Clinical and Molecular Profiling in GNAO1 Permits Phenotype-Genotype Correlation.

BACKGROUND: Defects in GNAO1, the gene encoding the major neuronal G-protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes. OBJECTIVES: We aimed to analyze the clinical phenotype and the molecular characterization of GNAO1-related disorders. METHODS: Patients were recruited in collaboration with the Spanish GNAO1 Association. For patient phenotyping, direct clinical evaluation, analysis of homemade-videos, and an online questionnaire completed by families were analyzed. We studied Gαo cellular expression, the interactions of the partner proteins, and binding to guanosine triphosphate (GTP) and G-protein-coupled receptors (GPCRs). RESULTS: Eighteen patients with GNAO1 genetic defects had a complex neurodevelopmental disorder, epilepsy, central hypotonia, and movement disorders. Eleven patients showed neurological deterioration, recurrent hyperkinetic crisis with partial recovery, and secondary complications leading to death in three cases. Deep brain stimulation improved hyperkinetic crisis, but had inconsistent benefits in dystonia. The molecular defects caused by pathogenic Gαo were aberrant GTP binding and hydrolysis activities, an inability to interact with cellular binding partners, and reduced coupling to GPCRs. Decreased localization of Gαo in the plasma membrane was correlated with the phenotype of "developmental and epileptic encephalopathy 17." We observed a genotype-phenotype correlation, pathogenic variants in position 203 were related to developmental and epileptic encephalopathy, whereas those in position 209 were related to neurodevelopmental disorder with involuntary movements. Milder phenotypes were associated with other molecular defects such as del.16q12.2q21 and I344del. CONCLUSION: We highlight the complexity of the motor phenotype, which is characterized by fluctuations throughout the day, and hyperkinetic crisis with a distinct post-hyperkinetic crisis state. We confirm a molecular-based genotype-phenotype correlation for specific variants. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Crisis oculógiras asociadas a fármacos: descripción de cuatro casos y revisión de la bibliografía / Medication-related oculogyric crises: a description of four cases and a review of the literature

Introducción. Las crisis oculógiras se consideran una forma de distonía focal y pueden observarse como reacciones secundarias a fármacos. El cuadro puede confundirse con crisis epilépticas. Objetivo.Describir la clínica y evolución de pacientes con crisis oculógiras relacionadas con fármacos y realizar una revisión del tema. Casos clínicos. Estudio retrospectivo y descriptivo de cuatro pacientes evaluados en el servicio de neurología por crisis oculógiras. Los pacientes tenían un diagnóstico que asociaba un trastorno de conducta que requirió tratamiento con fármacos antipsicóticos. Los episodios de crisis oculógiras no presentaron correlación con los hallazgos en el electroencefalograma. Presentaron buena respuesta a la disminución de dosis o a la suspensión del agente causal aparente. Conclusiones. El cuadro no sólo se presenta en pacientes tratados con antipsicóticos, sino que también se asocia con otros fármacos de uso frecuente en la práctica pediátrica diaria. En las crisis oculógiras como motivo de consulta, deben valorarse los diagnósticos diferenciales para evitar estudios innecesarios y realizar un correcto manejo terapéutico(AU)

Introduction. Oculogyric crises are considered to be a form of focal dystonia and can be observed as reactions to pharmaceuticals. The signs and symptoms may be confused with epileptic crises. Aims. To describe the clinical features and progress of patients with pharmaceutical-related oculogyric crises and to carry out a review of the topic. Case reports. We conducted a retrospective, descriptive study of four patients evaluated in the neurology service due to oculogyric crises. The patients had been diagnosed with an associated conduct disorder requiring treatment with antipsychotic drugs. The episodes of oculogyric crises did not correlate with the findings in the electroencephalogram. They responded well to the reduction in dosage or to withdrawal of the apparent causing agent. Conclusions. The clinical picture does not present only in patients treated with antipsychotics but is also linked with other pharmaceuticals that are frequently used in daily paediatric practice. When oculogyric crises are the reason for visiting, differential diagnoses must be taken into account in order to avoid unnecessary studies and to carry out an appropriate therapeutic management(AU)

Disecciones arteriales craneocervicales en la edad pediátrica: ¿una patología emergente o infradiagnosticada? / Dissections of craniocervical arteries in the paediatric age: a pathology that is emerging or under-diagnosed?

Introducción. Las disecciones craneocervicales constituyen una reconocida causa de ictus en la infancia y adolescencia, y son responsables del 0,4-20% del total de casos. Objetivo. Describir una población de niños con disecciones arteriales, analizando su presentación clínica, factores de riesgo, signos angiográficos, evolución y tratamiento. Pacientes y métodos. Se llevó a cabo un estudio descriptivo, retrospectivo y colaborativo (Hospital Sant Joan de Déu de Barcelona y Centro Hospitalario Pereira Rossell de Montevideo), durante los años 2000 a 2009, de niños entre 1 mes a 17 años, con disecciones arteriales craneocervicales. Resultados. Se identificaron 10 casos con diagnóstico de disección arterial, siete varones y tres niñas. Nueve presentaron traumatismo previo al inicio de los síntomas neurológicos. Del total de pacientes, cinco comenzaron con hemiparesia, tres con síndrome hemicerebeloso, uno con afectación del VI par, y uno con soplo craneal. De éstos, tres tuvieron convulsiones y seis cefaleas que precedieron al cuadro clínico. El deterioro de la circulación anterior tuvo lugar en cinco niños, y l de la posterior en los otros cinco. Cuatro pacientes presentaron afectación arterial intracraneal, y seis, extracraneal. Se realizó anticoagulación en cinco pacientes, antiagregación en tres y no se trataron los dos restantes. No hubo fallecimientos, complicaciones por la anticoagulación, ni recurrencias en el período de seguimiento clínico. Conclusiones. Las disecciones craneocervicales son una causa frecuente de ictus en la infancia. La sospecha clínica debe ser alta ante todo paciente con sintomatología focal neurológica en relación con un traumatismo craneocervical (AU)

