RESUMO
Several neurodegenerative disorders are known to predominantly affect the white matter of the brain including vanishing white matter disease (VWMD), an autosomal recessive disorder characterized by leukodystrophy of varying severity in addition to variable systemic involvement. We report a consanguineous Arab family with three affected children, all of whom presented with severe neonatal epilepsy and profound neurodegenerative disease characterized by marked leukodystrophy with white matter cavitation mimicking VWMD. We combined autozygome and exome analysis to identify a novel variant in the gene encoding a member of the eIF2B-related family of proteins (MRI1). This is a poorly understood family of proteins of unclear function. Our results represent the first link between a variant in a member of this family and a human disease, and suggest that it converges with the highly homologous eIF2B, known to be mutated in VWMD, on the molecular pathogenesis of neurodegeneration.
Assuntos
Aldose-Cetose Isomerases/genética , Epilepsias Mioclônicas/genética , Loci Gênicos , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Leucoencefalopatias/genética , Adulto , Aldose-Cetose Isomerases/metabolismo , Árabes , Epilepsias Mioclônicas/diagnóstico por imagem , Epilepsias Mioclônicas/enzimologia , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/enzimologia , Humanos , Lactente , Recém-Nascido , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/enzimologia , Masculino , RadiografiaAssuntos
Epilepsias Mioclônicas , Hiperinsulinismo , Hipoglicemia , Adolescente , Eletroencefalografia , Epilepsias Mioclônicas/enzimologia , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Feminino , Glutamato Desidrogenase/genética , Glutamato Desidrogenase/metabolismo , Humanos , Hiperinsulinismo/enzimologia , Hiperinsulinismo/genética , Hiperinsulinismo/fisiopatologia , Hipoglicemia/enzimologia , Hipoglicemia/genética , Hipoglicemia/fisiopatologia , Lactente , MutaçãoRESUMO
Progressive myoclonic epilepsies (EPM) are difficult to treat and refractory to most antiepileptic drugs. Besides epilepsy, EPMs also involve continuous neurological deterioration. Oxidative stress is thought to be an important factor in this process. We therefore analyzed a series of antioxidant enzymes in the blood of patients and compared with healthy age matched controls. In addition patients were given high doses of N-acetylcysteine (NAC), a glutathione percursor to determine if symptoms of EPM would improve. Five patients, four with EPM 1 (Unverricht-Lundborg disease) and one patient with EPM2 (Lafora body disease) were treated with 6 g/day of NAC. Before treatment, plasma samples were analyzed for glutathione peroxidase activity, catalase activity, extracellular superoxide dismutase (SOD) and CuZn-SOD and compared with the controls. Erythrocyte CuZn-SOD was significantly lower in the EPM patients compared to controls. NAC improved markedly and stabilized the neurological symptoms in patients with EPM 1 but had a doubtful effect in the patient with EPM 2.
Assuntos
Epilepsias Mioclônicas/enzimologia , Glutationa Peroxidase/metabolismo , Superóxido Dismutase/metabolismo , Acetilcisteína/uso terapêutico , Adulto , Epilepsias Mioclônicas/sangue , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/fisiopatologia , Eritrócitos/enzimologia , Feminino , Humanos , Doença de Lafora/sangue , Doença de Lafora/tratamento farmacológico , Doença de Lafora/enzimologia , Doença de Lafora/fisiopatologia , Masculino , Valores de Referência , Síndrome de Unverricht-Lundborg/tratamento farmacológico , Síndrome de Unverricht-Lundborg/metabolismo , Síndrome de Unverricht-Lundborg/fisiopatologiaRESUMO
West syndrome is an epileptic encephalopathy which includes psychomotor deterioration. In rare cases, it is due to an inherited, progressive metabolic disease. We report a 2 year-old child with dihydropteridine reductase deficiency who developed hypsarrhythmia and infantile spasms which were documented on video-polygraphic EEG. Despite dietary restriction of phenylalanine, and oral administration of amine precursors, the initial course was unfavorable. A beneficial effect from hydrocortisone was then observed, with control of spasms and improvement of psychomotor delay.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticonvulsivantes/uso terapêutico , Eletroencefalografia , Epilepsias Mioclônicas , Hidrocortisona/uso terapêutico , Fenilcetonúrias , Anti-Inflamatórios/administração & dosagem , Anticonvulsivantes/administração & dosagem , Criança , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/enzimologia , Humanos , Hidrocortisona/administração & dosagem , Recém-Nascido , Masculino , Índice de Gravidade de Doença , Espasmos Infantis/diagnóstico , Resultado do Tratamento , Gravação em VídeoAssuntos
