European Human Genetics Conference 2007 June 16 – 19, 2007 ...

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Therapy for genetic disease P1409. The Hunter Outcome Survey (HOS): clinical characteristics of patients with mucopolysaccharidosis type II J. E. Wraith 1 , M. Beck 2 , R. Giugliani 3 , B. K. Burton 4 , L. DeMeirleir 5 , J. Zeman 6 , on behalf of the HOS investigators; 1 Royal Manchester Children’s Hospital, Manchester, United Kingdom, 2 Children’s Hospital University of Mainz, Mainz, Germany, 3 Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil, 4 Children’s Memorial Hospital, Chicago, IL, United States, 5 University Hospital of the Vrije Unversiteit Brussel, Brussels, Belgium, 6 Charles University, Prague, Czech Republic. Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare, progressive, X-linked disorder of glycosaminoglycan (GAG) metabolism caused by a deficiency of the enzyme iduronate-2-sulfatase. This results in progressive GAG accumulation within multiple tissues and organs. In 2006, a global survey of MPS II patients - the Hunter Outcome Survey (HOS) - was established to enhance our understanding of the natural history of MPS II, monitor the safety and efficacy of enzyme replacement therapy, and provide the basis for the development of clinical management guidelines. As of October 2006, 100 patients had enrolled in HOS at centres in 11 countries. The median ages at enrolment, onset of symptoms and diagnosis of MPS II were 11.3 years, 1.5 years and 3.5 years, respectively. The prevalence of clinical features at the time of enrolment into HOS was variable; nasal obstruction was reported in 28% of patients, enlarged tonsils or adenoids in 68%, enlarged liver or spleen in 88%, joint stiffness in 87% and facial dysmorphia by 98%. Cardiovascular manifestations of MPS II were found in approximately 75% of patients. These included murmur in 77%, valve disease in 69%, and cardiomyopathy in 12% of patients. Life-table analyses indicated that by age 7 years, approximately 50% of patients with Hunter syndrome display some cardiovascular abnormalities, increasing to 95% by age 15 years. As enrolment increases, HOS will improve our understanding of MPS II, advance the assessment of the long-term impact of ERT, and allow the development of evidence-based clinical management guidelines. P1410. Oxidative stress in Peroxisomal disorders H. T. El-Bassyouni; National Research Center, Guiza, Egypt. Peroxisomal disorders are subdivided into peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme deficiencies. Many peroxisomal diseases exhibit excessive oxidative stress leading to neurological alterations and dysfunction. This study aimed to investigate whether oxidative stress is involved in the pathogenesis of peroxisomal disorders by estimating various oxidative stress parameters in cases suffering from peroxisomal disorders. A total of twenty patients with peroxisomal disorders, their ages ranged from 6 months to 13 years (mean 5.9 ±3.2) were compared to fourteen healthy controls. All individuals were subjected to full history taking including three-generation pedigree analysis concerning parental consanguinity and similarly affected members in the family with meticulous clinical examination to detect any malformation or anomaly. VLCFAs and phytanic acid estimation was done to verify the diagnosis. Other investigations including brain magnetic resonant image (MRI), electric encephalogram (EEG), visual evoked potential (VEP), auditory potential and plain X- rays were done to asses the pathological condition of the patients. Oxidative stress parameters including nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD) were estimated in both patients and controls. This study showed significant increase of both MDA and NO in PBDs. It was also demonstrated that SOD was significantly low in PDB more than controls. Conclusion: Lacking functional peroxisomes leads to generalized increase in oxidative stress confirming the important role of peroxisomes in homeostasis of reactive oxygen species (ROS) and the implications of its disturbances in cell pathology. The study recommends supplementation with antioxidants besides other lines of treatments. P1411. Activation of PPAR pathway stimulates mitochondrial oxidative phosphorylation and is a potential therapy in respiratory chain defects. J. Bastin 1 , F. Aubey 1 , A. Munnich 2 , F. Djouadi 1 ; 1 CNRS UPR 9078, Paris, France, 2 INSERM U781, Paris, France. The mitochondrial Respiratory Chain (RC) disorders are the largest group of inborn errors of metabolism and still remain without treatment in most cases. Here, we tested whether bezafibrate, a drug acting as a Peroxisome Proliferator Activated Receptor (PPAR) agonist, could induce a stimulation of RC residual capacities in four patient cell lines carrying mutations in the Fp (flavoprotein, complex II, CII), or BCS1 (complex III, CIII), or SURF1 (complex IV, CIV), or COX10 (CIV) genes. Exposure to bezafibrate (400µM, 72h) was found to increase (+38 to +50%) the CII, CIII and CIV activities in control fibroblasts, and immunoblots showed parallel increases (+82 to +150%) in Fp, Core 2, SURF1, COX2 and COX4 protein levels. A similar treatment by bezafibrate improved RC capacities in BCS1- and COX10-deficient fibroblasts, as indicated by the stimulation of CIII (+133%) and CIV (+71%) enzyme activity, and by the higher expression of representative proteins. This was related to a drug-induced augmentation in the mRNA abundance of the mutated BCS1 or COX 10 gene. Fp and SURF1 mRNA were also induced