NR4A2 Mutations Can Cause Intellectual Disability and Language Impairment With Persistent Dystonia-Parkinsonism

Dystonia; Parkinson's disease/Parkinsonism; Genetic linkageMalaltia de Parkinson/Parkinsonisme; Vinculació genètica; DistoniaEnfermedad de Parkinson/Parkinsonismo; Enlace genético; DistoníaThis work was supported by the Health Institute Carlos III—General Subdirectorate for Research Evaluation and Promotion (PI16/01575, PI18/01898, PI18/00147, PI19/01576), the Spanish Ministry of Economy and Competitiveness (SAF2007-60700), the Ministry of Economy, Innovation, Science and Business of the Government of Andalucía (CVI-02526, CTS-7685), the Ministry of Health and Social Welfare of the Government of Andalucía (PI-0459-2018, PE-0210-2018, PE-0186-2019) and by the Valencian Government (PROMETEO/2018/135), within the framework of the National Research and Development Plan co-funded with European Regional Development Funds. Part of the equipment employed in this study was funded by the Valencian Government and co-financed with European Regional Development Funds (OP ERDF of Valencian Community 2014-2020). I. Hinarejos has a PFIS-PhD fellowship (FI19/00072), S. Jesús has a contract “Acción B Clínicos-Investigadores” (Action B Clinicians-Researchers) contract (B-0007-2019) funded by the Ministry of Health and Family of the Government of Andalucía, and D. Macías-García has a Río Hortega contract (CM18/00142) funded by the Health Institute Carlos III

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

Cerebellar atrophy; Exome sequencing; Movement disordersAtrofia del cerebelo; Secuenciación del exoma; Trastornos del movimientoAtròfia del cerebel; Seqüenciació de l'exoma; Trastorns del movimentOur 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)

NR4A2 Mutations Can Cause Intellectual Disability and Language Impairment With Persistent Dystonia-Parkinsonism

TheNR4A2/NURR1gene (MIM*601828) has recently been associated with autosomal-dominantearly-onset dystonia-parkinsonism with intellectual disability.1NR4A2codifies for a nuclear tran-scription factor and is expressed mainly in the substantia nigra, ventral tegmental area, and limbicareas.2To date, 14 different alterations inNR4A2have been described associated with variousclinical phenotypes, mainly with neurodevelopment disorders (table e-1, links.lww.com/NXG/A371). We describe here an interesting case suffering a persistent dystonia-parkinsonism syndrome(DPS) with motor tics, which expands the clinical phenotype ofNR4A2-associated DPS

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

Diagnóstico genético de neuropatías periféricas hereditarias e investigación de la patogenicidad de una mutación mediante el empleo de un organismo modelo

