ABSTRACT
Developmental and epileptic encephalopathies (DEE) are complex pediatric epilepsies, in which heterogeneous pathogenic factors play an important role. Next-generation-sequencing based tools have shown excellent effectiveness. The constant increase in the number of new genotype-phenotype associations suggests the periodic need for re-interpretation and re-analysis of genetic studies without positive results. In this study, we report the diagnostic utility of targeted gene panel sequencing and whole exome sequencing in 55 Argentine subjects with DEE, focusing on the utility of re-interpretation and re-analysis of undetermined and negative genetic diagnoses. The new information in biomedical literature and databases was used for the re-interpretation. For re-analysis, sequencing data processing was repeated using updated bioinformatics tools. Initially, pathogenic variants were detected in 21 subjects (38%). After an average time of 29 months, 25% of the subjects without a genetic diagnosis were re-categorized as diagnosed. Finally, the overall diagnostic yield increased to 53% (29 subjects). In consequence of the re-interpretation and re-analysis, we identified novel variants in the genes: CHD2, COL4A1, FOXG1, GABRA1, GRIN2B, HNRNPU, KCNQ2, MECP2, PCDH19, SCN1A, SCN2A, SCN8A, SLC6A1, STXBP1 and WWOX. Our results expand the diagnostic yield of this subgroup of infantile and childhood seizures and demonstrate the importance of re-evaluation of genetic tests in subjects without an identified causative etiology.
Subject(s)
Brain Diseases/genetics , Epilepsy/genetics , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Adolescent , Child , Child, Preschool , Female , Genetic Association Studies/methods , Genetic Testing/methods , Genotype , High-Throughput Nucleotide Sequencing/methods , Humans , Male , Phenotype , Exome Sequencing/methods , Young AdultABSTRACT
The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology.
Subject(s)
High-Throughput Nucleotide Sequencing , Humans , Exome SequencingABSTRACT
Machado-Joseph disease (MJD) is the most frequent dominantly inherited spinocerebellar ataxia. A marked phenotypic variability is a characteristic of this disorder that could involve non-cerebellar presentations. Based on several case reports describing pyramidal dysfunction as the main symptom at onset, a clinical form resembling hereditary spastic paraplegia has been proposed. We report here two further cases of MJD patients whose initial clinical presentation suggested hereditary spastic paraplegia, and a summary of the main findings of previously similar published reports. Our findings lent support to the proposal of a MJD subtype distinguished by a marked pyramidal dysfunction at onset, simulating a clinical picture of hereditary spastic paraplegia.
Subject(s)
Machado-Joseph Disease/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Phenotype , Repressor Proteins/genetics , Spastic Paraplegia, Hereditary/genetics , Adult , Ataxin-3 , Diagnosis, Differential , Female , Humans , Machado-Joseph Disease/diagnosis , Male , Pedigree , Spastic Paraplegia, Hereditary/diagnosisABSTRACT
La ataxia espinocerebelosa tipo 3 o enfermedad de Machado-Joseph (SCA-3/EMJ) es la forma más frecuente de ataxia espinocerebelosa autosómica dominante. Se caracteriza por una marcada variabilidad fenotípica, pudiendo causar formas no cerebelosas de presentación. En base a algunos casos comunicados, se ha propuesto una forma de presentación clínica similar a la de una paraparesia espástica hereditaria, con la presencia de signos de disfunción piramidal predominantes como la manifestación clínica inicial. Presentamos dos nuevos casos de SCA-3/EMJ con un cuadro clínico inicial sugerente de paraparesia espástica hereditaria y una revisión de los casos clínicos similares previamente informados. Nuestros hallazgos apoyan la propuesta de un subtipo de SCA-3/EMJ caracterizado por la presencia de marcada disfunción piramidal como manifestación inicial, simulando un cuadro clínico de paraparesia espástica hereditaria.
Machado-Joseph disease (MJD) is the most frequent dominantly inherited spinocerebellar ataxia. A marked phenotypic variability is a characteristic of this disorder that could involve non-cerebellar presentations. Based on several case reports describing pyramidal dysfunction as the main symptom at onset, a clinical form resembling hereditary spastic paraplegia has been proposed. We report here two further cases of MJD patients whose initial clinical presentation suggested hereditary spastic paraplegia, and a summary of the main findings of previously similar published reports. Our findings lent support to the proposal of a MJD subtype distinguished by a marked pyramidal dysfunction at onset, simulating a clinical picture of hereditary spastic paraplegia.
