Assuntos
Processamento Alternativo/genética , Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA/genética , Mutação/genética , Proteínas Repressoras , Adulto , Criança , Ilhas de CpG/genética , Feminino , Genótipo , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG , Fenótipo , Valor Preditivo dos Testes , Síndrome de Rett/etiologia , Síndrome de Rett/genéticaRESUMO
We report a novel point mutation in the gene for the mitochondrially encoded ND6 subunit of the NADH:ubiquinone oxidoreductase (complex I of the respiratory chain) in a patient with MELAS syndrome. The mutation causes a change from alanine to valine in the most conserved region of the ND6 subunit. The patient was heteroplasmic for the mutation in both muscle and blood, but the mutation was not detected in the patient's mother. A marked reduction of complex I activity was found in the patient's muscular tissue. This is the first report of a mutation in the ND6 subunit causing MELAS. Our data confirm the genetic heterogeneity in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome, and confirms that MELAS can be caused by mutation in polypeptide-coding mtDNA genes.
Assuntos
DNA Mitocondrial/genética , Síndrome MELAS/enzimologia , Síndrome MELAS/genética , Mutação/genética , NADH Desidrogenase/química , NADH Desidrogenase/genética , Sequência de Bases , Pré-Escolar , Análise Mutacional de DNA , DNA Mitocondrial/sangue , Feminino , Humanos , Síndrome MELAS/sangue , Mitocôndrias Musculares/enzimologia , NADH Desidrogenase/metabolismo , Subunidades Proteicas , Mapeamento por RestriçãoRESUMO
Measles, mumps and rubella (MMR) vaccination was included in the Danish childhood vaccination programme in 1987. During the following 10-y period, 550 notification records of adverse events after MMR vaccination at 15 mo of age have been registered, and a total of 41 notifications have included "gait disturbance". This corresponds to a frequency of 8 per 100,000 doses of MMR vaccine used for 15-mo-old children. The symptoms and signs are characteristic of cerebellar ataxia. In 28 notifications, the descriptions by the doctors included only "gait disturbance", while in 13 an additional interpretation was included. Thirty-two parents (78%) filled in a questionnaire and 26 (63%) agreed to participate in a clinical follow-up study. The gait disturbance symptoms mainly occurred 7-14 d after the vaccination, and the duration was median 1-2 wk (range 1 d to more than 4 mo). One-third of the children had symptoms lasting more than 2 wk. Significantly more children with long duration of symptoms had some kind of complaint or clinical signs at the follow-up in 1997. Gait disturbance registered after MMR vaccination seems to be more frequent than hitherto reported. Most cases are mild and short-lasting and a longer duration of symptoms seems to be predictive of late sequelae. A clinical diagnosis of cerebellar ataxia after MMR and the exact frequency of this adverse event remains to be tested in prospective studies.
Assuntos
Ataxia Cerebelar/diagnóstico , Marcha , Vacina contra Sarampo/efeitos adversos , Transtornos dos Movimentos/diagnóstico , Vacina contra Caxumba/efeitos adversos , Vacina contra Rubéola/efeitos adversos , Fatores Etários , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Lactente , Masculino , Vacina contra Sarampo-Caxumba-Rubéola , Transtornos dos Movimentos/etiologia , Exame Neurológico , Inquéritos e Questionários , Fatores de Tempo , Vacinas Combinadas/efeitos adversosRESUMO
In an analysis of 30 families affected by spinal muscular atrophy (SMA) we have used the solid-phase minisequencing method to determine the ratio between the number of telomeric and centromeric copies of the survival motor neuron gene (SMN and cBCD541 respectively) on normal and SMA chromosomes. This has enabled us to establish haplotypes with regard to SMN and cBCD541, and estimate their frequencies, on both types of chromosomes. Six predominant haplotypes were identified, three for normal chromosomes and three for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of cBCD541. We found evidence for the presence of patients homozygous for a deletion of SMN and with only one copy of cBCD541, but found none deleted for all copies of this gene. Several asymptomatic carriers of SMA with only a single copy of SMN and no copy of cBCD541 were identified. We could not confirm the hypothesis that the presence of more copies of cBCD541 is correlated to a less severe course of the disease. The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of cBCD541 were found to differ significantly between normal and SMA chromosomes. This distribution can be explained by an underrepresentation of the haplotype completely lacking SMN genes, which is expected to cause early embryonic death in homozygotes. This first report of a direct haplotype analysis of SMN and cBCD541 should help clarify the role of cBCD541 in the pathogenesis of SMA.