Cromossomos Humanos Par 6/genética , Proteínas Metiltransferases/genética , Animais , Sequência de Bases , Bandeamento Cromossômico , Mapeamento Cromossômico , Primers do DNA/genética , Epilepsias Mioclônicas/enzimologia , Epilepsias Mioclônicas/genética , Marcadores Genéticos , Humanos , Células Híbridas , Reação em Cadeia da Polimerase , Proteína D-Aspartato-L-Isoaspartato MetiltransferaseRESUMO
Progressive myoclonus epilepsy of the Lafora type or Lafora disease (EPM2; McKusick no. 254780) is an autosomal recessive disorder characterized by epilepsy, myoclonus, progressive neurological deterioration and glycogen-like intracellular inclusion bodies (Lafora bodies). A gene for EPM2 previously has been mapped to chromosome 6q23-q25 using linkage analysis and homozygosity mapping. Here we report the positional cloning of the 6q EPM2 gene. A microdeletion within the EPM2 critical region, present inhomozygosis in an affected individual, was found to disrupt a novel gene encoding a putative protein tyrosine phosphatase (PTPase). The gene, denoted EPM2, presents alternative splicing in the 5' and 3' end regions. Mutational analysis revealed that EPM2 patients are homozygous for loss-of-function mutations in EPM2. These findings suggest that Lafora disease results from the mutational inactivation of a PTPase activity that may be important in the control of glycogen metabolism.
Assuntos
Epilepsias Mioclônicas/genética , Genes/genética , Proteínas Tirosina Fosfatases/genética , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 6/genética , DNA/análise , DNA/genética , Análise Mutacional de DNA , DNA Complementar/química , DNA Complementar/genética , Epilepsias Mioclônicas/enzimologia , Epilepsias Mioclônicas/patologia , Feminino , Humanos , Masculino , Repetições de Microssatélites , Dados de Sequência Molecular , Mutação , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms. With few exceptions, patients follow a homogeneous clinical course despite the existence of genetic heterogeneity. Biopsy of various tissues, including brain, revealed characteristic polyglucosan inclusions called Lafora bodies, which suggested LD might be a generalized storage disease. Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain. Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD. These mutations are predicted to cause deleterious effects in the putative protein product, named laforin, resulting in LD.
Assuntos
Cromossomos Humanos Par 6 , Epilepsias Mioclônicas/genética , Mutação , Proteínas Tirosina Fosfatases/genética , Processamento Alternativo , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Sequência Consenso , Epilepsias Mioclônicas/enzimologia , Feminino , Ligação Genética , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Proteínas Tirosina Fosfatases não Receptoras , RNA Mensageiro/metabolismoRESUMO
Two mutations in the cystatin B gene, a 3' splice mutation and a stop codon mutation, were previously found in patients with progressive myoclonus epilepsy of Unverricht-Lundborg type [Pennacchio et al. (1996): Science 271:1731-1734]. We present here a new mutation 2404deltaTC: a 2-bp deletion within the third exon of the cystatin B gene in an Unverricht-Lundborg patient. This mutation results in a frameshift and consequently premature termination of protein synthesis. Complete sequencing of the coding region and splice junctions of the cystatin B gene showed that neither of the two previously known mutations was present in this patient. The level of cystatin B mRNA in an immortalized cell line was found to be decreased, as had been reported for other Unverricht-Lundborg patients. The new mutation further supports the argument that defects in the cystatin B gene cause the Unverricht-Lundborg form of progressive myoclonus epilepsy. We describe a simple PCR method which can detect the 2404deltaTC deletion. This assay, together with previously described PCR assays for the other two known mutations, should prove useful in confirming clinically difficult diagnoses of Unverricht-Lundborg disease.
