662 results on '"Desnick RJ"'
Search Results
2. EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks
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Gouya, L, Ventura, P, Balwani, M, Bissell, DM, Rees, DC, Stölzel, U, Phillips, JA, Kauppinen, R, Langendonk, Janneke, Desnick, RJ, Deybach, JC, Bonkovsky, HL, Parker, CA, Naik, H, Badminton, M, Stein, PE, Minder, E, Windyga, J, Bruha, R, Cappellini, MD, Sardh, E, Harper, PG, Sandberg, S, Aarsand, AK, Andersen, JB, Alegre, F, Ivanova, A, Talbi, N, Chan, A, Querbes, W, Ko, JJ, Penz, C, Liu, S, Lin, T, Simon, A, Anderson, KM, Gouya, L, Ventura, P, Balwani, M, Bissell, DM, Rees, DC, Stölzel, U, Phillips, JA, Kauppinen, R, Langendonk, Janneke, Desnick, RJ, Deybach, JC, Bonkovsky, HL, Parker, CA, Naik, H, Badminton, M, Stein, PE, Minder, E, Windyga, J, Bruha, R, Cappellini, MD, Sardh, E, Harper, PG, Sandberg, S, Aarsand, AK, Andersen, JB, Alegre, F, Ivanova, A, Talbi, N, Chan, A, Querbes, W, Ko, JJ, Penz, C, Liu, S, Lin, T, Simon, A, and Anderson, KM
- Published
- 2020
3. Increasing Tamoxifen Dose in Breast Cancer Patients Based on CYP2D6 Genotypes and Endoxifen Levels: Effect on Active Metabolite Isomers and the Antiestrogenic Activity Score
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Barginear, MF, Jaremko, M, Peter, I, Yu, C, Kasai, Y, Kemeny, M, Raptis, G, and Desnick, RJ
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- 2011
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4. Assignment of human alpha 1-antitrypsin to chromosome 14 by somatic cell hybrid analysis.
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Darlington, GJ, Astrin, KH, Muirhead, SP, Desnick, RJ, and Smith, M
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Hybrid Cells ,Chromosomes ,Human ,13-15 ,Animals ,Humans ,Mice ,Rats ,Liver Neoplasms ,Experimental ,Purine-Nucleoside Phosphorylase ,alpha 1-Antitrypsin ,Cell Differentiation ,Gene Expression Regulation ,Genetic Linkage ,Liver Neoplasms ,Experimental/genetics ,Purine-Nucleoside Phosphorylase/genetics ,alpha 1-Antitrypsin/genetics - Abstract
Human alpha 1-antitrypsin ( alpha-1-AT;Pi) production was analyzed in 11 primary mouse hepatoma-human lymphoid cell hybrids and in 14 secondary rat hepatoma-human fetal liver fibroblast hybrids. The presence of human alpha-1-AT was determined by Laurell immunoelectrophoresis of concentrated and isotopically labeled supernatant medium. Human alpha-1-AT production segregated in the mouse-human hybrids concordantly with human purine nucleoside phosphorylase and with chromosome 14. All rat-human hybrids that were alpha-1-AT positive were also positive for human purine nucleoside phosphorylase and chromosome 14. Our study demonstrated the usefulness of rodent hepatoma cell hybrids for mapping human liver-specific genes because differentiated functions are expressed despite the fact that the human parental cells did not express these functions. Our study also showed that human alpha-1-AT gene product can be processed for secretion in the rodent hepatoma cellular environment. The mouse-human hybrids showed that no other human chromosome carries genes necessary for processing or secretion of human alpha-1-AT in the hybrid cell milieu.
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- 1982
5. Chromosomal localization of the gene for Gaucher disease.
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Devine, EA, Smith, M, Arredondo-Vega, FX, Shafit-Zagardo, B, and Desnick, RJ
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Genetics ,Biological Sciences ,Clinical Research ,Biotechnology ,Animals ,Cell Line ,Chromosome Mapping ,Chromosomes ,Human ,1-3 ,Gaucher Disease ,Glucosidases ,Humans ,Hybrid Cells ,Hydrogen-Ion Concentration ,Karyotyping ,Mice ,beta-Glucosidase ,Gaucher's disease ,Gaucher's disease -- Congresses - Abstract
The structural gene for human GBA has been assigned to chromosome 1 using somatic cell hybridization techniques for gene mapping. The human enzyme was detected in mouse RAG cell-human fibroblast cell hybrids by a sensitive double antibody immunoprecipitation assay using a mouse anti-human GBA antibody. No cross-reactivity between mouse beta-glucosidase and human GBA or GBN was observed. For the initial assignment, fifty-two primary, secondary, and tertiary man-mouse hybrids lines, derived from three separate fusion experiments, were analyzed for human GBA and enzyme markers for the human chromosomes. Without exception, the presence of human GBA in these hybrid clones was correlated with the presence of human chromosome 1 or its enzymatic markers, PGM1 and FH. All other human chromosomes were eliminated by the independent segregation of GBA and their respective enzyme markers and/or chromosomes. Using a RAG-human fibroblast line with a mouse-human rearrangement of human chromosome 1, the locus for GBA was limited to the region 1p11 leads to 1qter. Further regional localization was obtained using subclones of hybrids derived from the fusion of a human fibroblast line, 46,XX,del(1)(pter leads to q42:), with mouse RAG fibroblasts. All hybrid subclones containing a normal chromosome 1 were positive for GBA. In contrast, subclones with a single deleted chromosome 1 were negative for GBA by immunoprecipitation and by the natural substrate assays. These results further localized the gene for GBA to the narrow region, 1q42 leads to 1qter.
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- 1982
6. Assignment of the gene for cytosolic alanine aminotransferase (AAT1) to human chromosome 8
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ASTRIN, KH, ARREDONDO‐VEGA, FX, DESNICK, RJ, and SMITH, M
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Biological Sciences ,Genetics ,Alanine Transaminase ,Animals ,Chromosomes ,Human ,6-12 and X ,Cytosol ,Electrophoresis ,Starch Gel ,Genes ,Humans ,Hybrid Cells ,Isoenzymes ,Liver ,Liver Neoplasms ,Experimental ,Rats ,Clinical Sciences ,Genetics & Heredity - Abstract
The segregation of human cytosolic alanine aminotransferase (AAT1) and the individual human chromosomes has been studied in 27 secondary and tertiary rat hepatoma-human (liver) fibroblast hybrids. The staining solution used to visualize AAT activity on starch gels was specific for AAT since it was visualized only when all components of the stain were present. The locus for human AAT1 has been assigned to chromosome 8.
- Published
- 1982
7. Regional assignment of the structural gene for human acid β-glucosidase to q42→qter on chromosome 1
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Devine, EA, Smith, M, Arredondo-Vega, FX, Shafit-Zagardo, B, and Desnick, RJ
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Biological Sciences ,Genetics ,Clinical Research ,Chromosome Mapping ,Chromosomes ,Chromosomes ,Human ,1-3 ,Genes ,Glucosidases ,Humans ,Hybrid Cells ,beta-Glucosidase ,Genetics & Heredity - Abstract
The structural gene for human acid beta-glucosidase (GBA) has been regionally assigned to a narrow region on chromosome 1 using somatic cell hybridization, specific immunoprecipitation, and assay with the natural substrate. A human fibroblast line, 46,XX,del(1)(pter leads to q42:), was fused with mouse RAG fibroblasts and the heterokaryons were subcloned. All hybrid subclones containing a normal chromosome 1 were positive for GBA. In contrast, subclones with a single del(1) were negative for GBA by both immunoprecipitation and natural substrate assays. These results were consistent with the previous assignment of GBA to the region 1p11 leads to qter and further localized the gene to the narrow region 1q42 leads to qter.