Subject(s)
Adult , Female , Humans , Male , Machado-Joseph Disease/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Phenotype , Repressor Proteins/genetics , Spastic Paraplegia, Hereditary/genetics , Diagnosis, Differential , Machado-Joseph Disease/diagnosis , Pedigree , Spastic Paraplegia, Hereditary/diagnosisABSTRACT
La ataxia espinocerebelosa tipo 3 o enfermedad de Machado-Joseph (SCA-3/EMJ) es la forma más frecuente de ataxia espinocerebelosa autosómica dominante. Se caracteriza por una marcada variabilidad fenotípica, pudiendo causar formas no cerebelosas de presentación. En base a algunos casos comunicados, se ha propuesto una forma de presentación clínica similar a la de una paraparesia espástica hereditaria, con la presencia de signos de disfunción piramidal predominantes como la manifestación clínica inicial. Presentamos dos nuevos casos de SCA-3/EMJ con un cuadro clínico inicial sugerente de paraparesia espástica hereditaria y una revisión de los casos clínicos similares previamente informados. Nuestros hallazgos apoyan la propuesta de un subtipo de SCA-3/EMJ caracterizado por la presencia de marcada disfunción piramidal como manifestación inicial, simulando un cuadro clínico de paraparesia espástica hereditaria.(AU)
Machado-Joseph disease (MJD) is the most frequent dominantly inherited spinocerebellar ataxia. A marked phenotypic variability is a characteristic of this disorder that could involve non-cerebellar presentations. Based on several case reports describing pyramidal dysfunction as the main symptom at onset, a clinical form resembling hereditary spastic paraplegia has been proposed. We report here two further cases of MJD patients whose initial clinical presentation suggested hereditary spastic paraplegia, and a summary of the main findings of previously similar published reports. Our findings lent support to the proposal of a MJD subtype distinguished by a marked pyramidal dysfunction at onset, simulating a clinical picture of hereditary spastic paraplegia.(AU)
Subject(s)
Adult , Female , Humans , Male , Machado-Joseph Disease/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Phenotype , Repressor Proteins/genetics , Spastic Paraplegia, Hereditary/genetics , Diagnosis, Differential , Machado-Joseph Disease/diagnosis , Pedigree , Spastic Paraplegia, Hereditary/diagnosisABSTRACT
Tonic spasms have been most commonly associated with multiple sclerosis. To date, few reports of series of patients with neuromyelitis optica and tonic spasms have been published. Methods: We analyzed the characteristics and frequency of tonic spasms in 19 subjects with neuromyelitis optica. Data was collected using a semi-structured questionnaire for tonic spasms, by both retrospectively reviewing medical records and performing clinical assessment. Results: All patients except one developed this symptom. The main triggering factors were sudden movements and emotional factors. Spasms were commonly associated to sensory disturbances and worsened during the acute phases of the disease. Carbamazepine was most commonly used to treat the symptom and patients showed good response to the drug. Conclusions: Tonic spasms are a common clinical manifestation in patients with neuromyelitis optica. .
Espasmos tônicos têm sido mais frequentemente associados com esclerose múltipla. Foram publicados até agora poucos relatos de série de pacientes com neuromielite óptica e espasmos tônicos. Métodos: Foram analisadas as características e a frequência de espasmos tônicos em 19 indivíduos com neuromielite óptica. Os dados foram coletados por meio de um questionário semiestruturado para espasmos tônicos, mediante a avaliação retrospectiva dos prontuários e a análise dos dados clínicos Resultados: Todos os pacientes com neuromielite óptica exceto um apresentaram espasmos tônicos. Os principais fatores desencadeantes foram movimentos bruscos e fatores emocionais. Espasmos foram frequentemente associados a perturbações sensoriais e se agravaram durante a fase aguda da doença. A carbamazepina foi utilizada frequentemente para tratar os sintomas, com boa resposta. Conclusões: Os espasmos tônicos são manifestações clínicas frequentes em pacientes com neuromielite óptica. .