Introduction. Cranio-cervical arterial dissections are a recognized cause of ischemic stroke in childhood, with an approximate incidence of 0.4 to 20%. Aim. To describe a population of children with cranio-cervical arterial dissections, analyzing clinical presentation, risk factors, angiographic findings, evolution and treatment. Patients and methods. A descriptive, retrospective, longitudinal collaborative review (Sant Joan de Déu and Pereira Rossell Children’s Hospital), of children one month to 17 years old of age was conducted, during the period of time between 2000 to 2009. Results. Ten cases with arterial dissection were identified, 7 of them were boys and 3 girls. Nine had a traumatism preceding neurological symptoms. Clinical presentation included 5 patients with hemiparesis, 3 with hemicerebelus syndrome, 1 with VI cranial nerve palsy and 1 with intracranial soplus as the only symptom at physical examination. Three of them had seizures, while headache preceding the onset of cerebral ischemic symptoms was founded in 6 of them. Dissection involved anterior circulation in 5 patients and posterior circulation in the other 5. In reference to the localization of arterial compromise 4 patients had intracranial dissections and 6 had extracranial dissections. Anticoagulation therapy was done in 5, antiagregation in 3, and treatment abstention in two. None of them suffered neither complications due to anticoagulation therapy nor dead or recurrent dissections in long term follow up (2 months to 8 years). Conclusions. Cranio-cervical dissections are a frequent cause of stroke in childhood. Clinical suspicious related to craniocervical traumatisms and subsequent neurological symptoms should be high (AU)

Utilidad del análisis del líquido cefalorraquídeo para el estudio de las deficiencias del metabolismo de neurotransmisores y pterinas y del transporte de glucosa y folato a través de la barrera hematoencefálica / Usefulness of analysis of cerebrospinal fluid for the diagnosis of neurotransmitters and pterin defects and glucose and folate transport deficiencies across blood brain barrier

Fundamento y objetivo: En la última década se ha descrito diferentes errores congénitos del metabolismo de los neurotransmisores (NT), en especial de las vías dopaminérgica y serotoninérgica y de las pterinas. También se ha descrito defectos primarios en el transporte de glucosa y 5-metiltetrahidrofolato (5-MTHF) a través de la barrera hematoencefálica, todos ellos enfermedades raras para cuyo diagnóstico es necesario el estudio en líquido cefalorraquídeo (LCR). Nuestro objetivo ha sido evaluar los resultados de la aplicación de un protocolo de análisis de LCR en España y Portugal durante 3 años en pacientes pediátricos con trastornos neurológicos de origen desconocido. Pacientes y método: Se estudió a 127 individuos control y 283 pacientes con trastornos neurológicos de origen desconocido. El análisis de NT se realizó mediante HPLC con detección electroquímica y el análisis de pterinas y 5-MTHF, mediante HPLC con detección de fluorescencia. Resultados: Se ha diagnosticado 3 deficiencias de tirosina hidroxilasa en una misma familia, 2 casos de distonía sensible a L-dopa, 2 familias con defiencia de guanosinatrifosfato-ciclohidrolasa dominante (14 casos), 2 deficiencias del transportador de glucosa y 43 deficiencias de folato en LCR. Conclusiones: Este estudio ha permitido el diagnóstico de nuevos pacientes y, lo que es más importante, el establecimiento en todos ellos de un tratamiento farmacológico o nutricional. Las deficiencias de 5-MTHF han sido las más frecuentes y se las ha detectado en diferentes grupos de pacientes

Background and objective: In the last few years, it has been described inborn errors of neurotransmitter and pterin metabolism and defects in folate and glucose transport across blood brain barrier. All these defects are classified as rare diseases and needs cerebrospinal fluid (CSF) sample analysis for diagnosis. Our aim was to evaluate the results of the application of a CSF analysis protocol in a pediatric population from Spain and Portugal presenting with neurological disorders of unknown origin. Patients and method: We studied CSF samples from and 283 patients with neurological disorders of unknown origin and 127 controls. Neurotransmitters were analysed by HPLC with electrochemical detection, and pterins and 5-methyltetrahydrofolate were determined by HPLC with fluorescence detection. Results: We diagnosed 3 patients with tyrosine hidroxylase deficiency, 2 with dopa responsive dystonia, 14 with GTP-ciclohydrolase deficiency, 2 with glucose transport deficiency and 43 with cerebral folate deficiency. Conclusions: This study allowed us to diagnose new patients, and more importantly, the establishment in all of them of a pharmacological or nutritional treatment. The most frequent defect found was CSF 5-methyltetrahydrofolate deficiency, which was present in different groups of patients