RESUMO
GNE myopathy is an autosomal recessive distal myopathy caused by loss-of-function mutations in the GNE gene, which encodes UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE), a key enzyme in sialic-acid biosynthesis. By comprehensive screening of manifesting patients using a fine-mapped targeted next-generation sequencing (NGS), we identified copy number variations (CNVs) in 13 patients from 11 unrelated families. The nine unique CNVs largely vary in size from 0.3 to 72 kb. Over half of the cases carry different deletions spanning merely exon 2, which contains the 5' untranslated region (5'UTR) of the muscle major transcript hGNE1. Of most unique CNVs, either the telomeric or the centromeric breakpoint locates within intron 2, indicating rearrangement hotspots. Haplotype analysis suggested the existence of a founder allele with exon 2 deletion. The breakpoints for all CNVs were determined by long-range PCR and sequencing. All of the breakpoints of gross deletion/duplications reside within directly oriented pairs of Alu repeats. The results of this study firstly widen the spectra of mutations to CNVs encompassing 5'UTR, underscoring the pivotal role of the hGNE1 transcript. Alu-mediated non-recurrent CNVs may have been overlooked in a wide variety of recessive phenotypes, especially in those associated with genomic Alu-rich genes such as GNE.
Assuntos
Regiões 5' não Traduzidas/genética , Variações do Número de Cópias de DNA/genética , Miopatias Distais/genética , Complexos Multienzimáticos/genética , Adulto , Sequência de Bases , Feminino , Predisposição Genética para Doença , Testes Genéticos , Genoma/genética , Estudo de Associação Genômica Ampla , Haplótipos/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Deleção de Sequência/genética , Adulto JovemRESUMO
<p><b>INTRODUCTION</b>The aim of this study was to review the clinical, computed tomography (CT) and magnetic resonance imaging (MRI) diagnosis and the frequency of positive neuroimaging findings in patients with cerebral venous thrombosis (CVT) involving the superior sagittal sinus.</p><p><b>MATERIALS AND METHODS</b>A clinical and radiological database of patients with final diagnosis of CVT was compiled from the inpatient hospital information service of a tertiary neurological hospital over 5 years. CT and MRI studies in 22 patients were retrospectively examined for direct signs of venous sinus thrombosis and for complications of CVT. The diagnosis of CVT before and after CT and MRI was reviewed.</p><p><b>RESULTS</b>Clinical diagnosis of possible CVT was suspected in only 1 patient. When the diagnosis was not suspected, CT diagnosis was difficult and there was a high false negative rate of 52.6%. MRI fared better, but the false negative rate was still 11%. Directs signs of venous sinus thrombosis such as the triangle sign, empty delta sign on CT and loss of the normal flow voids on MRI, could be retrospectively detected in 57.9%, 100% and 100% of patients respectively. Although 4 patients presented with subarachnoid haemorrhage, these direct signs were present in 3 patients.</p><p><b>CONCLUSION</b>Clinical diagnosis of CVT is rarely suspected before CT and MRI, and although subtle positive signs are often present, these may not be appreciated unless there is a high index of suspicion or image review at multidisciplinary team meetings.</p>