- Published
- 1982
8. Regional gene assignment of human porphobilinogen deaminase and esterase A4 to chromosome 11q23 leads to 11qter.
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Wang, AL, Arredondo-Vega, FX, Giampietro, PF, Smith, M, Anderson, WF, and Desnick, RJ
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- 1981
9. Chromosomal localization of the gene for Gaucher disease
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Smith, M, Devine, EA, Arredondo- Vega, FX, Shafit-Zagardo, B, and Desnick, RJ
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Gaucher's disease ,Gaucher's disease -- Congresses - Abstract
Two isozymes with a - glucosidase activity have beenidentified in normal human tissues using the artificialsubstrate, 4-methylwnbelliferyl- S-D-glucopyranoside (4MUGlc).The acid (EC 3.2.1. 45) and neutral (EC 3.2.1.21)B- glucosidases (designated GBA and GBN, respectively) havebeen differentiated by their relative pH optima (Beutlerand Kuhl, 1970; Ho, et al., 1972; Turner et al., 1977;Mueller and Rosenberg, 1977), subcellular localizations(Ho, 1972; Peters et al., 1973), substrate specificities(Patrick, 1965; Ho, 1972; Peters et al., 1976), sensitivitiesto anionic detergents and acidic phospholipids(Peters et al., 1976), affinity for concanavalin A (Beutleret al., 1975; Shafit- Zagardo et al . , 1980) and most recentlyby their differential electrophoretic migration oncellulose acetate gels (Shafit- Zagardo et al., 1980). Theacid isozyme, a membrane bound activity, has been shown tobe deficient in the various subtypes of Gaucher disease,lysosomal storage diseases characterized by the accumulationof glucosyl ceramide (Brady, 1978). To date, thechromosomal assignment of the structural gene for either ofthe human 8 -glucosidase isozymes has not been determined .We report here .the regional assignment of the structuralgene for human GBA using human-rodent somatic cellhybrids . A sensitive immunoprecipitation assay was developedfor the selective detection of the human enzyme in thepresence of mouse 6 -glucosidase activity. Initial data for the regional assignment of the locus on chromosome 1 wasobtained from a hybrid clone containing a 11\\)USe-hwuanchromosome 1 rearrangement. Further regional localizationof the locus for GBA near lqter was obtained using aninformative hybrid clone carrying a human chromosome 1deletion. In addition to the immunoprecipitation assay,use of the specific natural substrate further supported theassignment of the structural gene for GBA to this region.
- Published
- 1982
10. Assignment of the gene for neutral alpha-glucosidase AB to chromosome 11.
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Martiniuk, F, Smith, M, Ellenbogen, A, Desnick, RJ, Astrin, K, Mitra, J, and Hirschhorn, R
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Cell Line ,Hybrid Cells ,Chromosomes ,Human ,6-12 and X ,Animals ,Humans ,Mice ,Glucosidases ,alpha-Glucosidases ,Isoenzymes ,Immunoelectrophoresis ,Chromosome Mapping ,Genes ,Genetics & Heredity ,Genetics - Published
- 1983
11. Regional assignment of the structural gene for human acid beta-glucosidase to q42 leads to qter on chromosome 1.
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Devine, EA, Smith, M, Arredondo-Vega, FX, Shafit-Zagardo, B, and Desnick, RJ
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Hybrid Cells ,Chromosomes ,Chromosomes ,Human ,1-3 ,Humans ,Glucosidases ,beta-Glucosidase ,Chromosome Mapping ,Genes ,Clinical Research ,Genetics & Heredity ,Genetics - Abstract
The structural gene for human acid beta-glucosidase (GBA) has been regionally assigned to a narrow region on chromosome 1 using somatic cell hybridization, specific immunoprecipitation, and assay with the natural substrate. A human fibroblast line, 46,XX,del(1)(pter leads to q42:), was fused with mouse RAG fibroblasts and the heterokaryons were subcloned. All hybrid subclones containing a normal chromosome 1 were positive for GBA. In contrast, subclones with a single del(1) were negative for GBA by both immunoprecipitation and natural substrate assays. These results were consistent with the previous assignment of GBA to the region 1p11 leads to qter and further localized the gene to the narrow region 1q42 leads to qter.
- Published
- 1982
12. Exome sequencing of extreme clopidogrel response phenotypes identifiesB4GALT2as a determinant of on-treatment platelet reactivity
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Scott, SA, primary, Collet, J-P, additional, Baber, U, additional, Yang, Y, additional, Peter, I, additional, Linderman, M, additional, Sload, J, additional, Qiao, W, additional, Kini, AS, additional, Sharma, SK, additional, Desnick, RJ, additional, Fuster, V, additional, Hajjar, RJ, additional, Montalescot, G, additional, and Hulot, J-S, additional
- Published
- 2016
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13. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium
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SERI M, CUSANO R, GANGAROSSA S, CARIDI G, BORDO D, LO NIGRO C, GHIGGERI GM, RAVAZZOLO R, SAVINO M, DEL VECCHIO M, D'APOLITO M, ZELANTE LL, SAVOIA A, BALDUINI CL, NORIS P, MAGRINI U, BELLETTI S, HEATH KE, BABCOCK M, GLUCKSMAN MJ, ALIPRANDIS E, BIZZARO N, DESNICK RJ, MARTIGNETTI J.A., IOLASCON, ACHILLE, Seri, M, Cusano, R, Gangarossa, S, Caridi, G, Bordo, D, LO NIGRO, C, Ghiggeri, Gm, Ravazzolo, R, Savino, M, DEL VECCHIO, M, D'Apolito, M, Iolascon, Achille, Zelante, Ll, Savoia, A, Balduini, Cl, Noris, P, Magrini, U, Belletti, S, Heath, Ke, Babcock, M, Glucksman, Mj, Aliprandis, E, Bizzaro, N, Desnick, Rj, and Martignetti, J. A.
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Models, Molecular ,Cytoplasm ,Genotype ,Neutrophils ,Protein Conformation ,Chromosomes, Human, Pair 22 ,Hearing Loss, Sensorineural ,Molecular Sequence Data ,Mutation, Missense ,Myosins ,Crystallography, X-Ray ,Cataract ,Leukocytes ,Animals ,Humans ,Amino Acid Sequence ,Alleles ,Nephritis ,Myosin Heavy Chains ,Sequence Homology, Amino Acid ,Molecular Motor Proteins ,Muscle, Smooth ,Syndrome ,Thrombocytopenia ,Protein Structure, Tertiary ,Phenotype ,Mutation ,Blood Platelet Disorders ,Chickens - Abstract
The autosomal dominant, giant-platelet disorders, May-Hegglin anomaly (MHA; MIM 155100), Fechtner syndrome (FTNS; MIM 153640) and Sebastian syndrome (SBS), share the triad of thrombocytopenia, large platelets and characteristic leukocyte inclusions ('Döhle-like' bodies). MHA and SBS can be differentiated by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished by the additional Alport-like clinical features of sensorineural deafness, cataracts and nephritis. The similarities between these platelet disorders and our recent refinement of the MHA (ref. 6) and FTNS (ref. 7) disease loci to an overlapping region of 480 kb on chromosome 22 suggested that all three disorders are allelic. Among the identified candidate genes is the gene encoding nonmuscle myosin heavy chain 9 (MYH9; refs 8-10), which is expressed in platelets and upregulated during granulocyte differentiation. We identified six MYH9 mutations (one nonsense and five missense) in seven unrelated probands from MHA, SBS and FTNS families. On the basis of molecular modelling, the two mutations affecting the myosin head were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique carboxy-terminal tailpiece. The remaining missense mutations, all affecting highly conserved coiled-coil domain positions, imparted destabilizing electrostatic and polar changes. Thus, our results suggest that mutations in MYH9 result in three megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts and nephritis.