Assuntos
Centrômero , Atrofia Muscular Espinal/genética , Proteínas do Tecido Nervoso/genética , Reação em Cadeia da Polimerase/métodos , Telômero , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Feminino , Dosagem de Genes , Genes , Humanos , Masculino , Linhagem , Proteínas de Ligação a RNA , Proteínas do Complexo SMNRESUMO
A girl presented at age 8 months with generalized hypotonia and areflexia. The parents were unrelated and without symptoms. At the age of 2 years and 10 months she was able to stand and walk with support. Intellectual development was normal. The mean fibre size in the lateral vastus muscle was normal, the variability was slightly increased. Type I and II fibres tended to be aggregated, but there was no type grouping. Motor and sensory nerve conduction velocities were less than 6 m/s. The sural nerve lacked myelin sheaths, and large non-myelinated axons were surrounded by concentric layers ('onion bulbs') of basal lamina material. The disease was classified as 'autosomal recessive hereditary motor and sensory neuropathy type III(HMSN (III) with basal lamina onion bulbs'. The muscle biopsy findings suggest that congenital amyelination or hypomyelination does not necessarily result in neurogenic atrophy.
Assuntos
Neuropatia Hereditária Motora e Sensorial/patologia , Fibras Musculares Esqueléticas/patologia , Nervo Sural/patologia , Biópsia , Feminino , Histocitoquímica , Humanos , Lactente , Hipotonia Muscular/patologiaRESUMO
Clinical genetic evidence suggests the existence of an autosomal recessive form of congenital nemaline myopathy in addition to the autosomal dominant one(s). One mutation in an Australian kindred has been identified as causing an autosomal dominant form of the disease. This mutation in the alpha-tropomyosin gene TPM3 has previously been excluded as causing autosomal recessive nemaline myopathy. We searched systematically for genetic linkage to autosomal recessive nemaline myopathy (NEM2) by studying microsatellite marker alleles in seven multiplex families from Finland, Denmark, Wales, England and The Netherlands. Significant evidence of linkage was found to markers of chromosome 2q, the highest multipoint lod score value being 5.34 for the marker D2S151. Recombinant genotypes in affected individuals demarcate the the region in which the NEM2 gene is likely to reside as a 13 cM region between the markers D2S150 and D2S142. These results confirm the existence of at least one distinctive form of autosomal recessive nemaline myopathy and provide a basis for the identification of its gene.
Assuntos
Cromossomos Humanos Par 2 , Genes Recessivos , Ligação Genética/genética , Miopatias da Nemalina/genética , Austrália , Humanos , Repetições de Microssatélites , Recombinação Genética , Tropomiosina/genéticaRESUMO
A 6-year-old girl had progressive ataxia, and visual disturbances resulting in blindness. She died in her sleep at age 22 years. She shared with her sister and paternal relatives bilateral pes cavus deformities and impaired deep-tendon reflexes which suggested Charcot-Marie-Tooth disease. Her sister, who also had both polyneuropathy and a progressive central nervous system (CNS) disease, did not have pigmentary retinopathy. At autopsy, the patient was found to have neuronal ceroid-lipofuscinosis (NCL) marked by intraneuronal accumulation of autofluorescent granular lipopigments in ballooned perikarya and conspicuous extraneuronal pigmentation of subcortical grey matter, but without axonal spheroids. These findings indicate a pigment variant of NCL and represent one of very few patients recorded. The ultrastructure of the intraneuronal pigments was uniformly granular, while that of the extraneuronal pigments found within processes of the neuropil and glial perikarya was more variegated. In addition to those patients with the pigment variant of NCL, described earlier by Jakob and Kolkmann [1973: Acta Neuropathol (Berl) 26:225-236], and Jervis and Pullarkat [1978: Neurology 28:500-503], our patient shared clinical symptoms with those described in a family afflicted with polyneuropathy and NCL by Wisniewski et al. [1987: J Child Neurol 2:33-41]. Currently, it is unclear whether they have similar atypical forms of juvenile NCL (JNCL). We conclude that the spectrum of pigment variants in lysosomal diseases is heterogeneous: only few and recently described patients have had NCL, while others most likely had other forms of lipidosis.
