RESUMEN
Continuous facial myokimia (CFM) are characterized by a contracted facial appearance and vermicular movements that spread across a hemiface. Pontine lesions are their most frequent cause. Although their occurrence during the course of multiple sclerosis is not uncommun, CFM are rarely the first sign of the disease. We report two cases of CMF as first manifestation of multiple sclerosis. Multiple sclerosis is the first diagnosis to suspect in young people with CFM.
Asunto(s)
Hemiatrofia Facial/diagnóstico , Enfermedades del Nervio Facial/diagnóstico , Esclerosis Múltiple/diagnóstico , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Examen Neurológico , Puente/patologíaRESUMEN
The myotubular myopathy is an X-linked centronuclear myopathy characterized by severe neonatal hypotonia and generalized muscle weakness which most frequently results in the premature death of the newborn infants by respiratory failure. The characteristic muscle histopathology consists in centrally positioned nuclei in most muscle fibers. In 1996, the gene responsible for the disease, MTM1, was identificated in Xq28 region. Since then, more than hundred mutations have been isolated. Genotype - phenotype correlation is complex because mutations are found along the entire coding sequence of the MTM1 gene. Most mutations are associated with very severe phenotype with death before the first year of life, however a milder phenotype has been individualized. It is important to be aware of the existence of such milder MTM phenotype because in those patients a very mild expression permit normal life into adulthood.
Asunto(s)
Miopatías Estructurales Congénitas/genética , Citogenética/métodos , Expresión Génica/genética , Humanos , Hipotonía Muscular/diagnóstico , Debilidad Muscular/diagnóstico , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miopatías Estructurales Congénitas/diagnóstico , Miopatías Estructurales Congénitas/metabolismo , Mutación Puntual/genética , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismo , Cromosoma X/genéticaRESUMEN
Clonidine, a centrally active alpha 2-adrenoreceptor agonist used to lower blood pressure, has been proposed to differentiate central from peripheral autonomic deficits and multiple system atrophy (MSA) from untreated idiopathic Parkinson's disease (IPD). A lack of growth hormone (GH) increase after clonidine infusion is found in patients with MSA, but not in those with IPD or with pure autonomic failure. We studied 19 IPD and 7 MSA patients to assess whether this test could be used in clinical practice to distinguish MSA from IPD, whatever the stage of the disease. Serum GH levels were measured 15, 30, 45 and 60 min after a 10-min infusion of 2 micrograms/kg clonidine. GH levels remained stable after clonidine infusion in all 7 MSA patients but increased in only 12 of the 19 IPD patients, while remaining stable in the other 7. No correlation was found with the presence of orthostatic hypotension. We conclude that the GH response to clonidine infusion has a very high sensitivity (100% in our series and in previous studies) for the diagnosis of MSA. However, this response cannot be used as a diagnostic test because of its poor specificity.
Asunto(s)
Clonidina , Hormona del Crecimiento/efectos de los fármacos , Atrofia de Múltiples Sistemas/diagnóstico , Enfermedad de Parkinson/diagnóstico , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
With the availability of a simple molecular test that distinguishes Friedreich ataxia, the most frequent form of inherited ataxia, from other recessive ataxias, it now becomes possible to unravel the genetic heterogeneity of the latter. We have now localised two genes causing autosomal recessive spinocerebellar ataxia in two consanguineous families. In the first family, the four affected Japanese sibs had spinocerebellar ataxia associated with elevated levels of serum creatine kinase, gamma-globulin, and alpha-foetoprotein. Homozygosity over a 20 cM region allowed to demonstrate linkage at 9q33.3-34.3 with a lod score of 3.0. Genotyping two unrelated Japanese patients from first degree consanguineous parents revealed that one was homozygous for the same region but did not share the biochemical features. In the second family, an Israeli uncle and a niece were affected by an early-onset recessive ataxia and subsequently developed hearing impairment and optic atrophy. Homozygosity over a 17 cM region allowed demonstration of linkage at 6p21-23 with a lod score of 3.25. These two localisations of autosomal recessive ataxia genes represent a first step toward the identification of genetically homogenous, non-Friedreich, ataxic patients and subsequent cloning of the genes.