- Published
- 2000
14. Galactose infusion therapies improves cardiac function in the cardiac of Fabry's disease. Two year experience ov chaperone-mediated enzyme enhancement
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Frustaci, A., Chimenti, C., Ricci, R., Natale, L, Russo, Matteo Antonio, and Desnick, Rj
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- 2001
15. A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci
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Kenny, EE, Pe'er, I, Karban, A, Ozelius, L, Mitchell, AA, Ng, SM, Erazo, M, Ostrer, H, Abraham, C, Abreu, MT, Atzmon, G, Barzilai, N, Brant, SR, Bressman, S, Burns, ER, Chowers, Y, Clark, LN, Darvasi, A, Doheny, D, Duerr, RH, Eliakim, R, Giladi, N, Gregersen, PK, Hakonarson, H, Jones, MR, Marder, K, McGovern, DPB, Mulle, J, Orr-Urtreger, A, Proctor, DD, Pulver, A, Rotter, JI, Silverberg, MS, Ullman, T, Warren, ST, Waterman, M, Zhang, W, Bergman, A, Mayer, L, Katz, S, Desnick, RJ, Cho, JH, Peter, I, Kenny, EE, Pe'er, I, Karban, A, Ozelius, L, Mitchell, AA, Ng, SM, Erazo, M, Ostrer, H, Abraham, C, Abreu, MT, Atzmon, G, Barzilai, N, Brant, SR, Bressman, S, Burns, ER, Chowers, Y, Clark, LN, Darvasi, A, Doheny, D, Duerr, RH, Eliakim, R, Giladi, N, Gregersen, PK, Hakonarson, H, Jones, MR, Marder, K, McGovern, DPB, Mulle, J, Orr-Urtreger, A, Proctor, DD, Pulver, A, Rotter, JI, Silverberg, MS, Ullman, T, Warren, ST, Waterman, M, Zhang, W, Bergman, A, Mayer, L, Katz, S, Desnick, RJ, Cho, JH, and Peter, I
- Abstract
Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10 -6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10 -8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10 -9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10 -8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10 -8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10 -9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim. © 2012 Kenny et al.
- Published
- 2012
16. Mutations in MYH9 in May-Hegglin anomaly, and Fechtner and Sebastian syndromes
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Seri, M, Cusano, R, Gangarossa, S, Caridi, G, Bordo, D, LO NIGRO, C, Ghiggeri, Gm, Ravazzolo, Roberto, Savino, M, DEL VECCHIO, M, D'Apolito, M, Iolascon, A, Zelante, Ll, Savoia, A, Balduini, Cl, Noris, P, Magrini, U, Belletti, S, Heath, Ke, Babcock, M, Glucksman, Mj, Aliprandis, E, Bizzaro, N, Desnick, Rj, and Martignetti, J. A.
- Published
- 2000
17. Exome sequencing of extreme clopidogrel response phenotypes identifies B4GALT2 as a determinant of on-treatment platelet reactivity.
- Author
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Scott, SA, Collet, J‐P, Baber, U, Yang, Y, Peter, I, Linderman, M, Sload, J, Qiao, W, Kini, AS, Sharma, SK, Desnick, RJ, Fuster, V, Hajjar, RJ, Montalescot, G, and Hulot, J‐S
- Subjects
CLOPIDOGREL ,EXOMES ,NUCLEOTIDE sequencing ,CORONARY disease ,MEMBRANE glycoproteins ,PATIENTS - Abstract
Interindividual variability in platelet aggregation is common among patients treated with clopidogrel and both high on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) increase risks for adverse clinical outcomes. CYP2C19 influences clopidogrel response but only accounts for ∼12% of the variability in platelet reactivity. To identify novel variants implicated in on-treatment platelet reactivity, patients with coronary artery disease (CAD) with extreme pharmacodynamic responses to clopidogrel and wild-type CYP2C19 were subjected to exome sequencing. Candidate variants that clustered in the LTPR subgroup subsequently were genotyped across the discovery cohort ( n = 636). Importantly, carriers of B4GALT2 c.909C>T had lower on-treatment P2Y12 reaction units (PRUs; P = 0.0077) and residual platelet aggregation ( P = 0.0008) compared with noncarriers, which remained significant after adjusting for CYP2C19 and other clinical variables in both the discovery ( P = 0.0298) and replication ( n = 160; PRU: P = 0.0001) cohorts. B4GALT2 is a platelet-expressed galactosyltransferase, indicating that B4GALT2 c.909C>T may influence clopidogrel sensitivity through atypical cell-surface glycoprotein processing and platelet adhesion. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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18. Pulmonary involvement in Type 1 Gaucher disease: functional and exercise findings in patients with and without clinical interstitial lung disease
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Miller, A, primary, Brown, LK, additional, Pastores, GM, additional, and Desnick, RJ, additional
- Published
- 2003
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19. Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients
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Levran, O, primary, Desnick, RJ, additional, and Schuchman, EH, additional
- Published
- 1992
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20. Frequency of unrecognized Fabry disease among young European-American and African-American men with first ischemic stroke.
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Wozniak MA, Kittner SJ, Tuhrim S, Cole JW, Stern B, Dobbins M, Grace ME, Nazarenko I, Dobrovolny R, McDade E, Desnick RJ, Wozniak, Marcella A, Kittner, Steven J, Tuhrim, Stanley, Cole, John W, Stern, Barney, Dobbins, Mark, Grace, Marie E, Nazarenko, Irina, and Dobrovolny, Robert
- Published
- 2010
- Full Text
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21. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.
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Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, Finkel R, Packman S, Bichet DG, Warnock DG, Desnick RJ, Fabry Disease Clinical Trial Study Group, Banikazemi, Maryam, Bultas, Jan, Waldek, Stephen, Wilcox, William R, Whitley, Chester B, McDonald, Marie, Finkel, Richard, and Packman, Seymour
- Abstract
Background: Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement.Objective: To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease.Design: Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial.Setting: 41 referral centers in 9 countries.Patients: 82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent.Intervention: Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months).Measurements: The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point.Results: Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group.Limitations: The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event.Conclusions: Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit. [ABSTRACT FROM AUTHOR]- Published
- 2007
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22. Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials.
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McGovern MM, Aron A, Brodie SE, Desnick RJ, and Wasserstein MP
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- 2006
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23. HLA-DQA1 and Polymarker Allele Frequencies in Two New York City Jewish Populations
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Medintz, I, Levine, L, McCurdy, L, Chiriboga, L, Kingston, C, Desnick, RJ, Eng, CM, and Kobilinsky, L
- Abstract
Allele and genotype frequencies were determined for the HLA-DQA1 and Amplitype® Polymarker loci (low density lipoprotein receptor (LDLR), glycophorin A (GYPA), hemoglobin G gammaglobin (HBGG), D7S8, and group-specific component (Gc)) in Hasidic and non-Hasidic Ashkenazi New York City Jewish subpopulations. For all loci tested, except HBGG, the 2 subpopulations meet the assumption of Hardy-Weinberg equilibrium. Comparison of various allele and genotype frequencies for the Hasidic and the non-Hasidic groups showed no significant differences. Comparison of the various allele frequencies in the two subpopulations to another Caucasian group revealed significant differences at the HLA-DQA1 and D7S8 loci in the Hasidic group. These frequency data can be used for comparison to other populations and for frequency estimates in DNA profiling.