by bezafibrate, but without changes in RC residual capacities due to the mutated protein instability. The molecular mechanisms underlying these effects likely involved PPARδ and the co-activator PGC1α that could induce the expression of genes encoding structural subunits or ancillary proteins of the OXPHOS apparatus, leading to stimulate the activity and protein levels of RC complex. These effects could find applications for the correction of some moderate RC disorders due to mutations in nuclear genes. P1412. Growth Hormone is Effective in Treatment of Short Stature Associated with SHOX Deficiency: Two-year Results of a Randomized, Controlled, Multi-Center Trial W. F. Blum 1 , B. J. Crowe 1 , C. A. Quigley 2 , H. Jung 3 , D. Cao 2 , J. L. Ross 4 , L. Braun 2 , G. Rappold 3 ; 1 Lilly Research Laboratories, Eli Lilly and Company, Bad Homburg, Germany, 2 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States, 3 Department of Molecular Human Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany, 4 Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, United States. SHOX encodes a homeodomain transcription factor responsible for a significant proportion of long-bone growth. Patients with mutations or deletions of SHOX, including those with Turner syndrome [TS] who are haploinsufficient for SHOX, have variable degrees of growth impairment, with or without a spectrum of skeletal anomalies consistent with dyschondrosteosis. Fifty-two prepubertal subjects (24 male, 28 female; age 3.0-12.3 years) with a molecularly-proven SHOX gene defect and height below the 3rd percentile for age and gender were randomized to either a growth hormone (GH)-treatment group (n=27) or an untreated control group (n=25) for 2 years. To compare the GH treatment effect between subjects with SHOX-deficiency (SHOX-D) and those with TS, a third study group, comprised 26 pts with TS aged 4.5-11.8 years, who also received GH. Between-group comparisons of height velocity, height standard deviation score (SDS) and height gain (cm) were performed using analysis of covariance accounting for diagnosis, sex and baseline age. The GH-treated SHOX-D group had a significantly greater first-year height velocity than the untreated control group (p
Therapy for genetic disease exon 7 inclusion and/or SMN2 gene transcription, therefore, could be a therapeutic approach for SMA. It has been shown that cellular pH microenvironment can modulate pre-mRNA alternative splicing in vivo. In this study, we tested whether inhibitors of the NA + /H + exchanger can modulate the exon 7 splicing of SMN2 mRNA. We found that treatment with a NA + /H + exchanger inhibitor, 5-(N-ethy1-N-isopropy1)-amiloride (NENI-amiloride), significantly enhances SMN2 exon 7 inclusion as well as SMN protein production in SMA cells. In addition, NENI- amiloride increases the number of nuclear gems in SMA cells. We further explored the underlying mechanism and our results suggest that NENI-amiloride may promote SMN2 exon 7 inclusion through up-regulation of the splicing factor SRp20 in the nucleus. In conclusion, our finding that NENI-amiloride, an inhibitor of the NA + /H + exchanger, can increase SMN protein production in SMA cells provides a new direction for the development of drugs for SMA treatment.
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Volume 15 Supplement 1 June 2007 ww
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Table of Contents Spoken Presentati
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Plenary Lectures Plenary Lectures P
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Plenary Lectures labile iron can be
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Concurrent Symposia S07. Vertebrate
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Concurrent Symposia S17. Towards a
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Concurrent Symposia 11 at E13.5 sim
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Concurrent Symposia 1 phomagenesis.
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cover cryptic mutations in Drosophi
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Concurrent Sessions first excluded
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Concurrent Sessions of 210 ancestry
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Concurrent Sessions C23. Literature
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Concurrent Sessions a boy with a ty
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Concurrent Sessions C40. Mutation o
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Concurrent Sessions C48. CHROMSCAN:
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Concurrent Sessions C57. RNAi-based
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Concurrent Sessions been replicated
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Concurrent Sessions involved in an
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Concurrent Sessions tion considers
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Clinical genetics lateral neurosens
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Clinical genetics apparently sporad
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Clinical genetics itar syndrome, wh
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Clinical genetics diseases, Foundat
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Clinical genetics P0041. The first
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Clinical genetics EFNB1 was found t
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Clinical genetics of the CSB gene.
