Familial adult myoclonus epilepsy (FAME) is an autosomal dominant condition characterized by the association of myoclonic tremor and epilepsy mainly with onset in adulthood. The clinical course is non-progressive or slowly progressive, as epilepsy is commonly controlled with appropriate antiseizure medication and individuals have a normal life expectancy. However, the myoclonus severity increases with age and leads to some degree of disability in the elderly. Because the non-coding repeat expansions responsible for FAME are not detected by routine genetic tests being used at this time, a clinical diagnosis accompanied by neurophysiological testing remains essential to guide the geneticist on the selection of the specific genetic technique.

To study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients. Two hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0-3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non-progressive disorders, infantile spasms, Doose syndrome, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments. Abnormal neurotransmitter values were identified in 68 (33%) patients. 5-Hydroxyindoleacetic acid (5-HIAA) deficit was the most prevalent alteration (91%). Low CSF 5-HIAA levels were significantly higher in 1- to 3-year-old children. A negative significant correlation was found between 5-HIAA levels and epilepsy duration before CSF study (Spearman's ρ=-0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5-HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills. A considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy. 5-Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.

The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown significance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the detected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients. Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dravet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mientras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases moleculares de las EED en población latino americana.

Generalized epilepsy and tremor phenotypes have been reported in some genetic disorders. Among them benign adult familial myoclonus epilepsy (BAFME) has been confirmed as a clearly defined clinical and genetic entity. On the other hand, non-progressive tremor and generalized epilepsy phenotypes have also been reported in patients with DHDDS variants. We report on a long term follow-up of patient with de novo missense variant of DHDDS, who revealed non progressive nature. This 18-year-old woman presented non-progressive tremor since her early infancy. She had rare seizures. Her tremor was considered as cortical myoclonic tremor with giant somatosensory evoked potentials. In patients with early onset, non-progressive tremor and rare generalized epilepsy phenotypes, DHDDS variants may be considered in the genetic differential diagnosis.