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- 1997
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24. Mutations in the nonmuscle myosin heavy chain IIA gene (MYH9) result in the diverse phenotypes of the May-Hegglin anomaly, Fechtner and Sebastian syndromes
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Heath, Ke, Seri, M., Savino, M., Cusano, R., Gangarossa, S., Gianluca Caridi, Bordo, D., Lo Nigro, C., Ghiggeri, Gm, Del Vecchi, M., D Apolito, M., Iolascon, A., Bordo, S., Zelante, Ll, Balduini, Cl, Noris, P., Magrini, U., Belletti, S., Babcock, M., Aliprandis, E., Glucksman, Mj, Bizzaro, N., Desnick, Rj, Ravazzolo, R., Savoia, A., and Martignetti, Ja
25. Accelerated skeletal deterioration after splenectomy in Gaucher type 1 disease
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Rose, JS, primary, Grabowski, GA, additional, Barnett, SH, additional, and Desnick, RJ, additional
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- 1982
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26. Gaucher's disease type 1: assessment of bone involvement by CT and scintigraphy
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Hermann, G, primary, Goldblatt, J, additional, Levy, RN, additional, Goldsmith, SJ, additional, Desnick, RJ, additional, and Grabowski, GA, additional
- Published
- 1986
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27. Toxic Keratopathy Associated with Suramin Therapy
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Stanley R. Yancovitz, Desnick Rj, Usha Mathur-Wagh, Sandra Handwerger, Donna Mildvan, and Teich Sa
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Acquired Immunodeficiency Syndrome ,business.industry ,Suramin ,Humans ,Medicine ,General Medicine ,Pharmacology ,business ,Corneal Diseases ,medicine.drug - Published
- 1986
28. A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B.
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McGovern MM, Wasserstein MP, Giugliani R, Bembi B, Vanier MT, Mengel E, Brodie SE, Mendelson D, Skloot G, Desnick RJ, Kuriyama N, and Cox GF
- Published
- 2008
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29. The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study.
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Wasserstein MP, Desnick RJ, Schuchman EH, Hossain S, Wallenstein S, Lamm C, and McGovern MM
- Abstract
OBJECTIVES: Type B Niemann-Pick disease (NPD-B) caused by acid sphingomyelinase deficiency is a rare, autosomal recessive, lysosomal storage disorder with a broad range of disease severity. The objectives of this study were to document the natural history of the disease in a large, clinically heterogeneous patient population that was followed for a period of 10 years and to determine how genotype influences phenotype. METHODS: Twenty-nine patients with NPD-B had serial evaluations at least 9 months apart. Organ volumes, hematologic indices, lipid concentrations, pulmonary function, and hepatic activity were studied, and individual phenotypic severity was compared with genotype. RESULTS: All patients with intact spleens had splenomegaly (mean value: 12.7 multiples of normal [MN]; range: 4.5-27.3 MN), and all but 1 had hepatomegaly (mean volume: 1.91 MN; range: 0.93-3.21 MN). At initial visit, 39% had thrombocytopenia and 3% had leukopenia. At final visit, the percentages increased to 54% and 34%, respectively. Mean annual decreases in platelet count and leukocyte count were 7 x 10(3) and 0.2 x 10(3) per mm3, respectively. The typical atherogenic lipid profile was worse in older patients. A total of 69% of patients had low diffusion capacity for carbon monoxide, and more than one third had low forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity at initial visit. All measurements of pulmonary function showed a gradual deterioration over time. Liver dysfunction was characterized by stable elevation of hepatic transaminases and bilirubin. Homozygotes for DeltaR608, P323A, and P330R had milder disease than patients with all other genotypes. CONCLUSIONS: The natural history of NPD-B is characterized by hepatosplenomegaly with progressive hypersplenism, worsening atherogenic lipid profile, gradual deterioration in pulmonary function, and stable liver dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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30. A mutation of PCDH15 among Ashkenazi Jews with the type 1 Usher syndrome.
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Ben-Yosef T, Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RJ, Willner JP, Avraham KB, Ostrer H, Oddoux C, Griffith AJ, and Friedman TB
- Published
- 2003
31. The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities.
- Author
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Rhoads GG, Jackson LG, Schlesselman SE, de la Cruz FF, Desnick RJ, Golbus MS, Ledbetter DH, Lubs HA, Mahoney MJ, Pergament E, Simpson JL, Carpenter RJ, Elias S, Ginsberg NA, Goldberg JD, Hobbins JC, Lynch L, Shiono PH, Wapner RJ, and Zachary JM
- Published
- 1989
32. The Gene for May-Hegglin Anomaly Localizes to a <1-Mb Region on Chromosome 22q12.3-13.1
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Karen E. Heath, John A. Martignetti, Carlo L. Balduini, Robert J. Desnick, Juliette Harris, Anna Savoia, Nicola Bizzaro, Martignetti, Ja, Heath, Ke, Harris, J, Bizzaro, N, Savoia, Anna, Balduini, Cl, and Desnick, Rj
- Subjects
Male ,Platelets ,Candidate gene ,Anomalia May Hegglin ,Analisi di linkage ,Platelet disorder ,Chromosomes, Human, Pair 22 ,Döhle bodies ,Locus (genetics) ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Gene mapping ,Genetic linkage ,Macrothrombocytopenia ,Report ,medicine ,Genetics ,Humans ,Genetics(clinical) ,Genetics (clinical) ,030304 developmental biology ,Genes, Dominant ,0303 health sciences ,Polymorphism, Genetic ,Haplotype ,Chromosome Mapping ,medicine.disease ,Pedigree ,Linkage, analysis ,Haplotypes ,Italy ,030220 oncology & carcinogenesis ,May–Hegglin anomaly ,Female ,Blood Platelet Disorders ,Lod Score ,Chromosome 22 ,Software ,Microsatellite Repeats - Abstract
The May-Hegglin anomaly (MHA) is an autosomal dominant platelet disorder of unknown etiology. It is characterized by thrombocytopenia, giant platelets, and leukocyte inclusion bodies, and affected heterozygotes are predisposed to bleeding episodes. The MHA gene has recently been localized, by means of linkage analysis, to a 13.6-cM region on chromosome 22, and the complete chromosome 22 sequence has been reported. We recently performed a genome scan for the MHA gene in 29 members of a large, multigenerational Italian family, and we now confirm that the MHA locus is on chromosome 22q12. 3-13.1. The maximal two-point LOD score of 4.50 was achieved with the use of marker D22S283, at a recombination fraction of.05. Haplotype analysis narrowed the MHA critical region to 6.6 cM between markers D22S683 and D22S1177. It is of note that the chromosome 22 sequence allowed all markers to be ordered correctly, identified all the candidate genes and predicted genes, and specifically determined the physical size of the MHA region to be 0. 7 Mb. These results significantly narrow the region in which the MHA gene is located, and they represent the first use of chromosome 22 data to positionally clone a disease gene.
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33. Congenital erythropoietic porphyria.
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To-Figueras J, Erwin AL, Aguilera P, Millet O, and Desnick RJ
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- Humans, Uroporphyrins genetics, Porphyria, Erythropoietic genetics, Porphyria, Erythropoietic diagnosis, Porphyria, Erythropoietic therapy, Uroporphyrinogen III Synthetase genetics, Uroporphyrinogen III Synthetase metabolism
- Abstract
Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disease due to the deficient, but not absent, activity of uroporphyrinogen III synthase (UROS), the fourth enzyme in the heme biosynthesis pathway. Biallelic variants in the UROS gene result in decreased UROS enzymatic activity and the accumulation of non-physiologic Type I porphyrins in cells and fluids. Overproduced uroporphyrins in haematopoietic cells are released into the circulation and distributed to tissues, inducing primarily hematologic and dermatologic symptoms. The clinical manifestations vary in severity ranging from non-immune hydrops fetalis in utero to mild dermatologic manifestations in adults. Here, the biochemical, molecular and clinical features of CEP as well as current and new treatment options, including the rescue of UROS enzyme activity by chaperones, are presented., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2024
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34. Reduction in kidney function decline and risk of severe clinical events in agalsidase beta-treated Fabry disease patients: a matched analysis from the Fabry Registry.
