Se conoce la etiología en el 22% de los casos, 14% son debidas a anomalías cromosómicas, 5% se engloban dentro de un síndrome concreto y 3% son secundarias a factores ambientales. De manera global, el 60% de las malformaciones acaban en interrupción voluntaria del embarazo (IVE), 38% nacen vivos y 2% nacen muertos. El factor más importante para decidir seguir o no con el embarazo es el momento de detección de la anomalía. De los casos nacidos vivos, la supervivencia depende de las anomalías asociadas en otros órganos

Small for gestational age moderate to late preterm children: a neuropsychological follow-up

[EN] Determine whether SGA constitutes a neurodevelopmental risk-factor of MLP, exploring if potential developmental difficulties at toddlerhood persist and are related to school-age performance. 109 SGA and 109 adequate for gestational age MLP children were evaluated at 2 and at 6.5 y.o. SGA children obtained poorer results in several areas at both timepoints; and their development at toddlerhood strongly correlated with only some results at school-age. SGA confers vulnerability to MLP, evolving from global/unspecific difficulties in toddlerhood to a domain-specific profile (attentional/dysexecutive) at 6.5. Findings claim the need for neuropsychological follow-up in MLP to identify emerging difficulties

Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity

Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

26 páginas, 4 figuras, 3 tablasOur clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.This work was supported by the Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación y Fomento de la Investigación within the framework of the National R + D+I Plan co-funded with European Regional Development Funds (ERDF) [Grants PI18/00147 and PI21/00103 to CE]; the Fundació La Marató TV3 [Grants 20143130 and 20143131 to BPD and CE]; and by the Generalitat Valenciana [Grant PROMETEO/2018/135 to CE]. Part of the equipment employed in this work was funded by Generalitat Valenciana and co-financed with ERDF (OP ERDF of Comunitat Valenciana 2014–2020). PS had an FPU-PhD fellowship funded by the Spanish Ministry of Education, Culture and Sport [FPU15/00964]. IH has a PFIS-PhD fellowship [FI19/00072]. ASM has a contract funded by the Spanish Foundation Per Amor a l’Art (FPAA)Peer reviewe

Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation

Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, and the effects on cell membranes and the wider cell were also unknown. Using patient-derived cells, we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases. Lysosomes are also more numerous in Drosophila neural progenitor cells expressing mutant Atad3, which exhibit abundant membrane-bound cholesterol aggregates, many of which co-localize with lysosomes. By subjecting the Drosophila Atad3 mutant to nutrient restriction and cholesterol supplementation, we show that the mutant displays heightened cholesterol dependence. Collectively, these findings suggest that elevated cholesterol enhances tolerance to pathological ATAD3 variants; however, this comes at the cost of inducing cholesterol aggregation in membranes, which lysosomal clearance only partly mitigates.M.M.O. was supported by a predoctoral fellowship from the University of the Basque Country (PIF18/317) and later partially supported by the Ikerbasque, Basque Foundation for Science IKUR strategy Neurodegenprot project. A.L. and U.F.P. were recipients of pre-doctoral fellowships from the Basque Government (PRE_2019_1_0184 and PRE_2018_1_0253). The study was supported by funding to I.J.H. from the Instituto de Salud Carlos III (PI17-00380; PI20/00096) and the Basque Government Department of Health (Osasun Saila, Eusko Jaurlaritzako) (grants 2021111070; 2022333050; 2018111043; 2018222031). A.Sp. receives support from Miriam Marks Senior Fellowship, Brain Research UK (202021-26), the Research Councils UK (MR/X002365/1) and the Lily Foundation. W.H.Y. is supported by the National Institute of Neurological Disorders and Stroke (5R01 NS121298-03) of the National Institutes of Health, Oklahoma Center for Adult Stem Cell Research (OCASCR) (221009 and 241006) and Presbyterian Health Foundation (4411-09-10-0).Peer reviewe

Detección prenatal y seguimieto postnatal de las anomalías congénitas del sistema nervioso central.