Assuntos
Lipofuscinoses Ceroides Neuronais/patologia , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Pigmentação , Pigmentos Biológicos/análise , Córtex Cerebral/patologia , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Diagnóstico Diferencial , Epitélio/patologia , Feminino , Humanos , Túbulos Renais/patologia , Masculino , Microscopia Eletrônica , Lipofuscinoses Ceroides Neuronais/diagnóstico , Neurônios/patologia , Neurônios/ultraestrutura , Núcleo Familiar , Medula Espinal/patologiaRESUMO
We describe seven children with the carbohydrate-deficient glycoprotein syndrome, an autosomal recessive inborn error of protein glycosylation characterised by failure to thrive, neurological dysfunction and a unique pattern of physical abnormalities. Neuro-radiological investigations revealed cerebellar hypoplasia in all seven children. Two children also developed supratentorial atrophy following episodes of neurological deterioration.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Cerebelo/anormalidades , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Síndrome , Tomografia Computadorizada por Raios XRESUMO
Recent studies show that patients presenting with cytochrome oxidase (COX) deficiency in infancy may have reduced mitochondrial DNA (mtDNA) in muscle. The human mitochondrial transcription factor A (h-mtTFA) may be an important regulator of both transcription and replication of mtDNA. h-mtTFA levels were investigated in cell lines which were either free of mtDNA (rho 0) or temporarily depleted by treatment with dideoxycytidine (ddC), and in tissue from three patients with mtDNA depletion and cytochrome oxidase deficiency. h-mtTFA was compared with other mitochondrial proteins such as pyruvate dehydrogenase and porin by Western blotting. The ratio of mtDNA and h-mtTFA mRNA to reference nuclear probes was measured by dual labelling of dot blots. The ratio of mtDNA to nuclear DNA in skeletal muscle was low in muscle in the three patients and in other tissues in one. h-mtTFA was low in cells depleted either permanently or transiently of mtDNA, and this reduction in h-mtTFA roughly paralleled mtDNA levels. Similarly, treatment of rho 0 cell lines with ddC induced a reduction in mtDNA as well as h-mtTFA protein. The relationship between h-mtTFA and mtDNA levels suggests that they may be causally linked. MtDNA depletion was accompanied by an increase in the level of h-mtTFA RNA in the cell lines but low levels in the patient. This suggests that either h-mtTFA regulates mtDNA levels, or that h-mtTFA expression may be regulated by a feedback mechanism initiated by MtDNA Depletion.
Assuntos
Deficiência de Citocromo-c Oxidase , DNA Mitocondrial/genética , Proteínas de Ligação a DNA/metabolismo , Mitocôndrias Musculares/metabolismo , Miopatias Mitocondriais/genética , Proteínas Mitocondriais , Músculo Esquelético/metabolismo , Proteínas Nucleares , Fatores de Transcrição/metabolismo , Sequência de Bases , Linhagem Celular , Núcleo Celular/metabolismo , Pré-Escolar , DNA/análise , Primers do DNA , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Miopatias Mitocondriais/metabolismo , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Valores de Referência , Zalcitabina/farmacologiaRESUMO
An elevated CSF glutamate level has recently been reported in Rett syndrome. Because the anticonvulsant effect of Lamotrigine is probably due to inhibition of glutamate release, this drug was given as an add-on drug to 4 girls with Rett syndrome. All patients responded with a seizure reduction of 50% or more and an improved well-being. A controlled study at the early stages of the syndrome could be interesting.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Síndrome de Rett/complicações , Triazinas/uso terapêutico , Adulto , Líquido Cefalorraquidiano/química , Criança , Pré-Escolar , Feminino , Glutamatos/líquido cefalorraquidiano , Humanos , Lamotrigina , Síndrome de Rett/líquido cefalorraquidiano , Resultado do Tratamento , Triazinas/administração & dosagemRESUMO
The handicap section of the ICIDH was developed with the experience of adults in mind. In its original form the H Code is not immediately applicable to young children with disabilities. The Classification Group of the Nordic Neuropediatric Association has developed an adaptation of the H Code for use in children aged 6-7 years, and the adaptation is presented in this paper.