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Batista JL, Hariri A, Maski M, Richards S, Gudivada B, Raynor LA, Ponce E, Wanner C, and Desnick RJ
- Abstract
Background: Patients with Fabry disease (FD, α-galactosidase A deficiency or absence) accumulate glycosphingolipids, leading to progressive dysfunction of kidneys, heart and nervous system. Generalizable real-world outcomes following agalsidase beta treatment initiation outside trials are limited. We investigated the associations of long-term agalsidase beta treatment with estimated glomerular filtration rate (eGFR) changes over time and the risk of developing a composite clinical event in a matched analysis of treated and untreated patients with FD., Methods: Agalsidase beta-treated adult patients (aged ≥16 years) from the Fabry Registry and adult untreated patients from a natural history cohort were matched 1:1 and X:X (with one occurrence and multiple occurrences of each untreated patient, respectively) by sex, phenotype, age and (for eGFR slope analysis) baseline eGFR. Outcomes included eGFR slope over 5 years and composite clinical event risk (cardiovascular, cerebrovascular or renal event, or death) over 10+ years. As a surrogate indicator of therapeutic response in paediatric patients, the percentage experiencing normalization in plasma globotriaosylceramide (GL-3) from treatment initiation was assessed in patients aged 2 to <16 years., Results: Overall, eGFR slopes for 1:1-matched untreated and treated adult patients [122 pairs (72.1% male)] were -3.19 and -1.47 mL/min/1.73 m
2 /year, respectively (reduction in rate of decline = 53.9%, P = .007), and for X:X-matched [122 untreated/950 treated (59.4% male)] were -3.29 and -1.56 mL/min/1.73 m2 /year, respectively (reduction in rate of decline = 52.6%, P < .001). Agalsidase beta treatment was associated with lower risk of clinical events, with hazard ratios of 0.41 ( P = .003) and 0.67 ( P = .008) for 1:1-matched and X:X-matched analyses, respectively. Plasma GL-3 declined markedly in paediatric patients and normalized in most within 6 months of treatment initiation., Conclusion: Agalsidase beta treatment preserves kidney function and delays progression to severe clinical events among adult patients with FD. Plasma GL-3 levels analysed in paediatric patients showed normalization of elevated pre-treatment levels in most patients., Competing Interests: J.L.B., A.H., M.M., S.R., B.G., L.A.R. and E.P. are/were full-time employees of Sanofi and may hold/have held stock and/or stock options in that company. C.W. has received honoraria for board meetings and lecturing from Amicus Therapeutics, Chiesi Pharmaceuticals, Idorsia Pharmaceuticals, Sanofi and Takeda. R.J.D. is a consultant for Sanofi., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)- Published
- 2024
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35. Anderson-Fabry disease management: role of the cardiologist.
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Pieroni M, Namdar M, Olivotto I, and Desnick RJ
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- Humans, Diagnosis, Differential, Cardiologists, Fabry Disease diagnosis, Fabry Disease drug therapy, Cardiomyopathy, Hypertrophic diagnosis
- Abstract
Anderson-Fabry disease (AFD) is a lysosomal storage disorder characterized by glycolipid accumulation in cardiac cells, associated with a peculiar form of hypertrophic cardiomyopathy (HCM). Up to 1% of patients with a diagnosis of HCM indeed have AFD. With the availability of targeted therapies for sarcomeric HCM and its genocopies, a timely differential diagnosis is essential. Specifically, the therapeutic landscape for AFD is rapidly evolving and offers increasingly effective, disease-modifying treatment options. However, diagnosing AFD may be difficult, particularly in the non-classic phenotype with prominent or isolated cardiac involvement and no systemic red flags. For many AFD patients, the clinical journey from initial clinical manifestations to diagnosis and appropriate treatment remains challenging, due to late recognition or utter neglect. Consequently, late initiation of treatment results in an exacerbation of cardiac involvement, representing the main cause of morbidity and mortality, irrespective of gender. Optimal management of AFD patients requires a dedicated multidisciplinary team, in which the cardiologist plays a decisive role, ranging from the differential diagnosis to the prevention of complications and the evaluation of timing for disease-specific therapies. The present review aims to redefine the role of cardiologists across the main decision nodes in contemporary AFD clinical care and drug discovery., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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36. Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria.
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Yasuda M, Lee S, Gan L, Bergonia HA, Desnick RJ, and Phillips JD
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- Animals, Mice, Aminolevulinic Acid pharmacology, Aminolevulinic Acid therapeutic use, Cimetidine pharmacology, Nitric Oxide Synthase, Heme Oxygenase (Decyclizing), Heme, Protoporphyria, Erythropoietic drug therapy, Porphyria, Acute Intermittent drug therapy
- Abstract
Acute intermittent porphyria (AIP) is characterized by acute neurovisceral attacks that are precipitated by the induction of hepatic 5-aminolevulinic acid synthase 1 (ALAS1). In erythropoietic protoporphyria (EPP), sun exposure leads to skin photosensitivity due to the overproduction of photoreactive porphyrins in bone marrow erythroid cells, where heme synthesis is primarily driven by the ALAS2 isozyme. Cimetidine has been suggested to be effective for the treatment of both AIP and EPP based on limited case reports. It has been proposed that cimetidine acts by inhibiting ALAS activity in liver and bone marrow for AIP and EPP, respectively, while it may also inhibit the hepatic activity of the heme catabolism enzyme, heme oxygenase (HO). Here, we show that cimetidine did not significantly modulate the activity or expression of endogenous ALAS or HO in wildtype mouse livers or bone marrow. Further, cimetidine did not effectively decrease hepatic ALAS activity or expression or plasma concentrations of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which were all markedly elevated during an induced acute attack in an AIP mouse model. These results show that cimetidine is not an efficacious treatment for acute attacks and suggest that its potential clinical benefit for EPP is not via ALAS inhibition.
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- 2023
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37. Nemaline myopathy: reclassification of previously reported variants according to ACMG guidelines, and report of novel genetic variants.
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Haghighi A, Alvandi Z, Nilipour Y, Haghighi A, Kornreich R, Nafissi S, and Desnick RJ
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- Humans, Mutation, Genetic Testing methods, RNA Splicing, Heterozygote, Myopathies, Nemaline diagnosis, Myopathies, Nemaline genetics, Myopathies, Nemaline pathology
- Abstract
Nemaline myopathy (NM) is a heterogeneous genetic neuromuscular disorder characterized by rod bodies in muscle fibers resulting in multiple complications due to muscle weakness. NM patients and their families could benefit from genetic analysis for early diagnosis, carrier and prenatal testing; however, clinical classification of variants is subject to change as further information becomes available. Reclassification can significantly alter the clinical management of patients and their families. We used the newly published data and ACMG/AMP guidelines to reassess NM-associated variants previously reported by clinical laboratories (ClinVar). Our analyses on rare variants that were not canonical loss-of-function (LOF) resulted in the downgrading of ~29% (28/97) of variants from pathogenic or likely-pathogenic (P/LP) to variants of uncertain significance (VUS). In addition, we analyzed the splicing effect of variants identified in NM patients by clinical laboratories or research, using an accurate in silico prediction tool that applies a deep-learning network. We identified 55 rare variants that may impact splicing (cryptic splicing). We also analyzed six new NM families and identified eight variants in NEB and ACTA1, including three novel variants: homozygous pathogenic c.164A > G (p.Tyr55Cys), and homozygous likely pathogenic c.980T > C (p.Met327Thr) in ACTA1, and heterozygous VUS c.18694-3T > G in NEB. This study demonstrates the importance of reclassifying variants to facilitate more definitive "calls" on causality or no causality in clinical genetic testing of patients with NM. Reclassification of ~150 variants is now available for improved clinical management, risk counseling and screening of NM patients., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)
- Published
- 2023
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38. Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation.
