Study of paediatric patients with the clinical and biochemical phenotype of glucose transporter type 1 deficiency syndrome.

[ES] Introducción El síndrome de déficit del transportador de glucosa cerebral (GLUT1DS) puede presentar fenotipos variados, incluyendo epilepsia, déficit intelectual y trastorno del movimiento. La mayoría presenta hipoglucorraquia y/o defectos en el gen SLC2A1, aunque existen pacientes sin hipoglucorraquia y otros con genética de SLC2A1-negativa, o con defectos en otros genes y fenotipo compatible. Objetivos Describir las características clínicas, bioquímicas y genéticas y realizar un análisis univariante de un grupo de pacientes con fenotipo clínico y bioquímico de GLUT1DS, con o sin genética SLC2A1-positiva. Material y métodos Se incluyeron 13 pacientes con criterios clínico-bioquímicos de GLUT1DS. Se realizó secuenciación de SLC2A1 y MLPA. En los casos negativos se realizó exoma clínico. Resultados Seis presentaron fenotipo clásico, 2 discinesia paroxística, 2 trastornos del movimiento complejo, 2 ausencias precoces y otro presentó epilepsia con ausencias infantiles refractaria a farmacoterapia. Seis fueron SLC2A1-positivos. Y en 5 de los SLC2A1-negativos se identificó otro defecto genético. No hubo diferencias significativas entre los dos grupos en edad de inicio, presentación clínica, microcefalia, discapacidad intelectual ni respuesta a dieta cetogénica. De forma no significativa, los pacientes SCL2A1-positivos presentaron más cambios clínicos en relación con la ingesta (66,7% vs. 28,6%) y mayor persistencia de síntomas motores (66% vs. 28,6%). De forma significativa, presentaron menor glucorraquia (34,5 mg/dl vs. 46 mg/dl, p = 0,04) e índice glucorraquia/glucemia más bajo (0,4 vs. 0,48, p = 0,05) que los SLC2A1-negativos. Conclusiones GLUT1DS puede ser causado por defectos genéticos en otros genes diferentes de SLC2A1 en pacientes con fenotipo compatible, hipoglucorraquia y buena respuesta a dieta cetogénica. [EN] Introduction Glucose transporter type 1 (GLUT1) deficiency syndrome may present a range of phenotypes, including epilepsy, intellectual disability, and movement disorders. The majority of patients present low CSF glucose levels and/or defects in the SLC2A1 gene; however, some patients do not present low CSF glucose or SLC2A1 mutations, and may have other mutations in other genes with compatible phenotypes. Aims We describe the clinical, biochemical, and genetic characteristics of the disease and perform a univariate analysis of a group of patients with clinical and biochemical phenotype of GLUT1 deficiency syndrome, with or without SLC2A1 mutations. Material and methods The study included 13 patients meeting clinical and biochemical criteria for GLUT1 deficiency syndrome. SLC2A1 sequencing and multiplex ligation-dependent probe amplification were performed; exome sequencing was performed for patients with negative results. Results Six patients presented the classic phenotype; 2 paroxysmal dyskinesia, 2 complex movement disorders, 2 early-onset absence seizures, and one presented drug-resistant childhood absence epilepsy. Six patients were positive for SLC2A1 mutations; in the other 5, another genetic defect was identified. No significant differences were observed between the 2 groups for age of onset, clinical presentation, microcephaly, intellectual disability, or response to ketogenic diet. Patients with SLC2A1 mutations presented more clinical changes in relation to diet (66.7% vs. 28.6% in the SLC2A1-negative group) and greater persistence of motor symptoms (66% vs. 28.6%); these differences were not statistically significant. Significant differences were observed for CSF glucose level (34.5 vs. 46 mg/dL, P = .04) and CSF/serum glucose ratio (0.4 vs. 0.48, P < .05).S

Estudio de pacientes pediátricos con fenotipo clínico y bioquímico de síndrome de déficit de transportador de glucosa cerebral (GLUT-1)