[ES] La enfermedad de Charcot-Marie-Tooth (CMT) y neuropatías relacionadas comprenden un grupo de trastornos neurológicos con una amplia variabilidad clínica y genética. Las técnicas basadas en Next Generation Sequencing (NGS) han mejorado el diagnóstico genético, pero, a veces, el gran número de variantes identificadas dificulta determinar cuál de éstas es la causante de la enfermedad. En la mayoría de casos, se identifican variantes que deben ser investigadas mediante ensayos funcionales, empleando organismos modelo, con el fin de determinar su patogenicidad. En el presente Trabajo Final de Grado se ha realizado el análisis de datos procedentes de un panel de genes dirigido al diagnóstico de la enfermedad de CMT, atrofia espinal distal (AED), esclerosis lateral amiotrófica (ELA), y atrofia muscular espinal (AME). Con esta herramienta diagnóstica se han evaluado 44 pacientes, que cursan con alguna de estas enfermedades. En este conjunto, se han detectado variantes genéticas poco frecuentes en 33 genes. El rendimiento diagnóstico obtenido en el presente trabajo se encuentra en un 29,5%, pudiendo ampliarse hasta un 66% con posteriores investigaciones. La variante NM_004990; c.1808T>C; (P.F603S) detectada en el gen MARS, en el paciente SGT/742, ha sido investigada en profundidad. Debido al reducido número de casos descritos que asocian variantes genéticas en MARS a la enfermedad CMT, así como por la naturaleza de la mutación detectada, se decidieron abordar ensayos funcionales que pudieran confirmar la posible implicación de la misma en el fenotipo del paciente. Para ello, se ha investigado el efecto de la mutación trabajando con el gen ortólogo de MARS en el nematodo Caenorhabditis elegans: mars-1. En este trabajo se han conseguido cepas de gusanos transgénicas estables, sin embargo, no se ha observado un fenotipo anómalo asociado al gen portador de la mutación, en comparación con el gen mars-1 salvaje. Posteriores experimentos nos permitirán ajustar el diseño experimental y, en consecuencia, ser capaces de generar un modelo de la enfermedad en C. elegans.[EN] Charcot-Marie-Tooth disease (CMT) and related neuropathies comprise a group of heterogeneous hereditary neuropathies with wide genetic variability. The techniques based on Next Generation Sequencing (NGS) have improved the genetic diagnosis, although sometimes the large number of changes identified makes it difficult to determine the cause of the disease. In most cases, the identified variants must be investigated through functional assays using model organisms to determine their pathogenicity. In the present bachelor’s thesis, it has been analyzed the data from a panel of genes comprising 119 genes involved in CMT disease, distal spinal atrophy (AED), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (AME). With this diagnostic tool 44 patientsshowing any of these neuropathies have been studied. In this group, there have been detected lowfrequency genetic variants in 33 genes. The diagnostic performance obtained in this bachelor’s thesis is 29,5%, and can be expanded to 66% with further investigations. The genetic variant NM_004990; C.1808> C; (P.F603S) detected in the MARS gene in the patient SGT/742 has been investigated in depth. Due to the small number of cases described that associate genetic variants in MARS with CMT disease, as well as the nature of the detected mutation, it was decided to address functional assays that could confirm the possible implication of the mutation in the phenotype of the patient. It has been investigated the effect of the mutation working with the orthologous gene of MARS in the nematode Caenorhabditis elegans: mars-1. In this work, stable transgenic worm strains have been obtained; however, an abnormal phenotype associated with the mutation has not been observed, as compared to the wild mars- 1 gene. Further experiments will allow us to adjust the experimental design and, consequently, to be able to generate a model of the disease in C. elegans.Hinarejos Martínez, MI. (2017). Diagnóstico genético de neuropatías periféricas hereditarias e investigación de la patogenicidad de una mutación mediante el empleo de un organismo modelo. http://hdl.handle.net/10251/86540TFG

EMPEZAR A PROGRAMAR USANDO JAVA

Este libro es una introducción al diseño metodológico de programas en la que se incide en el uso de los tipos de datos que dichos programas manipulan para representar el dominio de los problemas que resuelven.En concreto, la aproximación al diseño de programas seguida en este libro es la denominada Programación Orientada a Objetos,usa Java como lenguaje vehicular, incluye los tópicos habituales de un curso de programación a pequeña escala y hace de la eficiencia el criterio último de diseño de programas y tipos de datos.Aunque este libro va dirigido principalmente a estudiantes de primer curso del nuevo Grado en Informática,también puede resultar de utilidad en otros estudios universitarios o, incluso,en aquellos ámbitos académicos e industriales donde una buena fundamentación en la construcción y análisis de programas es necesariaLlorens Agost, ML.; Gómez Adrian, JA.; Galiano Ronda, IR.; Herrero Cuco, C.; Marqués Hernández, F.; Casanova Faus, A.; González Mollá, J.... (2016). EMPEZAR A PROGRAMAR USANDO JAVA. Editorial Universitat Politècnica de València. http://hdl.handle.net/10251/70965EDITORIA