Subject(s)
Adolescent , Child , Child, Preschool , Female , Humans , Neuromyelitis Optica/complications , Spasm/etiology , Anticonvulsants/therapeutic use , Carbamazepine/therapeutic use , Neuromyelitis Optica/drug therapy , Neuromyelitis Optica/physiopathology , Risk Factors , Surveys and Questionnaires , Spasm/drug therapy , Spasm/physiopathologyABSTRACT
UNLABELLED: Tonic spasms have been most commonly associated with multiple sclerosis. To date, few reports of series of patients with neuromyelitis optica and tonic spasms have been published. METHODS: We analyzed the characteristics and frequency of tonic spasms in 19 subjects with neuromyelitis optica. Data was collected using a semi-structured questionnaire for tonic spasms, by both retrospectively reviewing medical records and performing clinical assessment. RESULTS: All patients except one developed this symptom. The main triggering factors were sudden movements and emotional factors. Spasms were commonly associated to sensory disturbances and worsened during the acute phases of the disease. Carbamazepine was most commonly used to treat the symptom and patients showed good response to the drug. CONCLUSIONS: Tonic spasms are a common clinical manifestation in patients with neuromyelitis optica.
Subject(s)
Neuromyelitis Optica/complications , Spasm/etiology , Adolescent , Anticonvulsants/therapeutic use , Carbamazepine/therapeutic use , Child , Child, Preschool , Female , Humans , Neuromyelitis Optica/drug therapy , Neuromyelitis Optica/physiopathology , Risk Factors , Spasm/drug therapy , Spasm/physiopathology , Surveys and QuestionnairesABSTRACT
Machado-Joseph disease (MJD) is the most frequent dominantly inherited spinocerebellar ataxia. A marked phenotypic variability is a characteristic of this disorder that could involve non-cerebellar presentations. Based on several case reports describing pyramidal dysfunction as the main symptom at onset, a clinical form resembling hereditary spastic paraplegia has been proposed. We report here two further cases of MJD patients whose initial clinical presentation suggested hereditary spastic paraplegia, and a summary of the main findings of previously similar published reports. Our findings lent support to the proposal of a MJD subtype distinguished by a marked pyramidal dysfunction at onset, simulating a clinical picture of hereditary spastic paraplegia.
Subject(s)
Machado-Joseph Disease/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Phenotype , Repressor Proteins/genetics , Spastic Paraplegia, Hereditary/genetics , Adult , Diagnosis, Differential , Female , Humans , Machado-Joseph Disease/diagnosis , Male , Pedigree , Spastic Paraplegia, Hereditary/diagnosisABSTRACT
Se realizo un estudio con el fin de conocer la incidencia de la crisis hipertensiva, las características clínicas de los enfermos y el manejo en el servicio de urgencias del Hospital Obrero Nº 2 de la CNS Cochabamba para, recomendar pautas de actuación en urgencias ante una crisis hipertensiva (CH) de acuerdo con los resultados. Es un estudio prospectivo, transversal y descriptivo, desarrollado en el Servicio de Urgencias de Medicina Interna de la Caja Nacional de Salud, de Agosto a Noviembre del año 2007. Se recogieron los datos de pacientes atendidos con CH mediante una hoja de recolección de datos. Los resultados fueron que de un total de 5.717 consultas,recogieron los datos de 124 pacientes con CH, lo que supone una prevalencia del 2.5 % del total de urgencias, presentándose como Urgencias Hipertensivas (UH) el 2,2% y como Emergencias Hipertensivas (EH) el 0,3%. La mayoría de los pacientes tenían mas de 60 años, predominaban las mujeres y ¾ partes tenían antecedentes de HTA, sin embargo solo al 66% se le había prescrito tratamiento, de los cuales apro ximadamente la mitad no cumplían el mismo. LA EH mas frecuente fue la ECV isquémica. Para el manejo de UH el grupo farmacológico más utilizado en el servicio de urgencias fueron los Inhibidores de la enzima convertidora de Angiotensina (IECAS), demostrando la mayor eficacia y seguridad terapéutica.
We made this study in order to know the incidence of hipertensive crises, the clinical characteristics of sick people and the manage in urgence Service of Worker Hospital No 2 of CNS Cochabmba in order to recomend tips of treatment in Urgence Service when an Hipertensive Crise (HC)presents. This is a prospective, transversal and descriptive study, worked out in Internal Medicine Urgence Service of CNS, from August to November of 2007. Data were collected from patients who were cared by HC by a data collection sheet. The results showed that from a total of 5717 consults, 124 were patients with HC, which implies a prevalence of 2,5% from the total urgencies, presenting themselves as Hipertensive Urgence (HU) in 2,2% and as Hipertesive Emergence (HE) in 0,3%. Most of the patients had more than 60 years old, with a predomine of women and ¾ parts had Hypertension antecedents, however only 66% were prescripted treatment , from which about a half did not fulfill the same. The HE most frequet was the isquemica VBI. For the manage of the HU the most used farmacologic group in Urgence service were IECAS, showing the best therapeutic safe.
