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.

No abstract

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.

Knobloch syndrome is an autosomal recessive disease characterized by the early onset of severe myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities, and midline encephalocele, mainly in the occipital region. Intra and interfamilial variability is present since the encephalocele is not found in all patients, and the degree of myopia is variable. Analysis of the associated malformations suggests alterations during early neuroectodermal morphogenesis. Only 24 cases have been reported. Recently, the gene responsible for the syndrome, mapped to 21q22.3, was identified. The present study reports on four new cases, revealing the existence of neuronal migratory defects associated with the disorder for the first time.

No abstract

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.

RESUMO -Foi realizado estudo clínico de 5 observações da doença de Krabbe (leueodistrofia 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 observações. A biópsia de nervo periférico foi realizada nos 5 casos e o estudo ultrastrutural revelou, em todos, aliterações características da doença de Krabbe. Os autores chamiam a atenção para os principais dados clínicos e laboratoriais que sugerem o diagnós-tico da doença, mesmo na impossibilidade da realização de exame ultrastrutural de nervo periférico e das dosagens enzimáticas, estas não realizadas em nosso país. A doença de Krabbe, ou leucodistrofia a células globóides, é entidade gené-tica que se transmite segundo o modo autossômico recessivo e se deve a deficiência da enzima lisosomial galactocerebrosídeo /?-galactosidade i*. Em consequência, há acúmulo cerebral de galactocerebrosídeo e de psicosina. O aparecimento desta última levaría a destruição dos oligodendrocitos, o que resulta numa desmielinização maciça no sistema nervoso central 7. A bainha de mielina do sistema nervoso periférico também é comprometida. O acúmulo de galactocerebrosí-deo elicita a formação das células globóides, que parecem ser macrófagos carregados desta substância e são patognomônicas da doença 2 . Nas células de Schwann e em células mesenquimais do nervo periférico, o galactocerebrosídeo forma estruturas lamelares cristaliformes características, cuja visualização à microscopia eletrônica é de importante valor diagnóstico 11 . Há diferentes formas clínicas da doença. De longe, a mais frequente é a forma infantil precoce que se inicia no Trabalho reaflizado no PALAVRAS-CHAVE: doença de

No abstract