215 p.Las anomalías congénitas del Sistema Nervioso Central (ACSNC) se dan en el 1% de los nacimientos y suponen una causa importante de muerte neonatal y discapacidad a largo plazo. El diagnóstico suele realizarse a nivel prenatal, el pronóstico puede ser variable y la decisión supone continuar o terminar el embarazo. El objetivo de este estudio es describir las características clínicas, epidemiológicas y pronóstico de las ACSNC en el País Vasco y principalmente en Gipuzkoa, a través de los datos recogidos en el registro de anomalías congénitas del País Vasco (RACAV) durante los años 1990 a 2011. Se ha observado un aumento de la prevalencia de las ACSNC a lo largo de este periodo, principalmente por el aumento de los casos detectados prenatalmente. Los defectos del tubo neural (DNT) son los más prevalentes, seguidos de la hidrocefalia. La prevalencia de DTN no ha disminuido a pesar de la instauración oficial de la recomendación de la toma de ácido fólico periconcepcional en el 2001. Se conoce la etiología en el 22% de los casos, 14% son debidas a anomalías cromosómicas, 5% se engloban dentro de un síndrome concreto y 3% son secundarias a factores ambientales. De manera global, el 60% de las malformaciones acaban en interrupción voluntaria del embarazo (IVE), 38% nacen vivos y 2% nacen muertos. El factor más importante para decidir seguir o no con el embarazo es el momento de detección de la anomalía. De los casos nacidos vivos, la supervivencia depende de las anomalías asociadas en otros órganos

Trimetazidine Induces Parkinsonism, Gait Disorders and Tremor

Objective: To study the adverse effects of trimetazidine on motor functions. Design: A retrospective study was carried out using electronic records to identify all patients seen between January 1990 and August 2003. Setting: A neurological out-patient clinic. Participants: Of the 10 258 patients who attended the clinic, 130 received trimetazidine. Treatment with this drug was discontinued in 128 patients. Of the 130 patients treated with trimetazidine, 29 also had other drugs capable of inducing parkinsonism withdrawn from their treatment. Main outcome measures: Identification of an improvement in motor function after drug withdrawal. Results: In 56 of the 130 patients who were treated with trimetazidine (43%), an adverse effect on motor function was detected that had been induced or aggravated by one of the withdrawn drugs. Indeed, druginduced parkinsonism was detected in 20 of these patients. Of these, ten were being treated with trimetazidine only, while the remaining ten were simultaneously receiving other drugs potentially capable of inducing parkinsonism. Treatment with trimetazidine worsened previously diagnosed Parkinson's disease in 12 patients, and gait disorders coupled with disequilibrium was observed in 15 patients. Trimetazidine induced tremor in nine patients. Conclusion: Trimetazidine can induce parkinsonism, gait disorder and tremor. These adverse effects have not been previously described for this drug

Experimental and Bioinformatic Insights into the Effects of Epileptogenic Variants on the Function and Trafficking of the GABA Transporter GAT-1

In this article, we identified a novel epileptogenic variant (G307R) of the gene SLC6A1, which encodes the GABA transporter GAT-1. Our main goal was to investigate the pathogenic mechanisms of this variant, located near the neurotransmitter permeation pathway, and compare it with other variants located either in the permeation pathway or close to the lipid bilayer. The mutants G307R and A334P, close to the gates of the transporter, could be glycosylated with variable efficiency and reached the membrane, albeit inactive. Mutants located in the center of the permeation pathway (G297R) or close to the lipid bilayer (A128V, G550R) were retained in the endoplasmic reticulum. Applying an Elastic Network Model, to these and to other previously characterized variants, we found that G307R and A334P significantly perturb the structure and dynamics of the intracellular gate, which can explain their reduced activity, while for A228V and G362R, the reduced translocation to the membrane quantitatively accounts for the reduced activity. The addition of a chemical chaperone (4-phenylbutyric acid, PBA), which improves protein folding, increased the activity of GAT-1WT, as well as most of the assayed variants, including G307R, suggesting that PBA might also assist the conformational changes occurring during the alternative access transport cycle