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Clinical genetics growth retardatio
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Clinical genetics PCR with a modifi
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Clinical genetics pound heterozygou
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Clinical genetics plicated: two cou
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Clinical genetics P0105. APC gene m
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Clinical genetics an indication of
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Clinical genetics great importance
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Clinical genetics P0133. Hidrotic e
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Clinical genetics eight patients as
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Clinical genetics P0152. Kabuki syn
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Clinical genetics P0161. Intrafamil
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Clinical genetics matter and normal
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Clinical genetics type at 550 bands
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Clinical genetics will be confirmed
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Clinical genetics nosed. Accurate r
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Clinical genetics which has not bee
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Clinical genetics P0217. Partial mo
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Clinical genetics fested progeroid
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Clinical genetics A 29 years old ma
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Clinical genetics ing loss (HHL). I
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Clinical genetics dació Son Llatze
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Clinical genetics These preliminary
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Clinical genetics P0272. Williams S
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Cytogenetics Po02. Cytogenetics P02
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Cytogenetics to reports from Saudi
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Cytogenetics P0298. Female-specific
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Cytogenetics P0306. Lipoatrophic pa
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Cytogenetics 22 leading to the form
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Cytogenetics somal sperm and that o
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Cytogenetics University of Belgrade
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Cytogenetics Within the same metaph
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Cytogenetics Less than 10 cases of
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Cytogenetics lar markers taken from
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Cytogenetics Brain Unaffected Schiz
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Cytogenetics ability with no speech
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Cytogenetics P0389. An age based cy
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Cytogenetics P0399. Molecular Chara
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Cytogenetics ing of complex examina
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Cytogenetics letion in 5q33 in all
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Cytogenetics and his son carried th
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Prenatal diagnosis tion about famil
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Prenatal diagnosis P0443. The risk
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Prenatal diagnosis in house PCR pro
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Prenatal diagnosis P0462. Increased
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Prenatal diagnosis P0471. Preimplan
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Prenatal diagnosis agreement with w
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Prenatal diagnosis of Turner Syndro
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Cancer genetics ously defined for d
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Cancer genetics Their frequencies w
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Cancer genetics tion Clinic-Portugu
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Cancer genetics tric carcinogenesis
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Cancer genetics P0532. Secondary ch
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Cancer genetics P0542. Differential
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Cancer genetics gastric cancer risk
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Cancer genetics ania, 3 The Institu
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Cancer genetics low: 8% (8/98 sampl
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Cancer genetics P0578. Somatic mito
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Cancer genetics P0587. Differential
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Cancer genetics cinoma (ESCC), whic
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Cancer genetics method to measure t
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Cancer genetics pression (compared
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Cancer genetics to available biolog
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Molecular and biochemical basis of
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Genetic analysis, linkage, and asso
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Normal variation, population geneti
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Page 299 and 300: Normal variation, population geneti
Page 309 and 310: Genomics, technology, bioinformatic
Page 327 and 328: Genetic counselling, education, gen
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Page 349: Therapy for genetic disease P1405.
Page 353 and 354: Author Index 1 Arslan-Krichner, M.:
Page 355 and 356: Author Index Borkowska, A.: P1089 B
Page 357 and 358: Author Index Coviello, D.: P0078, P
Page 359 and 360: Author Index Estivill, X.: P1216, P
Page 361 and 362: Author Index Graf, S. A.: P0021 Gra
Page 363 and 364: Author Index 1 Josifiova, D.: PL07
Page 365 and 366: Author Index Laurier, V.: C03 Lauri
Page 367 and 368: Author Index Melo, D. G.: P0260, P0
Page 369 and 370: Author Index Osorio, P.: P0218 Osta
Page 371 and 372: Author Index Reese, T.: C06 Regal,
Page 373 and 374: Author Index 1 Shaposhnikov, S.: P0
Page 375 and 376: Author Index Touitou, I.: P0733 Tou
Page 377 and 378: Author Index Xiao, C.: P1241 Xie, G
Page 379 and 380: Keyword Index ARMR: P0907 array CGH
Page 381 and 382: Keyword Index Consanguineous marria
Page 383 and 384: Keyword Index 1 Fronto-temporal dem
Page 385 and 386: Keyword Index IRF5: P1086 IRF6: P07
Page 387 and 388: Keyword Index NBS1 gene: P0567 NBS-
Page 389 and 390: Keyword Index P1085 Rep1: P1104 rep
Page 391 and 392: Keyword Index vision: P0632 Vitamin
Page 393 and 394: Notes 1
Page 395 and 396: A natural choice in Fabry Disease P
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European Human Genetics Conference 2007 June 16 – 19, 2007 ...

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