Assuntos
Cistatinas/genética , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Mutação , Reação em Cadeia da Polimerase/métodos , Sequência de Aminoácidos , Cistatina B , Inibidores de Cisteína Proteinase/genética , Epilepsias Mioclônicas/enzimologia , Humanos , Dados de Sequência MolecularRESUMO
Myoclonic epilepsy with ragged-red fibers (MERRF) is a maternally inherited disorder of oxidative phosphorylation due to specific point mutations within the mitochondrial tRNA(Lys) gene. Mitochondrial dysfunction in the central nervous system (CNS) of patients with MERRF accounts for the neurological manifestations of the disease. Antibodies against subunits of complex I, III, IV and V of the respiratory chain were used to study the expression of these proteins in the frontal cortex, cerebellum and medulla from an autoptic case of MERRF. We found a selective decreased expression of subunit II of cytochrome c oxidase (COX-II) in these regions. Immunohistochemical abnormalities were more widespread than the lesions described by traditional histopathological techniques and made possible an attempt of explanation for the neurological symptoms of the patient.
Assuntos
Encéfalo/patologia , Epilepsias Mioclônicas/patologia , Fibras Nervosas/ultraestrutura , Adolescente , Adulto , Anticorpos Monoclonais , Encéfalo/enzimologia , Cerebelo/enzimologia , Cerebelo/patologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Criança , Pré-Escolar , Complexo IV da Cadeia de Transporte de Elétrons/biossíntese , Epilepsias Mioclônicas/enzimologia , Humanos , Imuno-Histoquímica , Masculino , Bulbo/enzimologia , Bulbo/patologia , Pessoa de Meia-Idade , Fibras Nervosas/enzimologiaRESUMO
We looked for the A-->G transition at position 8344 of mtDNA in 150 patients, most of them with diagnosed or suspected mitochondrial disease, to assess the specificity of this mutation for the MERRF phenotype, to define the clinical spectrum associated with the mutation, and to study the relationship between percentage of mutation in muscle and clinical severity. Our results confirm the high correlation between the A-->G transition at position 8344 and the MERRF syndrome, but they also show that this mutation can be associated with other phenotypes, including Leigh's syndrome, myoclonus or myopathy with truncal lipomas, and proximal myopathy. The absence of the mutation in four typical MERRF patients suggests that other mutations in the tRNA(Lys) gene, or elsewhere in the mitochondrial DNA, can produce the same phenotype.
Assuntos
Encefalopatias Metabólicas/genética , DNA Mitocondrial/genética , Epilepsias Mioclônicas/genética , Miopatias Mitocondriais/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Mutação Puntual/genética , Adulto , Sequência de Bases , Encefalopatias Metabólicas/enzimologia , Citrato (si)-Sintase/metabolismo , Epilepsias Mioclônicas/enzimologia , Feminino , Humanos , Doença de Leigh/enzimologia , Doença de Leigh/genética , Síndrome MERRF/genética , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/enzimologia , Dados de Sequência Molecular , Músculos/enzimologia , Oftalmoplegia Externa Progressiva Crônica/enzimologia , Linhagem , FenótipoRESUMO
More than half of the intramuscular blood vessels in muscle biopsies from five patients with myoclonus epilepsy with ragged-fibers (MERRF) who had a point mutation in mitochondrial DNA at the tRNALys region were darkly stained with succinate dehydrogenase (SDH) stain, showing the morphologic characteristics of strongly SDH-reactive blood vessels (SSV), but they had no cytochrome c oxidase (CCO) activity. By electron cytochemistry, the mitochondria in the smooth muscle cells of SSV had no CCO activity. On the other hand, SSV in muscle biopsies from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) had normal CCO activity as shown by light and electron microscopy. The defect in CCO activity in the arteriolar smooth muscle cells and in muscle fibers suggests that CCO deficiency is related to the pathophysiology of MERRF.