Asunto(s)
Cromosomas Humanos Par 6 , Cromosomas Humanos Par 9 , Sordera/genética , Disinergia Cerebelosa Mioclónica/genética , Atrofia Óptica/genética , Enfermedades del Sistema Nervioso Periférico/genética , Ataxias Espinocerebelosas/genética , Mapeo Cromosómico , Consanguinidad , Femenino , Homocigoto , Humanos , Masculino , LinajeRESUMEN
OBJECTIVE: To determine the correlation of clinical and pathologic features with prion protein (PrP) gene polymorphism at codon 129 and with biochemical characteristics of the protease-resistant PrP (PrPres) in sporadic Creutzfeldt-Jakob disease (CJD). METHODS: Clinical data acquisition, determination of the codon 129 genotype of the PrP gene, brain pathologic study, and immunoblot analysis of crude brain extracts were carried out in 14 patients. RESULTS: The first group of 10 subjects showed the classic clinical triad, with dementia, myoclonus, and periodic sharp waves on EEG. None of the subjects had amyloid plaques, but PrP immunoreactivity was of diffuse synaptic type in the cerebellar cortex. All subjects were methionine-methionine at codon 129 and the PrPres had a biochemical profile of type 1 (unglycosylated band of 21.5 kD). A second group of three patients showed cerebellar ataxia and later dementia. Periodic sharp waves on EEG were absent. PrP amyloid plaques predominated in the cerebellar cortex, along with diffuse PrP immunoreactivity. These subjects were valine-valine at codon 129 and had a type 2 PrPres (unglycosylated band of 19.4 kD). In the last patient cerebellar ataxia and dementia appeared simultaneously. Many Kuru-type plaques were present in the cerebellar cortex; many PrP amyloid plaques were present in the basal ganglia. This patient was methionine-valine at codon 129 and the PrPres was of type 1. CONCLUSIONS: The codon 129 genotype is only one of the factors determining CJD phenotype, and the biochemical pattern of PrP has no direct correlation with this phenotype.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/genética , Anciano , Western Blotting , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Femenino , Genotipo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo GenéticoRESUMEN
BACKGROUND: Cerebellar ataxia or peripheral neuropathy can be signs of vitamin E deficiency. We report two cases. CASE REPORTS: Two patients developed vitamin E deficiency subsequent to intestinal malabsorption. The first patient had a duodenogastric communication and dilatation of the first jejunal loop. The second patient had deficient pancreas secretion and dilatation of the biliary tree. DISCUSSION: Vitamin E deficiency is generally secondary to acquired or hereditary malabsorption syndrome. It can also occur in the absence of malabsorption by hereditary deficiency in alpha-tocopherol transporter. Vitamin E supplements are required for malabsorption. The etiology work-up of neuropathy or cerebellar ataxia should include vitamin E assay.
Asunto(s)
Enfermedades del Sistema Nervioso Periférico/etiología , Degeneraciones Espinocerebelosas/etiología , Deficiencia de Vitamina E/complicaciones , Adolescente , Electromiografía , Femenino , Humanos , Síndromes de Malabsorción/complicaciones , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Trastornos de la Sensación/diagnóstico , Trastornos de la Sensación/etiología , Degeneraciones Espinocerebelosas/diagnóstico , Vitamina E/uso terapéutico , Deficiencia de Vitamina E/tratamiento farmacológico , Deficiencia de Vitamina E/etiologíaRESUMEN
X-linked recessive myotubular myopathy (XLMTM) is a very severe congenital muscular disease characterised by an impaired maturation of muscle fibres, and caused by defects in the MTM1 gene. This gene defines a new family of putative tyrosine phosphatases conserved through evolution. We have determined intronic flanking sequences for all the 15 exons to facilitate the detection of mutations in patients and genetic counselling. We characterised a new polymorphic marker in the immediate vicinity of the gene, which might prove useful for linkage analysis. Sequencing of the TATA-less predicted promoter provides the basis for transcriptional regulatory studies.
Asunto(s)
Ligamiento Genético , Enfermedades Musculares/genética , Proteínas Tirosina Fosfatasas/genética , Cromosoma X , Secuencia de Bases , ADN , Exones , Humanos , Intrones , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Proteínas Tirosina Fosfatasas no ReceptorasRESUMEN
A family with two male cousins affected with myotubular myopathy (MTM) was referred to us for genetic counselling. Linkage analysis appeared to exclude the Xq28 region. As a gene for X linked MTM was recently identified in Xq28, we screened the obligatory carrier mothers for mutation. We found a 4 bp deletion in exon 4 of the MTM1 gene, which originated from the grandfather of the affected children and which was transmitted to three daughters. This illustrates the importance of mutation detection to avoid pitfalls in linkage analysis that may be caused by such cases of germinal mosaicism.
