RESUMEN
We report the identification of a novel mutation at a highly conserved residue within the N-terminal region of spermine synthase (SMS) in a second family with Snyder-Robinson X-linked mental retardation syndrome (OMIM 309583). This missense mutation, p.G56S, greatly reduces SMS activity and leads to severe epilepsy and cognitive impairment. Our findings contribute to a better delineation and expansion of the clinical spectrum of Snyder-Robinson syndrome, support the important role of the N-terminus in the function of the SMS protein, and provide further evidence for the importance of SMS activity in the development of intellectual processing and other aspects of human development.
Asunto(s)
Discapacidad Intelectual Ligada al Cromosoma X/genética , Mutación Missense , Espermina Sintasa/genética , Adulto , Niño , Análisis Mutacional de ADN , Femenino , Genes Recesivos , Humanos , Masculino , Linaje , SíndromeRESUMEN
Knobloch syndrome (KS) is a rare disease characterized by severe ocular alterations, including vitreoretinal degeneration associated with retinal detachment and occipital scalp defect. The responsible gene, COL18A1, has been mapped to 21q22.3, and, on the basis of the analysis of one family, we have demonstrated that a mutation affecting only one of the three COL18A1 isoforms causes this phenotype. We report here the results of the screening of both the entire coding region and the exon-intron boundaries of the COL18A1 gene (which includes 43 exons), in eight unrelated patients with KS. Besides 20 polymorphic changes, we identified 6 different pathogenic changes in both alleles of five unrelated patients with KS (three compound heterozygotes and two homozygotes). All are truncating mutations leading to deficiency of one or all collagen XVIII isoforms and endostatin. We have verified that, in exon 41, the deletion c3514-3515delCT, found in three unrelated alleles, is embedded in different haplotypes, suggesting that this mutation has occurred more than once. In addition, our results provide evidence of nonallelic genetic heterogeneity in KS. We also show that the longest human isoform (NC11-728) is expressed in several tissues (including the human eye) and that lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but that those patients who lack all forms present more-severe ocular alterations. Despite the small sample size, we found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms; in addition, it seems that absence of all collagen XVIII isoforms causes predisposition to epilepsy.
Asunto(s)
Colágeno/genética , Anomalías del Ojo/genética , Heterogeneidad Genética , Mutación/genética , Fragmentos de Péptidos/genética , Degeneración Retiniana/genética , Desprendimiento de Retina/genética , Adolescente , Adulto , Niño , Preescolar , Colágeno/sangre , Colágeno Tipo XVIII , Endostatinas , Exones/genética , Femenino , Haplotipos/genética , Humanos , Lactante , Recién Nacido , Intrones/genética , Masculino , Datos de Secuencia Molecular , Linaje , Fragmentos de Péptidos/sangre , Fenotipo , Polimorfismo Genético/genética , Isoformas de Proteínas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , SíndromeRESUMEN
Two patients with acute encephalopathy with bilateral striatal necrosis are presented and the literature on the subject is reviewed. The disease is characterized by abrupt onset following a systemic infectious illness, with disturbance of consciousness, absence of speech, dystonic movements of the limbs, general stiffness, opisthotonus, tremor, facial grimacing, and stereotyped reaction to painful stimuli. After a variable period of time, there is gradual improvement of the neurological status with clearing of consciousness and recovery of motor functions. Mild CSF pleocytosis is the only abnormal laboratory test encountered. Cranial imaging shows from the beginning of the illness, bilateral involvement of the striatum that may persist indefinitely. The pathogenesis of this disorder remains unknown although an infectious or para-infectious mechanism seems to be the most likely possibility.
Asunto(s)
Encefalopatías/diagnóstico , Cuerpo Estriado/diagnóstico por imagen , Enfermedad Aguda , Encefalopatías/líquido cefalorraquídeo , Encefalopatías/diagnóstico por imagen , Líquido Cefalorraquídeo/citología , Niño , Preescolar , Cuerpo Estriado/patología , Femenino , Humanos , Masculino , Necrosis , Putamen/diagnóstico por imagen , Putamen/patología , Tomografía Computarizada por Rayos XRESUMEN
Foi realizado estudo clínico de 5 observaçöes da doença de Krabbe (leucidistrofia a células globóides). O diagnóstico de certeza, seja pelo estudo neuropatológico pós mortem (2 casos), seja pela dosagem enzimática em fibroblastos em cultura (2 casos), foi alcançado em 4 observaçöes. A biópsia de nervo periférico foi realizada nos 5 casos e o estudo ultrastrutural revelou, em todos, alteraçöes características da doença de Krabbe. Os autores chamam a atençäo para os principais dados clínicos e laboratoriais que sugerem o diagnóstico da doença, mesmo na impossibilidade da realizaçäo de exame ultrastrutural de nervo periférico e das dosagens enzimáticas, estas näo realizadas em nosso país
Asunto(s)
Humanos , Masculino , Femenino , Recién Nacido , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/líquido cefalorraquídeo , Nervio Sural/ultraestructuraRESUMEN
A clinical study on five cases of Krabbe's disease (globoid cell leukodystrophy) was performed. A final diagnosis was done either with post-mortem study (two cases) or by enzymatic assays carried on cultured fibroblasts (two cases). Peripheral nerve biopsy for electron microscopy was performed in all cases, and the ultrastructural alterations characteristics of Krabbe's disease were always found. The authors emphasize the suggestive clinical and laboratory data which enable the diagnosis of Krabbe's disease in the absence of the ultrastructural exam of peripheral nerve, or the enzymatic assays not performed in this country.