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van Loggerenberg W, Sowlati-Hashjin S, Weile J, Hamilton R, Chawla A, Sheykhkarimli D, Gebbia M, Kishore N, Frésard L, Mustajoki S, Pischik E, Di Pierro E, Barbaro M, Floderus Y, Schmitt C, Gouya L, Colavin A, Nussbaum R, Friesema ECH, Kauppinen R, To-Figueras J, Aarsand AK, Desnick RJ, Garton M, and Roth FP
- Subjects
- Humans, Mutation, Missense genetics, Amino Acid Substitution, Molecular Dynamics Simulation, Hydroxymethylbilane Synthase chemistry, Hydroxymethylbilane Synthase genetics, Hydroxymethylbilane Synthase metabolism, Porphyria, Acute Intermittent diagnosis, Porphyria, Acute Intermittent genetics
- Abstract
Defects in hydroxymethylbilane synthase (HMBS) can cause acute intermittent porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ∼⅓ of clinical HMBS variants are missense variants, and most clinically reported HMBS missense variants are designated as "variants of uncertain significance" (VUSs). Using saturation mutagenesis, en masse selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino acid substitutions. The resulting variant effect maps generally agreed with biochemical expectations and provide further evidence that HMBS can function as a monomer. Additionally, the maps implicated specific residues as having roles in active site dynamics, which was further supported by molecular dynamics simulations. Most importantly, these maps can help discriminate pathogenic from benign HMBS variants, proactively providing evidence even for yet-to-be-observed clinical missense variants., Competing Interests: Declaration of interests F.P.R. is an investor in Ranomics, Inc., and is an investor in and advisor for SeqWell, Inc., BioSymetrics, Inc., and Constantiam Biosciences, Inc., and has accepted conference travel support from Illumina, Inc. L.F., A.C., and R.N. are employed by and invested in Invitae. R.J.D. has received both a grant and royalties and has also served as a consultant for Alnylam Pharmaceuticals., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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39. Dersimelagon in Erythropoietic Protoporphyrias. Reply.
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Balwani M, Desnick RJ, and Belongie K
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- Humans, Protoporphyria, Erythropoietic diagnosis, Protoporphyria, Erythropoietic genetics
- Published
- 2023
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40. Pain in acute hepatic porphyrias: Updates on pathophysiology and management.
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Kazamel M, Pischik E, and Desnick RJ
- Abstract
Acute hepatic porphyrias (AHPs) typically present with recurrent acute attacks of severe abdominal pain and acute autonomic dysfunction. While chronic symptoms were historically overlooked in the literature, recent studies have reported increased prevalence of chronic, mainly neuropathic, pain between the attacks. Here we characterize acute and chronic pain as prominent manifestations of the AHPs and discuss their pathophysiology and updated management. In addition to the severe abdominal pain, patients could experience low back pain, limb pain, and headache during acute attacks. Chronic pain between the attacks is typically neuropathic and reported mainly by patients who undergo recurrent attacks. While the acute abdominal pain during attacks is likely mediated by autonomic neuropathy, chronic pain likely represents delayed recovery of the acute neuropathy with ongoing small fiber neuropathy in addition to peripheral and/or central sensitization. δ-aminolaevulinic acid (ALA) plays a major role in acute and chronic pain via its neurotoxic effect, especially where the blood-nerve barrier is less restrictive or absent i.e., the autonomic ganglia, nerve roots, and free nerve endings. For earlier diagnosis, we recommend testing a spot urine porphobilinogen (PBG) analysis in any patient with recurrent severe acute abdominal pain with no obvious explanation, especially if associated with neuropathic pain, hyponatremia, autonomic dysfunction, or encephalopathy. Of note, it is mandatory to exclude AHPs in any acute painful neuropathy. Between the attacks, diagnostic testing for AHPs should be considered for patients with a past medical history of acute/subacute neuropathy, frequent emergency room visits with abdominal pain, and behavioral changes. Pain during the attacks should be treated with opiates combined with hemin infusions. Symptomatic treatment of chronic pain should start with gabapentinoids and certain antidepressants before opiates. Givosiran reduces levels of ALA and PBG and likely has long-term benefits for chronic pain, especially if started early during the course of the disease., Competing Interests: Author MK received consulting fees from Alnylam Pharmaceuticals. Author EP received consulting fees from Alnylam Pharmaceuticals and Recordati Rare Diseases. Author RD is a consultant for Alnylam Pharmaceuticals and Recordati Rare Diseases. He has received grants from both entities. He receives royalties for a licensed patent to Alnylam Pharmaceuticals., (Copyright © 2022 Kazamel, Pischik and Desnick.)
- Published
- 2022
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41. A pilot study of oral iron therapy in erythropoietic protoporphyria and X-linked protoporphyria.
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Balwani M, Naik H, Overbey JR, Bonkovsky HL, Bissell DM, Wang B, Phillips JD, Desnick RJ, and Anderson KE
- Abstract
The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports. There is no systematic study to evaluate the benefits or risks of iron supplementation in these patients. We assessed the potential efficacy of oral iron therapy in decreasing erythrocyte protoporphyrin (ePPIX) levels in patients with EPP or X-linked protoporphyria (XLP) and low ferritin in an open-label, single-arm, interventional study. Sixteen patients (≥18 years) with EPP or XLP confirmed by biochemical and/or genetic testing, and serum ferritin ≤30 ng/mL were enrolled. Baseline testing included iron studies, normal hepatic function, and elevated plasma porphyrins and ePPIX levels. Oral ferrous sulfate 325 mg twice daily was administered for 12 months. The primary efficacy outcome was the relative difference in total ePPIX level between baseline and 12 months after starting treatment with iron. Secondary measures included improvement in serum ferritin, plasma porphyrins, and clinical symptoms. Thirteen patients had EPP (8 females, 5 males) and 3 had XLP (all females) and the mean age of participants was 38.8 years (SD 14.5). Ten patients completed all study visits limiting interpretation of results. In EPP patients, a transient increase in ePPIX levels was observed at 3 months in 9 of 12 (75%) patients. Iron was discontinued in 2 of these patients after meeting the protocol stopping rule of a 35% increase in ePPIX. Seven patients withdrew before study end. Ferritin levels increased on iron replacement indicating an improvement in iron status. A decrease in ePPIX was seen in both XLP patients who completed the study (relative difference of 0.67 and 0.5 respectively). No substantial changes in ePPIX were seen in EPP patients at the end of the study ( n = 8; median relative difference: -0.21 (IQR: -0.44, 0.05). The most common side effects of iron treatment were gastrointestinal symptoms. Hepatic function remained normal throughout the study. Our study showed that oral iron therapy repletes iron stores and transiently increases ePPIX in some EPP patients, perhaps due to a transient increase in erythropoiesis, and may decrease ePPIX in XLP patients. Further studies are needed to better define the role of iron repletion in EPP. Trial registration: NCT02979249., Competing Interests: The authors report no related conflicts of interest., (© 2022 Published by Elsevier Inc.)
- Published
- 2022
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42. ABCB6 polymorphisms are not overly represented in patients with porphyria.
- Author
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Farrell CP, Nicolas G, Desnick RJ, Parker CJ, Lamoril J, Gouya L, Karim Z, Tchernitchko D, Chan B, Puy H, and Phillips JD
- Subjects
- ATP-Binding Cassette Transporters, Animals, Humans, Mice, Mice, Knockout, Porphobilinogen Synthase deficiency, Porphyrias genetics, Porphyrias, Hepatic genetics, Protoporphyria, Erythropoietic genetics
- Abstract
The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
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43. Acute Hepatic Porphyrias: "Purple Flags"-Clinical Features That Should Prompt Specific Diagnostic Testing.