Asunto(s)
Heterogeneidad Genética , Ligamiento Genético , Mosaicismo , Hipotonía Muscular/genética , Cromosoma X , Análisis Mutacional de ADN , Femenino , Asesoramiento Genético , Pruebas Genéticas , Humanos , Recién Nacido , Masculino , Debilidad Muscular/genética , Linaje , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas no ReceptorasRESUMEN
X-linked recessive myotubular myopathy (XLMTM; MTM1) is a severe neonatal disorder often causing perinatal death of the affected males. The responsible gene, designated MTM1, was localized to proximal Xq28 and recently isolated. The characterization of MTM1 allowed us to screen for causing mutations in three families, previously investigated by linkage analysis. Using exon amplification, single strand conformation polymorphism, and subsequent sequencing analysis, three new mutations and their mutational origin were characterized by analyzing 10 exons. An acceptor splice site and a frameshift mutation were correlated with the concurrent appearance of XLMTM in two families. A third intronic mutation was also analyzed by reverse transcription PCR and revealed a cryptic splice site mutation cosegregating with the presumed XLMTM haplotype in the third family. These results further support the implication of the MTM1 gene in XLMTM and allow efficient and reliable carrier and prenatal diagnosis in these families. Direct mutational diagnosis of families at risk in combination with haplotype analysis avoid the drawbacks using only linkage analysis, make genetic counselling far more reliable, and early clinical management of this disease more appropriate. Moreover, pedigree analyses provide first information on de novo mutation frequency in this newly identified human disease gene.
Asunto(s)
Enfermedades Fetales/genética , Hipotonía Muscular/genética , Debilidad Muscular/genética , Mutación , Diagnóstico Prenatal , Proteínas Tirosina Fosfatasas/genética , Cromosoma X , Análisis Mutacional de ADN , Exones , Femenino , Enfermedades Fetales/enzimología , Amplificación de Genes , Genes Recesivos , Ligamiento Genético , Pruebas Genéticas/métodos , Humanos , Masculino , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/enzimología , Debilidad Muscular/diagnóstico , Debilidad Muscular/enzimología , Embarazo , Proteínas Tirosina Fosfatasas no ReceptorasRESUMEN
UNLABELLED: To compare T2-weighted turbo spin-echo (turboSE) and turbo inversion recovery magnitude (turboIRM) sequences in the detection of multiple sclerosis of the spinal cord. METHODS: 28 patients with clinically confirmed multiple sclerosis and signs of cervical cord involvement were examined on a 1.5 tesla MR system. Sagittal T2-weighted turboSE sequences were followed by sagittal turboIRM sequences. 24 patients also underwent a cranial study. RESULTS: Using turboIRM sequence, all the patients showed at least one spinal cord plaque with a total of 91 plaques. Using turboSE sequence, 61 lesions were identified in 25 patients. Spinal plaques were seen best on turboIRM sequences with a higher contrast between the lesion and the normal spinal cord. In 10 patients with cord plaques in both sequences, the cranial study was normal or non conclusive. CONCLUSIONS: The turboIRM sequences detect more cord lesions and with a better contrast than the turboSE sequence. This results confirm those described in other studies and demonstrate the inadequacy of the fast spin echo sequences. Assessment of spinal plaques is particularly important when MR findings of the brain are negative or non conclusive.
Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/patología , Médula Espinal/patología , Adulto , Encéfalo/patología , Encefalopatías/patología , Femenino , Humanos , Aumento de la Imagen , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedades de la Médula Espinal/patologíaRESUMEN
X-linked recessive myotubular myopathy (XLMTM) is characterized by severe hypotonia and generalized muscle weakness, with impaired maturation of muscle fibres. The gene responsible, MTM1, was identified recently by positional cloning, and encodes a protein (myotubularin) with a tyrosine phosphatase domain (PTP). Myotubularin is highly conserved through evolution and defines a new family of putative tyrosine phosphatases in man. We report the identification of MTM1 mutations in 55 of 85 independent patients screened by single-strand conformation polymorphism for all the coding sequence. Large deletions were observed in only three patients. Five point mutations were found in multiple unrelated patients, accounting for 27% of the observed mutations. The possibility of detecting mutations and determining carrier status in a disease with a high proportion of sporadic cases is of importance for genetic counselling. More than half of XLMTM mutations are expected to inactivate the putative enzymatic activity of myotubularin, either by truncation or by missense mutations affecting the predicted PTP domain. Additional mutations are missenses clustered in two regions of the protein. Most of these affect amino acids conserved in the homologous yeast and Caenorhabditis elegans proteins, thus indicating the presence of other functional domains.