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Articles by N Simpson
Total Records ( 2 ) for N Simpson
  W. G Leen , J Klepper , M. M Verbeek , M Leferink , T Hofste , B. G van Engelen , R. A Wevers , T Arthur , N Bahi Buisson , D Ballhausen , J Bekhof , P van Bogaert , I Carrilho , B Chabrol , M. P Champion , J Coldwell , P Clayton , E Donner , A Evangeliou , F Ebinger , K Farrell , R. J Forsyth , C. G. E. L de Goede , S Gross , S Grunewald , H Holthausen , S Jayawant , K Lachlan , V Laugel , K Leppig , M. J Lim , G Mancini , A. D Marina , L Martorell , J McMenamin , M. E. C Meuwissen , H Mundy , N. O Nilsson , A Panzer , B. T Poll The , C Rauscher , C. M. R Rouselle , I Sandvig , T Scheffner , E Sheridan , N Simpson , P Sykora , R Tomlinson , J Trounce , D Webb , B Weschke , H Scheffer and M. A. Willemsen
 

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004–2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month–16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9–2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19–0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.

  M. M. W Chong , N Simpson , M Ciofani , G Chen , A Collins and D. R. Littman
 

The stability of a lineage program (cellular memory) is dependent on mechanisms that epigenetically maintain active or repressed states of gene expression (transcriptional memory). Although epigenetic silencing of genes has been clearly demonstrated from yeast to mammals, heritable maintenance of active transcription has been less clearly defined. To investigate the potential role of active transcriptional memory during lineage diversification, we employed targeted mutation of a positive-acting cis element in the Cd4 locus to determine the impact on CD4 expression and the differentiation of CD4+ helper T cells in mice. We show that the proximal enhancer (E4P) of Cd4 is essential for CD4 expression in immature CD4+8+ thymocytes. Futhermore, its loss resulted in reduced and unstable expression of CD4 in mature T cells. However, if the enhancer was deleted after cells had already committed to the helper T-cell lineage, CD4 expression remained high and was stable upon cell division. "Active" histone modifications, once initiated by E4P, were also propagated independently of the enhancer. Thus, E4P is responsible for establishing an epigenetically inherited active Cd4 locus in the helper T-cell lineage. To our knowledge, this is the first genetic demonstration of active transcriptional memory in mammalian cells.

 
 
 
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