Assuntos
Deficiência de Citocromo-c Oxidase , Epilepsias Mioclônicas/enzimologia , Síndrome MERRF/enzimologia , Músculos/irrigação sanguínea , Músculos/patologia , Adolescente , Adulto , Biópsia , Vasos Sanguíneos/enzimologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/patologia , Feminino , Histocitoquímica , Humanos , Síndrome MELAS/enzimologia , Síndrome MELAS/patologia , Síndrome MERRF/complicações , Síndrome MERRF/patologia , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Succinato Desidrogenase/metabolismoRESUMO
A new family of myoclonic epilepsy with ragged-red fibers (MERRF) was studied at clinical, histological, biochemical and molecular genetic levels. There was a remarkable variation in the age of onset, the clinical presentation and the severity of symptoms. Multiple defects affecting respiratory chain complexes I, III and IV were detected in 2 patients. The point mutation at 8344 of the mitochondrial genome was found in all the maternal lineage with a relatively narrow range of variation in the percentage of mutant mitochondrial genomes. The one exception was represented by a set of dizygotic twins, one clinically affected and showing high proportions of mutant mitochondrial DNAs (mtDNAs) in blood cells, while the other was asymptomatic and showed very small amounts of mutant mt-DNAs in blood and skin. This could suggest an early segregation of the mitochondrial genome during ovogenesis.
Assuntos
DNA Mitocondrial/genética , Doenças em Gêmeos/genética , Epilepsias Mioclônicas/genética , Mitocôndrias Musculares/enzimologia , Mutação , Gêmeos Dizigóticos , Adulto , Sequência de Bases , Citocromos/metabolismo , Complexo II de Transporte de Elétrons , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Epilepsias Mioclônicas/enzimologia , Epilepsias Mioclônicas/patologia , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Complexos Multienzimáticos/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oligodesoxirribonucleotídeos , Oxirredutases/metabolismo , Linhagem , Reação em Cadeia da Polimerase/métodos , Succinato Desidrogenase/metabolismo , Nervo Sural/patologiaRESUMO
We report the clinical, electroencephalographic, neurophysiologic, and neuroimaging findings in eight children with infant-onset progressive myoclonus epilepsy, all of whom had muscle biopsies performed as as part of the diagnostic evaluation. Each child had myoclonic seizures, generalized tonic-clonic seizures, and neurologic regression or marked developmental delay. Four children died before 3 years of age. Electroencephalograms in seven children showed an abnormally slow background with bilateral multifocal paroxysmal discharges but no burst suppression pattern or photoparoxysmal response. Muscle biopsy specimens were submitted for histopathology and respiratory-chain enzyme studies. Nonspecific abnormalities on light microscopy or electron microscopy were found in seven samples, including increased subsarcolemmal deposits of mitochondria or morphologic mitochondrial changes, but no ragged-red fibers were seen. Respiratory-chain enzyme studies were performed on five samples and in three children (all of whom had a history of elevated lactate in serum or cerebrospinal fluid), there were low levels of rotenone-sensitive reduced nicotinamide adenine dinucleotide (NADH) cytochrome c reductase characteristic of a defect in the complex I part of the respiratory-chain pathway. This study has shown that infant-onset progressive myoclonus epilepsy can be distinguished from other myoclonic epilepsy syndromes of infancy by clinical and electrographic features. Furthermore, respiratory-chain enzyme defects are a relatively common cause of infant-onset progressive myoclonus epilepsy. The absence of ragged-red fibers on muscle histopathology does not preclude a mitochondrial enzyme abnormality.
Assuntos
Epilepsias Mioclônicas/fisiopatologia , Biópsia , Eletroencefalografia , Epilepsias Mioclônicas/diagnóstico por imagem , Epilepsias Mioclônicas/enzimologia , Epilepsias Mioclônicas/patologia , Potenciais Evocados , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/etiologia , Masculino , Mitocôndrias Musculares/enzimologia , Músculos/enzimologia , Músculos/patologia , Condução Nervosa , Tomografia Computadorizada por Raios XRESUMO
We describe a young man with a progressive neurological disorder including myoclonus, mental retardation, muscle weakness and a mitochondrial myopathy (myoclonus epilepsy and ragged red fibres--MERRF). Multiple abnormalities of the mitochondrial respiratory chain in skeletal muscle are shown by direct measurement of the flux through the individual complexes, low-temperature redox spectroscopy and decreased immunodetectable subunits of complexes I and IV by immunoblotting. No abnormality of mitochondrial DNA was found. This is the first report of combined defects of complexes I, III and IV as a cause of this clinical syndrome. However, we propose that the occurrence of multiple respiratory chain defects may be more common than previously recognised and that this particular combination of defects, involving complexes I, III and IV, may be the predominant biochemical abnormality in MERRF.