- Author
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Anderson KE, Desnick RJ, Stewart MF, Ventura P, and Bonkovsky HL
- Subjects
- Humans, Diagnostic Techniques and Procedures, Heme therapeutic use, Pain, Porphobilinogen Synthase deficiency, Hyponatremia drug therapy, Porphyrias, Hepatic diagnosis
- Abstract
Background: Porphyrias are a group of rare diseases leading to dysregulation in heme biosynthesis and the accumulation of heme precursors, including porphyrinogens, which in their oxidized states [porphyrins] are reddish or purple. Acute hepatic porphyrias (AHP) comprise four diseases that cause acute debilitating neurovisceral attacks. Despite diagnostic advances, AHP is often undiagnosed or misdiagnosed due to a lack of disease awareness, low clinical suspicion, variable presentation, and nonspecific symptoms that mimic more common diseases. Delays in diagnosis and treatment increase the risk of serious acute and chronic complications., Methods: In order to assess whether symptoms alone or in combination might be utilized as important indicators or "purple flags" that, when present, should alert clinicians to suspect AHP and pursue specific diagnostic testing, we conducted a comprehensive review of the literature on AHP, including cohort studies and case reports over two epochs, from 1980 to 2006 and from 2012 to 2018., Results: We found that severe abdominal pain, with or without acute central nervous system manifestations and peripheral neuropathy, continues to be the most frequent symptom. Hyponatremia, change in urine color, and certain chronic symptoms were also identified as features that should raise suspicion of AHP. To improve diagnosis of AHP, clinicians need to take a broad perspective, including demographic data and medical history, into consideration., Conclusions: The clinical features of AHP continue to be severe pain, especially pain in the abdomen. Other features that should raise suspicion are autonomic, peripheral, or central neuropathies, hyponatremia, and red-purple urine color., Competing Interests: Conflicts of Interest Karl E. Anderson: Advisory Committees or Review Panels: Alnylam Pharmaceuticals, Inc.; Consulting: Mitsubishi Tanabe Pharma America, Inc., Recordati Rare Diseases; Grant/Research Support: Alnylam Pharmaceuticals, Inc., Recordati Rare Diseases. Robert J. Desnick: Advisory Committees or Review Panels: Recordati Rare Diseases; Consulting: Alnylam Pharmaceuticals, Inc.; Grant/Research Support: Alnylam Pharmaceuticals, Inc.; Patent Held/Filed: Alnylam Pharmaceuticals, Inc. Herbert L. Bonkovsky: Advisory Committees or Review Panels: Recordati Rare Diseases, Clinuvel, Inc.; Consulting: Alnylam Pharmaceuticals, Inc, Clinuvel, Inc., Mitsubishi Tanabe Pharma America, Inc.; Grant/Research Support: Gilead Sciences, Alnylam Pharmaceuticals, Inc.; Mitsubishi Tanabe Pharmaceuticals. M. Felicity Stewart: No paid consultancies or research support from any commercial organization. Paolo Ventura: Advisory Committees or Review Panels: Orphan Europe, Alnylam Pharmaceuticals, Inc.; Consulting: Alnylam Pharmaceuticals, Inc.; Grant/Research Support: Alnylam Pharmaceuticals, Inc., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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44. ZFN-mediated in vivo gene editing in hepatocytes leads to supraphysiologic α-Gal A activity and effective substrate reduction in Fabry mice.
- Author
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Pagant S, Huston MW, Moreira L, Gan L, St Martin S, Sproul S, Holmes MC, Meyer K, Wechsler T, Desnick RJ, and Yasuda M
- Subjects
- Animals, Dependovirus genetics, Disease Models, Animal, Enzyme Activation, Gene Expression, Gene Transfer Techniques, Genetic Engineering, Genetic Therapy, Genetic Vectors genetics, Humans, Mice, Transgenes, Fabry Disease genetics, Fabry Disease therapy, Gene Editing, Hepatocytes metabolism, Zinc Finger Nucleases metabolism, alpha-Galactosidase genetics, alpha-Galactosidase metabolism
- Abstract
Fabry disease, a lysosomal storage disorder resulting from the deficient activity of α-galactosidase A (α-Gal A), is characterized by cardiac, renal, and/or cerebrovascular disease due to progressive accumulation of the enzyme's substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). We report here the preclinical evaluation of liver-targeted in vivo genome editing using zinc-finger nuclease (ZFN) technology to insert the human α-galactosidase A (hGLA) cDNA into the albumin "safe harbor" locus of Fabry mice, thereby generating an albumin-α-Gal A fusion protein. The mature α-Gal A protein is secreted into the circulation for subsequent mannose-6-phosphate receptor-mediated tissue uptake. Donor vector optimization studies showed that replacing the hGLA cDNA signal peptide sequence with that of human iduronate 2-sulfatase (IDS) achieved higher transgene expression. Intravenous adeno-associated virus (AAV) 2/8-mediated co-delivery of the IDS-hGLA donor and ZFNs targeting the albumin locus resulted in continuous, supraphysiological plasma and tissue α-Gal A activities, which essentially normalized Gb3 and Lyso-Gb3 levels in key tissues of pathology. Notably, this was achieved with <10% of hepatocytes being edited to express hGLA, occurring mostly via non-homologous end joining (NHEJ) rather than homology-directed repair (HDR). These studies indicate that ZFN-mediated in vivo genome editing has the potential to be an effective one-time therapy for Fabry disease., Competing Interests: Declaration of interests R.J.D. is a consultant to Genzyme-Sanofi and Sangamo Therapeutics, Inc. He owns founder stock in Amicus Therapeutics and options for Sangamo Therapeutics, Inc. and receives royalties from Genzyme-Sanofi. R.J.D. and M.Y. received a research grant from Sangamo Therapeutics, Inc. to perform these studies. M.W.H., S.S.M., S.S., K.M., M.C.H., and T.W. are full-time employees and/or shareholders of Sangamo Therapeutics, Inc., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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45. Erythropoietic protoporphyria: time to prodrome, the warning signal to exit sun exposure without pain-a patient-reported outcome efficacy measure.
- Author
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Wensink D, Langendonk JG, Overbey JR, Balwani M, Van Broekhoven EJE, Wagenmakers MAEM, Wilson JHP, Wheeden K, Naik H, and Desnick RJ
- Subjects
- Humans, Pain, Patient Reported Outcome Measures, Retrospective Studies, Protoporphyria, Erythropoietic diagnosis, Protoporphyria, Erythropoietic drug therapy, Sunlight adverse effects
- Abstract
Purpose: Patients with erythropoietic protoporphyria (EPP), a severe painful photodermatosis, experience prodromal sensations when exposed to sunlight, which are the "warning signals" to exit the sun, as prolonged exposure causes an excruciatingly painful phototoxic attack. The unique prodromal cutaneous sensations are reversible and differ from the severe burning pain attack lasting 2-7 days. Previously, afamelanotide treatment was studied using time to pain or time outside as primary outcome measures. Since patients have an ingrained fear of sunlight, these measures did not capture the full treatment effect. We retrospectively characterized and evaluated time to prodrome (TTP) as a safer, patient-reported outcome (PRO) measure in afamelanotide-treated patients., Methods: Structured interviews recorded TTP before and during afamelanotide treatment in retrospective US and Dutch cohort studies., Results: Thirty-one US and 58 Dutch EPP patients participated. Before afamelanotide treatment, 54.8% US and 39.7% Dutch patients reported TTP onset <10 minutes in direct sunlight. In both studies, patients' TTP's were significantly longer during afamelanotide treatment (p < 0.0001). All US patients' TTP increased; no TTP was <10 minutes. Among Dutch patients 81% improved; only 10.3% reported TTPs < 10 minutes., Conclusion: EPP patients reported substantial improvements in TTP during afamelanotide treatment. TTP could provide a safer, PRO-based efficacy endpoint for assessing future EPP treatments., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
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- 2021
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46. Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium.
