Avaliação sistematica dos aspectos clinicos e geneticos de pacientes com epilepsias mioclonicas progressivas

AUTOR(ES)
DATA DE PUBLICAÇÃO

2003

RESUMO

Progressive Mioclonic Epilepsies (PME) are arare heterogeneous group of genetically determined disorders characterized by epilepsy, mioclonic jerks and progressive neuroIogicaI decline including dementia and ataxia. There are five main disorders which can cause PME: Unverricht-Lundborg disease (ULD) and Lafora disease (LD), ceroides neuronal lipofuscinoses (LCN), mitochondriaI encephalomyopathies and sialidoses. The objective of this work was to establish specific diagnosis in a group of patients with PME.We also intended to: a) determine the most frequent causes of PME in our cohort of patients, b) determine the usefulness of a number of tests in determining the specifc diagnosis, c) establish phenotype-genotype correlation in our patients and d) propose a more appropriate scheme for the diagnosis of specific causes of PME, in our patients. AlI patients included in this work had the probabIe diagnosis of PME.Diagnostic criterion was the presence of the classical symptons. Patients were anaIyzed by neuroIogicaI evaluation, electroencephalogram (EEG), magnetic resonance imaging (MRI), histopathoIogyc exams and moIecuIar analysis. Initially, probable diagnoses of PME, was based exclusively in information obtained by ciínical familiary histories and neurological exam (diagnostic leveI). EEG and MRI (diagnostic level II )were performed in all patients, whose information guided us to more specific tests (biochemicaI and histopathologyc exams). In addition we performed muscle, skin biopsy and molecular analysis of Cistatina B, EPM2A, HD, SCA-7 genes and A3243G, A8344G point mutations in the mitochondrial DNA (diagnostic level III). We have studied a total of belongs to 25 patientsl 21 unrelated families. The probable diagnosis of ULD (diagnostic leveI I) was present in 9 patients (6 families), LD was the probable diagnosis in 5 patients (5 families) and LCN was probably in 5 patient (4 families). Other 4 unrelated patients had probably mitochondrial encephalomyopathies, while 1 patient had probabilly a metabolic disease and 1 patient had the possible diagnosis ofHuntington disease (HD) juvenile form. EEG and MRI (diagnostic leveI TI)were not useful to establish the specific cause of PME; however MRI in one patient allowed to excluded the diagnosis of PME, since her MRI showed the presence of a destructive lesion in the central nervous system. Skin biopsy was performed in 6/9 patients with probable ULD and 9/9 were screened for mutation in the Cistatin B gene (diagnostic leveI ID). Histopathologyc analysis suggest the diagnosis of ULD in 6 patients belongs to 3 families. Molecular analysis confirmed the presence of Cistatin B point mutations in 3 patientes in one only family. Four patients with probable diagnosis LD were submitted to skin biopsy and EPM2A gene. Histopathologyc analysis confumed the presence of Lafora bodies in two patients. Molecular analysis did not revealed the presence of pathogenic mutations in the EPM2A gene, in our cohort of patients. Four patients with probable LCN were submitted to skin biopsy. Ttwo of these patients presented the typical histopathologyc of the late infantile type. AlI patients with probable mitochondrial encephalomyopathies were submitted to molecular analysis of the mtDNA and three of them had muscle biopsy. Two patients demonstrated molecular alterations, one presented a point mutation at positive the A3243G of in mtDNA confirming MELAS and another had the A8344G point mutation that is found in the MERRF. Muscular biopsy confumed the presence of ragged red fibers in these patients. Found in the patient with probable mitochondrial disease had a positive molecular result a type of spinocerebellar ataxia, SCA-7. The patient with clinical a metabolic deposit disease had the diagnosis confumed by specific biochemical tests (low sialidase levels in the urine) the sialidose. The patient of with probable diagnosis of juvenile HD had negative molecular results. In conclusion we established the specific diagnosis of PME in 11/25 patients (43%) or in 9/21 (44%) families. The most frequently causes of PME were: ULD (3 patients), LD (2 patients), LCN (2 patients) and mitocondrial encephalomyopathies (2 patients). Definitive diagnosis was possible combining clínical evaluation and laboratory tests, following a diagnostic scheme: molecular analysis necessary to confirm the diagnosis of ULD and mitocondrial encephalomyopathies; however, skin biopsy is still the gold standart for the diagnosis of LCNs and LD.

ASSUNTO(S)

ataxia neurologia pediatrica demencia

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