Assuntos
Ataxia Cerebelar/genética , Deficiência de Citocromo-c Oxidase , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Epilepsias Mioclônicas/genética , Perda Auditiva Neurossensorial/genética , Deficiência Intelectual/genética , Mitocôndrias/enzimologia , Complexos Multienzimáticos/deficiência , Doenças Neuromusculares/genética , Oxirredutases/deficiência , Quinona Redutases/deficiência , Succinato Desidrogenase/deficiência , Adulto , Ataxia Cerebelar/enzimologia , Pré-Escolar , DNA Mitocondrial/análise , Complexo II de Transporte de Elétrons , Epilepsias Mioclônicas/enzimologia , Perda Auditiva Neurossensorial/enzimologia , Humanos , Deficiência Intelectual/enzimologia , Masculino , NAD(P)H Desidrogenase (Quinona) , Doenças Neuromusculares/enzimologia , Doenças Neuromusculares/patologia , Fosforilação Oxidativa , SíndromeRESUMO
The populations of cytochrome c oxidase (CCO)-positive and -negative mitochondria were analyzed in the elongated cells containing occasional multiple nuclei (myotubes) in primary muscle cultures derived from patients with various forms of mitochondrial encephalomyopathies with CCO deficiency. Even in control muscle cultures, CCO-positive (79.7%) and -negative (20.3%) mitochondria were distributed randomly, showing intracellular mosaicism. All mitochondria in all muscle cultures from two patients with clinical characteristics of Leigh's disease exhibited faint to negative CCO activity. In these patients no enzyme activity could be detected in any tissue including intrafusal fibers and fibroblasts in muscle biopsies. In patients with the fatal infantile and the encephalomyopathic forms of CCO deficiency, and myoclonic epilepsy with ragged-red fibers, two different types of myotubes containing mostly CCO-positive mitochondria and only negative mitochondria, respectively, representing intercellular mosaicism, were demonstrated. The intercellular mosaicism in biopsied and cultured muscles in the case of CCO deficiency supports the contention that both CCO-positive and -negative mitochondria coexist in the early myogenic cell and are later randomly segregated during cell division (mitotic segregation), forming two different cells.
Assuntos
Deficiência de Citocromo-c Oxidase , Encefalomielite/patologia , Mitocôndrias Musculares/ultraestrutura , Músculos/ultraestrutura , Adolescente , Criança , Pré-Escolar , Técnicas de Cultura , Encefalomielite/enzimologia , Epilepsias Mioclônicas/enzimologia , Epilepsias Mioclônicas/patologia , Feminino , Histocitoquímica , Humanos , Lactente , Doença de Leigh/enzimologia , Doença de Leigh/patologia , Masculino , Microscopia Eletrônica , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/metabolismo , Músculos/enzimologia , Músculos/metabolismo , FenótipoRESUMO
Mitochondrial respiratory chain function was investigated with polarographic and enzymatic studies, and correlated with immunoblot studies using a battery of probes against respiratory chain holocomplexes in a series of patients with myoclonus epilepsy and ragged red fibers (MERRF) syndrome. State III respiration rates in intact skeletal muscle mitochondria were normal in two cases, suggested site I deficiency in one case and a mid-respiratory defect in another. Immunological studies of complex I showed reduced levels of several subunits with the apparent absence of two bands (which at 45 and 42 kDa, coincide with the predicted electrophoretic mobility of the ND5 gene product) in one case. Complex I, III and IV composition was normal in the other three cases indicating no major disruption of complex assembly. A differing severity of skeletal muscle respiratory chain impairment in a group of unrelated patients with severe cerebral clinical involvement is best explained by uneven tissue distribution between brain and muscle of a heteroplasmic mtDNA mutation. The relationship between MERRF and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) encephalopathies is reappraised by extension of this hypothesis.