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Saberi B, Naik H, Overbey JR, Erwin AL, Anderson KE, Bissell DM, Bonkovsky HL, Phillips JD, Wang B, K Singal A, M McGuire B, Desnick RJ, and Balwani M
- Subjects
- Adult, Age Factors, Aged, Carcinoma, Hepatocellular epidemiology, Carcinoma, Hepatocellular pathology, Cross-Sectional Studies, Female, Humans, Liver Neoplasms epidemiology, Liver Neoplasms pathology, Longitudinal Studies, Middle Aged, Porphyrias, Hepatic epidemiology, Porphyrias, Hepatic pathology, United States epidemiology, Young Adult, Carcinoma, Hepatocellular etiology, Liver Neoplasms etiology, Porphyrias, Hepatic complications
- Abstract
Background and Aims: The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States., Approach and Results: This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27 years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69 years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10 ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26 months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153 months., Conclusion: In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation., (© 2020 by the American Association for the Study of Liver Diseases.)
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- 2021
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47. Expression Profiling Identifies TWIST2 Target Genes in Setleis Syndrome Patient Fibroblast and Lymphoblast Cells.
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Crespo NE, Torres-Bracero A, Renta JY, Desnick RJ, and Cadilla CL
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- Ectodermal Dysplasia, Fibroblasts, Focal Facial Dermal Dysplasias, Gene Expression Profiling, Humans, Repressor Proteins genetics, Twist-Related Protein 1 genetics
- Abstract
Background : Setleis syndrome (SS) is a focal facial dermal dysplasia presenting with bilateral temporal skin lesions, eyelash abnormalities and absent meibomian glands. SS is a rare autosomal recessive disorder caused by mutations in the TWIST2 gene, which codes for a transcription factor of the bHLH family known to be involved in skin and facial development. Methods : We obtained gene expression profiles by microarray analyses from control and SS patient primary skin fibroblast and lymphoblastoid cell lines. Results : Out of 983 differentially regulated genes in fibroblasts (fold change ≥ 2.0), 479 were down-regulated and 509 were up-regulated, while in lymphoblasts, 1248 genes were down-regulated and 73 up-regulated. RT-PCR reactions confirmed altered expression of selected genes. Conclusions : TWIST2 is described as a repressor, but expression profiling suggests an important role in gene activation as well, as evidenced by the number of genes that are down-regulated, with a much higher proportion of down-regulated genes found in lymphoblastoid cells from an SS patient. As expected, both types of cell types showed dysregulation of cytokine genes. These results identify potential TWIST2 target genes in two important cell types relevant to rare disorders caused by mutations in this bHLH gene.
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- 2021
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48. Correction to: Porphyric Neuropathy: Pathophysiology, Diagnosis, and Updated Management.
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Kazamel M, Desnick RJ, and Quigley JG
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- 2020
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49. 5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin.
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Lahiji AP, Anderson KE, Chan A, Simon A, Desnick RJ, and Ramanujam VMS
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- 5-Aminolevulinate Synthetase blood, Adolescent, Adult, Child, Child, Preschool, Female, Heme genetics, Hemin administration & dosage, Humans, Infant, Infant, Newborn, Liver metabolism, Liver pathology, Male, Middle Aged, Mutation genetics, Porphobilinogen metabolism, Porphobilinogen Synthase blood, Porphyria, Acute Intermittent blood, Porphyria, Acute Intermittent drug therapy, Porphyria, Acute Intermittent pathology, Porphyrias, Hepatic blood, Porphyrias, Hepatic drug therapy, Porphyrias, Hepatic pathology, RNA, Messenger blood, Young Adult, 5-Aminolevulinate Synthetase genetics, Porphobilinogen Synthase deficiency, Porphobilinogen Synthase genetics, Porphyria, Acute Intermittent genetics, Porphyrias, Hepatic genetics
- Abstract
Background: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is an ultrarare autosomal recessive disease, with only eight documented cases, all of whom were males. Although classified as an acute hepatic porphyria (AHP), induction of the rate limiting hepatic enzyme 5-aminolevulinic acid synthase-1 (ALAS1) has not been demonstrated, and the marrow may also contribute excess 5-aminolevulinic acid (ALA). Two patients have died and reported follow up for the others is limited, so the natural history of this disease is poorly understood and treatment experience limited., Methods: We report new molecular findings and update the clinical course and treatment of the sixth reported ADP patient, now 31 years old and the only known case in the Americas, and review published data regarding genotype-phenotype correlation and treatment., Results: Circulating hepatic 5-aminolevulinic acid synthase-1 (ALAS1) mRNA was elevated in this case, as in other AHPs. Gain of function mutation of erythroid specific ALAS2 - an X-linked modifying gene in some other porphyrias - was not found. Seven reported ADP cases had compound heterozygous ALAD mutations resulting in very low residual ALAD activity and symptoms early in life or adolescence. One adult with a germline ALAD mutant allele developed ADP in association with a clonal myeloproliferative disorder, polycythemia vera., Conclusions: Elevation in circulating hepatic ALAS1 and response to treatment with hemin indicate that the liver is an important source of excess ALA in ADP, although the marrow may also contribute. Intravenous hemin was effective in most reported cases for treatment and prevention of acute attacks of neurological symptoms., Competing Interests: Declaration of Competing Interest AP Lahiji and VM Sadagopa Ramanujam declare no conflicts. A Chan and A Simon are employees of Alnylam Pharmaceuticals. KE Anderson and RJ Desnick consult for Alnylam Pharmaceuticals, Recordati Rare Diseases and Mitsubishi Tanabe Pharma America. All authors had access to the data and a role in writing the manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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50. Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE.
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Seo GH, Kim T, Choi IH, Park JY, Lee J, Kim S, Won DG, Oh A, Lee Y, Choi J, Lee H, Kang HG, Cho HY, Cho MH, Kim YJ, Yoon YH, Eun BL, Desnick RJ, Keum C, and Lee BH
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- Adolescent, Adult, Aged, Child, Child, Preschool, Databases, Genetic, Exome genetics, Female, Genetic Diseases, Inborn classification, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn pathology, Genetic Variation genetics, Humans, Infant, Infant, Newborn, Male, Middle Aged, Phenotype, Young Adult, Automation standards, Computational Biology, Genetic Diseases, Inborn genetics, Exome Sequencing
- Abstract
EVIDENCE, an automated variant prioritization system, has been developed to facilitate whole exome sequencing analyses. This study investigated the diagnostic yield of EVIDENCE in patients with suspected genetic disorders. DNA from 330 probands (age range, 0-68 years) with suspected genetic disorders were subjected to whole exome sequencing. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments. EVIDENCE reported a total 228 variants in 200 (60.6%) of the 330 probands. The average number of organs involved per patient was 4.5 ± 5.0. After clinical reassessment and/or family member testing, 167 variants were identified in 141 probands (42.7%), including 105 novel variants. These variants were confirmed as being responsible for 121 genetic disorders. A total of 103 (61.7%) of the 167 variants in 95 patients were classified as pathogenic or probably to be pathogenic before, and 161 (96.4%) variants in 137 patients (41.5%) after, clinical assessment and/or family member testing. Factor associated with a variant being regarded as causative includes similar symptom scores of a gene variant to the phenotype of the patient. This new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 42.7% diagnostic yield., (© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
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- 2020
- Full Text
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