Assuntos
Atividades Cotidianas , Pessoas com Deficiência/classificação , Criança , Humanos , Renda , Relações Interpessoais , Neurologia , Ocupações , Orientação , Pediatria , Países Escandinavos e Nórdicos , Sociedades Médicas , CaminhadaRESUMO
Among 2100 children with a diagnosis of cerebral palsy (CP) twenty carried the diagnosis: Previous CP, now normalized. Seventeen patients could be traced and were reevaluated. Cerebral palsy was diagnosed in these seventeen children (ten boys, seven girls) between the ages of three months and three years (average eleven months). They were found to be normal when reexamined between the ages of one year and five years (average two years two months). Two patients had tetraplegia, three diplegia, nine paraplegia ("paraplegia" were cases of diplegia with minimal affection of the upper limbs - now called "diplegia type I"), and one hemiplegia. One patient had atactic diplegia, and one was athetotic. The records of these seventeen patients were evaluated with respect to aetiology and symptomatology. Upon reexamination seven patients were found to be completely normal. Five patients had no motor symptoms but showed signs of specific neuropsychological difficulties. Two patients were intellectually retarded without motor symptoms. One showed signs of neuropathy, and one had fetal alcohol syndrome. Signs consistent with CP could be demonstrated in one patient only. This study shows that signs of CP may in rare cases disappear altogether.
Assuntos
Paralisia Cerebral/fisiopatologia , Encéfalo/diagnóstico por imagem , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/diagnóstico por imagem , Pré-Escolar , Seguimentos , Humanos , Lactente , Recém-Nascido , Remissão Espontânea , Tomografia Computadorizada por Raios XRESUMO
An unselected patient material of 182 children admitted consecutively with febrile convulsions during a period of two years was classified into five risk-groups. Continuous phenobarbital therapy for two years was recommended for 113 children (Groups I--IV). These children were followed-up as out-patients for at least one year after admission. In children receiving phenobarbital therapy, serum concentrations were controlled every third month. A total of 59 children completed the treatment according to the directives given and seven of these (12%) developed renewed febrile convulsions despite serum phenobarbital concentrations within the therapeutic range (70--120 mumol/l). No particular characteristics for these children could be established on the basis of the parameters registered. The therapeutic model established was found to be suitable for distinguishing between children with massive risk for renewed convulsions (Group I--IV) compared with children for whom treatment was not recommended (Group V).
Assuntos
Fenobarbital/uso terapêutico , Convulsões Febris/prevenção & controle , Convulsões/prevenção & controle , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Fenobarbital/efeitos adversos , Fenobarbital/sangue , Estudos Prospectivos , Recidiva , Convulsões Febris/tratamento farmacológicoRESUMO
Two cases of the Prader-Willi syndrome with 46,XY/47,XY,+mar are reported. The majority of Prader-Willi patients with chromosome abnormalities have either 15/15 translocations or mosaicism. Both of these aberrations presumably occur after fertilization. A possible relationship between high parental age and chromosome abnormalities in the Prader-Willi syndrome is discussed.
Assuntos
Mosaicismo , Síndrome de Prader-Willi/genética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Idade Materna , Idade Paterna , Cromossomo X , Cromossomo YRESUMO
Since the original description of cerebral gigantism, about 85 cases have been reported. Four papers comment on familial occurrence but never in parents and their children. This paper describes the syndrome in a mother and her child, which, together with facts pointing towards prenatal etiology, such as excessive birthweight, striking mutual resemblance and abnormal dermatoglyphics, points to a genetic defect. Previous endocrine studies are enlarged by the findings of normal serum somatomedin and serum prolactin.