[EN] Introduction: Glucose transporter type 1 (GLUT1) deficiency syndrome may present a range of phenotypes, including epilepsy, intellectual disability, and movement disorders. The majority of patients present low CSF glucose levels and/or defects in the SLC2A1 gene; however, some patients do not present low CSF glucose or SLC2A1 mutations, and may have other mutations in other genes with compatible phenotypes. Aims: We describe the clinical, biochemical, and genetic characteristics of the disease and perform a univariate analysis of a group of patients with clinical and biochemical phenotype of GLUT1 deficiency syndrome, with or without SLC2A1 mutations. Material and methods: The study included 13 patients meeting clinical and biochemical criteria for GLUT1 deficiency syndrome. SLC2A1 sequencing and multiplex ligation-dependent probe amplification were performed; exome sequencing was performed for patients with negative results. Results: Six patients presented the classic phenotype; 2 paroxysmal dyskinesia, 2 complex movement disorders, 2 early-onset absence seizures, and one presented drug-resistant childhood absence epilepsy. Six patients were positive for SLC2A1 mutations; in the other 5, another genetic defect was identified. No significant differences were observed between the 2 groups for age of onset, clinical presentation, microcephaly, intellectual disability, or response to ketogenic diet. Patients with SLC2A1 mutations presented more clinical changes in relation to diet (66.7%, vs 28.6% in the SLC2A1-negative group) and greater persistence of motor symptoms (66% vs 28.6%); these differences were not statistically significant. Significant differences were observed for CSF glucose level (34.5 vs 46mg/dL, P=.04) and CSF/serum glucose ratio (0.4 vs 0.48, P<.05). Conclusions: GLUT1 deficiency syndrome may be caused by mutations to genes other than SLC2A1 in patients with compatible phenotype, low CSF glucose level, and good response to the ketogenic diet. [ES] Introducción: El síndrome de déficit del transportador de glucosa cerebral (GLUT1DS) puede presentar fenotipos variados, incluyendo epilepsia, déficit intelectual y trastorno del movimiento. La mayoría presentan hipoglucorraquia y/o defectos en el gen SLC2A1, aunque existen pacientes sin hipoglucorraquia y otros con genética de SLC2A1-negativa, o con defectos en otros genes y fenotipo compatible. Objetivos: Describir las características clínicas, bioquímicas y genéticas y realizar un análisis univariante de un grupo de pacientes con fenotipo clínico y bioquímico de GLUT1DS, con o sin genética SLC2A1-positiva. Material y métodos: Se incluyeron 13 pacientes con criterios clínico-bioquímicos de GLUT1DS. Se realizó secuenciación de SLC2A1 y MLPA. En los casos negativos se realizó exoma clínico. Resultados: Seis presentaron fenotipo clásico, 2 discinesia paroxística, 2 trastornos del movimiento complejo, 2 ausencias precoces y otro presentó epilepsia con ausencias infantiles refractaria a farmacoterapia. Seis fueron SLC2A1-positivos. Y en 5 de los SLC2A1-negativos se identificó otro defecto genético. No hubo diferencias significativas entre los dos grupos en edad de inicio, presentación clínica, microcefalia, discapacidad intelectual ni respuesta a dieta cetogénica. De forma no significativa, los pacientes SCL2A1-positivos presentaron más cambios clínicos en relación con la ingesta (66,7% vs. 28,6%) y mayor persistencia de síntomas motores (66% vs. 28,6%). De forma significativa, presentaron menor glucorraquia (34,5 mg/dl vs. 46 mg/dl, p = 0.04) e índice glucorraquia/glucemia más bajo (0,4 vs. 0,48, p = 0,05) que los SLC2A1-negativos. Conclusiones: GLUT1DS puede ser causado por defectos genéticos en otros genes diferentes de SLC2A1 en pacientes con fenotipo compatible, hipoglucorraquia y buena repuesta a dieta cetogénica.‘‘Identification and clinical and biochemical characterisation of patients with GLUT1DS: treatment monitoring.’’ Translational research project 2017, CIBERER. Coordinator: Dr Luis González Gutiérrez-Solana (GCV6). Participating units: U703 (Artuch); U746 (Pérez); GCV5 (Couce); GCV6 (Gutiérrez-Solana); GCV7 (López Laso); GCV8 (del Toro). Research project: hereditary metabolic disorders.S

Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients

In order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis

Síndrome opsoclono-mioclono: características clínicas, aspectos terapéuticos y factores pronósticos en una cohorte pediátrica española

Resumen: Introducción: El síndrome opsoclono-mioclono-ataxia es un raro trastorno de inicio pediátrico; de base neuroinflamatoria y origen paraneoplásico, parainfeccioso o idiopático. Actualmente no hay biomarcadores, siendo el diagnóstico clínico. El pronóstico cognitivo parece estar relacionado con el inicio temprano de la terapia inmunomoduladora. Método: Se describen las características epidemiológicas, clínicas, terapéuticas y pronósticas a largo plazo de una cohorte de 20 pacientes españoles. Resultados: La edad media de debut fue de 21 meses (2-59 meses). La ataxia y el opsoclonus fueron los síntomas de inicio más frecuentes y predominantes en la evolución. El tiempo medio desde los primeros síntomas hasta el diagnóstico fue de 1,1 mes. Un tumor de extirpe neuroblástica fue detectado en el 45%, realizándose resección quirúrgica en siete y quimioterapia en dos pacientes. En el estudio de líquido cefalorraquídeo se constató pleocitosis en cuatro (25%), con negatividad de anticuerpos antineuronales y bandas oligoclonales en todos los casos estudiados. En el 100% se emplearon fármacos inmunomoduladores. En nueve pacientes el tratamiento combinado inmunomodulador se inició desde el momento del diagnóstico, y en cinco el tiempo medio de implementación fue de 2,2 meses. A largo plazo, seis de 10 pacientes con seguimiento superior a cinco años presentaban secuelas cognitivas leves o moderadas; cuatro pacientes presentaron recaídas, generalmente coincidiendo con el descenso de la corticoterapia. Conclusiones: El inicio precoz de la inmunoterapia, así como de la triple terapia en los casos que lo precisaron, se relacionó con una menor frecuencia de afectación cognitiva a los dos años del debut. Abstract: Introduction: Opsoclonus-myoclonus-ataxia syndrome is a rare neuroinflammatory disorder with onset during childhood; aetiology may be paraneoplastic, para-infectious, or idiopathic. No biomarkers have yet been identified, and diagnosis is clinical. Better cognitive prognosis appears to be related to early onset of immunomodulatory therapy. Methods: We describe the epidemiological, clinical, therapeutic, and long-term prognostic characteristics of a cohort of 20 Spanish patients. Results: The mean age of onset was 21 months (range, 2-59). Ataxia and opsoclonus were the most frequent symptoms both at disease onset and throughout disease progression. The mean time from onset to diagnosis was 1.1 months. Neuroblast lineage tumours were detected in 45% of patients; these were treated with surgical resection in 7 cases and chemotherapy in 2. Cerebrospinal fluid analysis revealed pleocytosis in 4 cases (25%) and neither antineuronal antibodies nor oligoclonal bands were detected in any patient. Immunomodulatory drugs were used in all cases. Nine patients started combined immunomodulatory treatment at the time of diagnosis, and 5 patients after a mean of 2.2 months. In the long term, 6 of the 10 patients followed up for more than 5 years presented mild or moderate cognitive sequelae. Four patients presented relapses, generally coinciding with the decrease of corticosteroid doses. Conclusions: Early initiation of immunotherapy, as well as triple combination therapy, where needed, was associated with a lower frequency of cognitive impairment 2 years after onset