Assuntos
DNA/metabolismo , Epilepsias Mioclônicas/metabolismo , Mitocôndrias Musculares/metabolismo , Doenças do Sistema Nervoso/metabolismo , Consumo de Oxigênio/fisiologia , Adulto , Western Blotting , Citocromos/metabolismo , Epilepsias Mioclônicas/enzimologia , Epilepsias Mioclônicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/ultraestrutura , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/patologia , Polarografia , SíndromeRESUMO
A 36-year-old man with myoclonic epilepsy and ragged-red fibers (MERRF) died after more than 18 years of follow-up study. He was 1 of 3 affected siblings and the offspring of an affected mother, suggesting maternal transmission. At autopsy, there was neuronal loss and gliosis in the dentate nucleus of the cerebellum and in the inferior olivary nucleus. Skeletal muscle showed ragged-red fibers, and paracrystalline inclusions in mitochondria by electron microscopy. Biochemical analysis showed a generalized partial defect of cytochrome c oxidase (COX) in mitochondria isolated from all tissues, including brain, heart, skeletal muscle, kidney, and liver. The Michaelis constant (Km) for cytochrome c was abnormally low, suggesting a defect of the mitochondrially encoded subunit II of COX. Immunological studies (enzyme-linked immunosorbent assay, dot-blot, Western blot, and immunohistochemistry) showed that the holoenzyme was decreased but subunit II was decreased more than the holocomplex or the nuclearly encoded subunit IV. However, Northern and Southern blots showed that the gene for subunit II, as well as the genes for subunits I, III, IV, and VIII, were of normal size and were normally transcribed. A point mutation or a small deletion of mitochondrial DNA, probably affecting the COX-II gene, may be responsible for the COX deficiency in this case of MERRF.
Assuntos
Deficiência de Citocromo-c Oxidase , Epilepsias Mioclônicas/enzimologia , Mitocôndrias/enzimologia , Doenças Musculares/enzimologia , Adolescente , Adulto , Ataxia/etiologia , Criança , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Doenças Musculares/etiologia , Doenças Musculares/patologia , LinhagemRESUMO
Very low levels of arylsulphatase A were found in a young patient with the clinical features of Lafora disease, confirmed by muscle biopsy. The deficiency was shown both in leukocytes and cultured fibroblasts. A cerebroside sulphate loading showed that 93% of [14C]cerebroside sulphate taken up by skin fibroblasts from the patient remained unmetabolized after a 24h pulse, ruling out pseudo-arylsulphatase A deficiency. In the healthy parents and siblings of the patient, biochemical data suggested heterozygosity for arylsulphatase A deficiency. The apparent co-inheritance of arylsulphatase A deficiency and Lafora disease in this family might be the consequence of genetic linkage between the two genes.
Assuntos
Arilsulfatases/deficiência , Epilepsias Mioclônicas/enzimologia , Sulfatases/deficiência , Adolescente , Arilsulfatases/genética , Células Cultivadas , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/genética , Fibroblastos/enzimologia , Humanos , Leucócitos/enzimologia , Masculino , Músculos/ultraestrutura , Sulfoglicoesfingolipídeos/metabolismo , Sulfoglicoesfingolipídeos/urina , beta-Galactosidase/metabolismoRESUMO
The genetics of the various forms of epilepsy can be best understood by knowing where the affected gene is located. Genetic methodologies used to explore the genetics of epilepsy now include segregation analysis, linkage analysis and recombinant DNA technology. Juvenile myoclonic epilepsy (JME), a form of idiopathic epilepsy with a strong genetic component, provides informative pedigrees for linkage studies. Preliminary results demonstrate the heterogenous nature of the JME syndrome.
Assuntos
Mapeamento Cromossômico , Epilepsias Mioclônicas/enzimologia , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/imunologia , Ligação Genética , Marcadores Genéticos , Testes Genéticos , Antígenos HLA/genética , Humanos , Linhagem , Polimorfismo de Fragmento de RestriçãoRESUMO
Two female patients of German origin, aged 38 and 21 years, with myoclonus epilepsy and cerebellar ataxia, but without dysmorphic signs and dementia, were found to excrete normal amounts of sialyl oligosaccharides in their urine. The younger patient showed cherry red spots in her ocular fundi. The older patient had a brother with an autopsy-proven neuronal storage disease compatible with sialidosis, and in her rectal biopsy lamellar inclusion bodies were detected. Enzyme assays in cultured fibroblasts of both patients revealed a profound but incomplete deficiency of oligosaccharide sialidase activity and normal beta-galactosidase activity. Adult sialidosis was diagnosed in both patients. In their fibroblasts, moderate elevations of bound sialic acid could also be measured. The small residual sialidase activity, which in the older patient had a normal KM value, is considered responsible for the late onset and slow clinical course of the disease. It is concluded that in adult sialidosis the extraneural storage process can be difficult to demonstrate in terms of metabolite accumulation or excretion during the course of intraneuronal storage.