Circulating microRNAs as potential biomarkers for genetic generalized epilepsies: a three microRNA panel.

BACKGROUND AND PURPOSE: Genetic generalized epilepsies (GGEs) encompass a group of syndromes of mainly genetic causes, characterized by the involvement of both hemispheres. MicroRNAs (miRNAs) are small non-coding RNAs with a critical role in the regulation of neuronal biological processes through gene expression modulation. Dysregulated miRNA expression has been shown in epilepsy. Due to their stability in biological fluids like serum, miRNAs have assumed a prominent role in biomarker research. Our aim was to evaluate circulating levels of three miRNAs in GGE patients and assess their putative diagnostic value. METHODS: MiR-146a, miR-155 and miR-132 were quantified by real-time polymerase chain reaction in the serum of 79 GGE patients (47 women, 32 men, 35.1 ± 12.4 years) and 67 healthy individuals (41 women, 26 men, 42.4 ± 10.1 years). Relative expression values were calculated using the 2-ΔΔCt method. Receiver operating characteristic curve analysis was performed to assess diagnostic value. MiRNA expression was correlated with clinicopathological features. RESULTS: Serum levels of miR-146a and miR-155 were significantly upregulated in GGE patients relative to controls (3.13 and 6.05, respectively). Combined miR-146a, miR-155 and miR-132 serum levels performed well as a diagnostic biomarker, discriminating GGE patients from controls with an area under the curve of 0.85, 80% specificity and 73% sensitivity. CONCLUSIONS: Our results indicate that miR-146a, miR-155 and miR-132 may partake in GGE epileptogenesis. A panel of three circulating miRNAs with potential value as a GGE biomarker is reported for the first time. Novel biomarkers may help to identify new treatment targets and contribute to improved patients' quality of life through earlier diagnosis and a more precise prognosis.

Treating TNF Receptor Associated Periodic Fever Syndrome in End-Stage Renal Failure.

Tumor necrosis factor receptor associated periodic syndrome (TRAPS) is a rare monogenic autoinflammatory disease. Its most severe manifestation is secondary amyloidosis. A 44-year-old male presented with nephrotic syndrome. Kidney biopsy was conclusive for secondary amyloidosis. The patient and his children had a history of recurrent febrile periods since infancy. All subjects were positive for a heterozygous variant of the TNFRSF1A gene, confirming TRAPS diagnosis. The patient progressed to end-stage renal failure and developed recurrent pericarditis episodes. He was started on anakinra while on hemodialysis with marked reduction of his serum amyloid A protein (SAA) levels. Meanwhile he received a cadaveric renal transplant and maintains anakinra treatment. Despite renal failure being the most feared complication of AA amyloidosis caused by TRAPS, little data is available about safety of anti-IL-1 treatment in patients with severe kidney failure. The authors report this case of a patient on dialysis treated with anakinra in which no complications were registered. Though amyloidosis is established, the authors believe containing its progression and reducing inflammatory activity can improve patient prognosis and reduce recurrence of amyloidosis in kidney transplant, as has been demonstrated in transplanted patients due to familial Mediterranean fever amyloidosis.

Esclerosis tuberosa: caracterización clínica e intento de correlación fenotipo/genotipo / Tuberous sclerosis: Clinical characteristics and their relationship to genotype/phenotype

INTRODUCCIÓN: La esclerosis tuberosa (ET) es una enfermedad de afectación multisistémica y gran variabilidad fenotípica. Están identificados 2 genes involved en la génesis de la enfermedad: TSC1 y TSC2. OBJETIVOS: Caracterizar clínicamente a los pacientes con ET seguidos en Neurología Pediátrica de un hospital de tercer nivel durante los últimos 10 años y correlacionar el genotipo con la gravedad de la clínica neurológica y los estudios de imagen. PACIENTES Y MÉTODOS: Estudio retrospectivo descriptivo, mediante consulta de la historia clínica y evaluación de las resonancias magnéticas (RM) de pacientes con ET. RESULTADOS: Se estudiaron 35 casos, con una mediana de edad, al diagnóstico, de 10 meses. En el 91,4% se registraron crisis epilépticas, con un predominio de espasmos epilépticos a la presentación. Más del 50% tenía deterioro cognitivo y el 49% trastornos de conducta. Se sometieron a estudio genético 24 ni˜nos con predominio de mutaciones TSC2 (58,3%). De los 11 casos de epilepsia refractaria, 6 tenían mutación del gen TSC2. De los 8 pacientes con déficit cognitivo moderado a grave, se identificaron 5 mutaciones TSC2. Se revisaron 26 RM y en el 76,9% se observó una afectación completa de los lóbulos cerebrales, lo que refleja una gran cantidad de lesiones. De los enfermos con mutaciones TSC2 y RM realizada, todos tenían alta carga de lesión y 5 epilepsia refractaria. DISCUSIÓN: En nuestra muestra, nos encontramos con un alto porcentaje de mutaciones en el gen TSC2. Esta mutación está asociada a un peor pronóstico neurológico, con crisis más farmacorresistentes y un atraso cognitivo más severo

INTRODUCTION: Tuberous sclerosis (TS) is an inherited disorder with multisystemic involvement and a high phenotypic variability. There are two genes that cause this condition: TSC1 and TSC2. OBJECTIVES: Our goal was to clinically characterize patients with TS followed up in the Pediatric Neurology Clinic of a tertiary hospital during the last 10 years, and correlate the genotype with the severity of neurological manifestations and imaging studies. PATIENTS AND METHODS: Retrospective analysis of patients with TS, including review of medical records and available MRI imaging. RESULTS: We studied 35 cases with a median age at diagnosis of ten months. Seizures were the first manifestation in 91.4% of cases, with a predominance of epileptic spasms. Over 50% had cognitive impairment and 49% behavioral disorders. A genetic study was performed on 24 children, and TSC2 mutations identified in 58.3% of them. Of the 11 cases of refractory epilepsy, six had the TSC2 gene mutation. In the group of eight patients with moderate/severe cognitive deficits, five had TSC2 mutations. We reviewed 26 MRI scans, in which it was observed that 76.9% had diffuse involvement of cerebral lobes, which reflects a greater burden of injury. Of the patients who had an MRI scan performed and had TSC2 mutations, all had a high tuber load, and5 of them had refractory epilepsy. DISCUSSION: In our sample we observe a high percentage of mutations in the TSC2 gene. This mutation carries a worse neurological prognosis, with drug-resistant epilepsy and a more severe cognitive impairme

[Tuberous sclerosis: clinical characteristics and their relationship to genotype/phenotype]. / Esclerosis tuberosa: caracterización clínica e intento de correlación fenotipo/genotipo.

INTRODUCTION: Tuberous sclerosis (TS) is an inherited disorder with multisystemic involvement and a high phenotypic variability. There are two genes that cause this condition: TSC1 and TSC2. OBJECTIVES: Our goal was to clinically characterize patients with TS followed up in the Pediatric Neurology Clinic of a tertiary hospital during the last 10 years, and correlate the genotype with the severity of neurological manifestations and imaging studies. PATIENTS AND METHODS: Retrospective analysis of patients with TS, including review of medical records and available MRI imaging. RESULTS: We studied 35 cases with a median age at diagnosis of ten months. Seizures were the first manifestation in 91.4% of cases, with a predominance of epileptic spasms. Over 50% had cognitive impairment and 49% behavioral disorders. A genetic study was performed on 24 children, and TSC2 mutations identified in 58.3% of them. Of the 11 cases of refractory epilepsy, six had the TSC2 gene mutation. In the group of eight patients with moderate/severe cognitive deficits, five had TSC2 mutations. We reviewed 26 MRI scans, in which it was observed that 76.9% had diffuse involvement of cerebral lobes, which reflects a greater burden of injury. Of the patients who had an MRI scan performed and had TSC2 mutations, all had a high tuber load, and5 of them had refractory epilepsy. DISCUSSION: In our sample we observe a high percentage of mutations in the TSC2 gene. This mutation carries a worse neurological prognosis, with drug-resistant epilepsy and a more severe cognitive impairment.

Hemodiafiltración venovenosa continua como solución para la intoxicación grave con Valproato de Sodio / No disponible

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Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin.

We studied 21 patients, from 18 families, with L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic disorder with a homogeneous presentation: progressive neurodegeneration with extrapyramidal and cerebellar signs, seizures, and subcortical leukoencephalopathy. Increased levels of L-2-hydroxyglutaric acid in body fluids proved the diagnosis of L-2-HGA in all 21 patients. We analyzed the L-2-HGA gene (L2HGDH), recently found to be mutated in consanguineous families with L-2-HGA, and identified seven novel mutations in 15 families. Three mutations appeared to be particularly prevalent in this Portuguese panel: a frameshift mutation (c.529delC) was detected in 12 out of 30 mutant alleles (40%), a nonsense mutation (c.208C>T; p.Arg70X) in 7/30 alleles (23%), and a missense mutation (c.293A>G; p.His98Arg) in four out of 30 mutant alleles (13%), suggesting that common origin may exist. Furthermore, two novel missense (c.169G>A; p.Gly57Arg, c.1301A>C; p.His434Pro) and two splice error (c.257-2A>G, c.907-2A>G) mutations were found. All the mutations presumably lead to loss-of-function with no relationship between clinical signs, progression of the disease, levels of L-2-HGA and site of the mutation. In the three remaining families, no pathogenic mutations in the L-2-HGA were found, which suggests either alterations in regulatory regions of the gene or of its intervening sequences, compound heterozygosity for large genomic deletion and, or further genetic heterogeneity.

Recessive ataxia with ocular apraxia: review of 22 Portuguese patients.

BACKGROUND: The recessive ataxias are a heterogeneous group of neurodegenerative disorders characterized by cerebellar ataxia associated with a number of different neurologic, ophthalmologic, or general signs. They are often difficult to classify in clinical terms, except for Friedreich ataxia, ataxia-telangiectasia, and a relatively small group of rare conditions for which the molecular basis has already been defined. OBJECTIVES: To study the clinical presentation and to define diagnostic criteria in a group of Portuguese patients with ataxia and ocular apraxia, an autosomal recessive form without the essential clinical and laboratory features of ataxia-telangiectasia. PATIENTS AND METHODS: We reviewed 22 patients in 11 kindreds, identified through a systematic survey of hereditary ataxias being conducted in Portugal. RESULTS: Age at onset ranged from 1 to 15 years, with a mean of 4.7 years. The duration of symptoms at the time of last examination varied from 5 to 58 years. All patients presented with progressive cerebellar ataxia, the characteristic ocular apraxia, and a peripheral neuropathy. Associated neurologic signs included dystonia, scoliosis, and pes cavus. Magnetic resonance imaging was performed in 16 patients, all of whom showed cerebellar atrophy. CONCLUSIONS: Ataxia with ocular apraxia may be more frequent than postulated before, and may be identified clinically using the following criteria: (1) autosomal recessive transmission; (2) early onset (for most patients in early childhood); (3) combination of cerebellar ataxia, ocular apraxia, and early areflexia, with later appearance of the full picture of peripheral neuropathy; (4) absence of mental retardation, telangiectasia, and immunodeficiency; and (5) the possibility of a long survival, although with severe motor handicap.

Clinical heterogeneity of autosomal recessive spastic paraplegias: analysis of 106 patients in 46 families.

BACKGROUND: Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive and predominant spasticity of the lower limbs, in which dominant, recessive, and X-linked forms have been described. While autosomal dominant HSP has been extensively studied, autosomal recessive HSP is less well known and is considered a rare condition. OBJECTIVE: To analyze the clinical presentation in a large group of patients with autosomal recessive HSP from Portugal and Algeria to define homogeneous groups that could serve as a guide for future molecular studies. RESULTS: Clinical features in 106 patients belonging to 46 Portuguese and Algerian families with autosomal recessive HSP are presented, as well as the results of molecular studies in 23 of these families. Five phenotypes are defined: (1) pure early-onset families, (2) pure lateonset families, (3) complex families with mental retardation, (4) complex families with mental retardation and peripheral neuropathy, and (5) complex families with cerebellar ataxia. Six additional families have specific complex presentations, each of which is unique in the present series. Pyramidal signs in the upper limbs and pes cavus are frequent findings, while pseudobulbar signs, including dysarthria, dysphagia, and brisk jaw jerks, are more frequent in the complex forms. The complex forms have a poorer prognosis, while pure forms, particularly those with early onset, are more benign. One Algerian pure early-onset kindred was linked to the locus on chromosome 8, previously reported in 4 Tunisian families. Two of the Portuguese kindreds with complex forms (one with mental retardation and the other associated with hypoplasia of the corpus callosum) showed linkage to the locus recently identified on chromosome 16. CONCLUSIONS: Although autosomal recessive HSP represents a heterogeneous group of diseases, some phenotypes can be defined by analyzing a large group of patients. The fact that only one Algerian family was linked to chromosome 8 suggests that this is a rare localization even in kindreds with the same ethnic background. Linkage to chromosome 16 was found in 2 clinically diverse Portuguese kindreds, illustrating that this locus is also rare and may correspond to different phenotypes.