Publications

Professor of Neurology, of Pediatrics (Genetics) and, by Courtesy, of Pathology at the Stanford University Medical Center

Publications

  • RESTORE: A Prospective Multinational Registry of Patients with Genetically Confirmed Spinal Muscular Atrophy - Rationale and Study Design. Journal of neuromuscular diseases Finkel, R. S., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Desguerre, I., Quijano-Roy, S., Saito, K., Droege, M., Dabbous, O., Khan, F., Renault, L., Anderson, F. A., Servais, L. 2020

    Abstract

    BACKGROUND: Dramatic improvements in spinal muscular atrophy (SMA) treatment have changed the prognosis for patients with this disease, leading to important new questions. Gathering representative, real-world data about the long-term efficacy and safety of emerging SMA interventions is essential to document their impact on patients and caregivers.OBJECTIVES: This registry will assess outcomes in patients with genetically confirmed SMA and provide information on the effectiveness and long-term safety of approved and emerging treatments.DESIGN AND METHODS: RESTORE is a prospective, multicenter, multinational observational registry. Patients will be managed according to usual clinical practice. Both newly recruitedSMAtreatment centers and sites involved in existing SMA registries, including iSMAC, Treat-NMD, French SMA Assistance Publique- Hopitaux de Paris (AP-HP), Cure-SMA, SMArtCARE, will be eligible to participate; de novo; sites already participating in another registry may be included via consortium agreements. Data from patients enrolled in partnering registries will be shared with the RESTORE Registry and data for newly diagnosed patients will be added upon enrollment. Patients will be enrolled over a 5-year period and followed for 15 years or until death. Assessments will include SMA history and treatment, pulmonary, nutritional, and motor milestones, healthcare resource utilization, work productivity, activity impairment, adverse events, quality of life, caregiver burden, and survival.Status:Recruitment started in September 2018. As of January 3, 2020, 64 patients were enrolled at 25 participating sites.CONCLUSIONS: The RESTORE Registry has begun recruiting recently diagnosed patients with genetically confirmed SMA, enabling assessment of both short- and long-term patient outcomes.

    View details for DOI 10.3233/JND-190451

    View details for PubMedID 32039859

  • Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2. Journal of neuromuscular diseases Glascock, J., Sampson, J., Connolly, A. M., Darras, B. T., Day, J. W., Finkel, R., Howell, R. R., Klinger, K. W., Kuntz, N., Prior, T., Shieh, P. B., Crawford, T. O., Kerr, D., Jarecki, J. 2020

    View details for DOI 10.3233/JND-190468

    View details for PubMedID 32007960

  • A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores. Neurology Fridman, V., Sillau, S., Acsadi, G., Bacon, C., Dooley, K., Burns, J., Day, J., Feely, S., Finkel, R. S., Grider, T., Gutmann, L., Herrmann, D. N., Kirk, C. A., Knause, S. A., Laurá, M., Lewis, R. A., Li, J., Lloyd, T. E., Moroni, I., Muntoni, F., Pagliano, E., Pisciotta, C., Piscosquito, G., Ramchandren, S., Saporta, M., Sadjadi, R., Shy, R. R., Siskind, C. E., Sumner, C. J., Walk, D., Wilcox, J., Yum, S. W., Züchner, S., Scherer, S. S., Pareyson, D., Reilly, M. M., Shy, M. E. 2020

    Abstract

    To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A).Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models.Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9).The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A.NCT01193075.

    View details for DOI 10.1212/WNL.0000000000009035

    View details for PubMedID 32047073

  • AVXS-101 PHASE 3 STUDY IN SPINAL MUSCULAR ATROPHY TYPE 1 Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Kausar, I., Feltner, D. E., Ogrinc, F. G., Ouyang, H., Macek, T. A., Kernbauer, E., Muehring, L. M., L'Italien, J., Sproule, D. M., Kaspar, B. K., Mendell, J. R. BMJ PUBLISHING GROUP. 2019: E69
  • Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease GENETICS IN MEDICINE Kishnani, P. S., Gibson, J. B., Gambello, M. J., Hillman, R., Stockton, D. W., Kronn, D., Leslie, N. D., Pena, L. M., Tanpaiboon, P., Day, J. W., Wang, R. Y., Goldstein, J. L., Haack, K., Sparks, S. E., Zhao, Y., Hahn, S., Pompe ADVANCE Study Consortium 2019; 21 (11): 2543–51
  • Adeno-associated virus serotype 9 (AAV9) antibodies in patients with spinal muscular atrophy (SMA) screened for treatment with onasemnogene abeparvovec Day, J. W., Finkel, R. S., Mercuri, E., Swoboda, K. J., Meriggioli, M., Kernbauer, E., Ogrinc, F. G., Menier, M., Sproule, D. M., Feltner, D. E., Mendell, J. R. MARY ANN LIEBERT, INC. 2019: A96
  • Intrathecal administration of AVXS-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 2 (SMA2): Phase 1/2A study (strong) Finkel, R. S., Day, J. W., Darras, B. T., Kuntz, N. L., Connolly, A. M., Crawford, T. O., Butterfield, R. J., Shieh, P. B., Tennekoon, G., Iannaccone, S. T., Meriggioli, M., Ogrinc, F. G., Kavanagh, S., Kernbauer, E., Whittle, J., L'Italien, J., Kaspar, B., Sproule, D. M., Spector, S. A., Feltner, D. E., Mendell, J. R. ELSEVIER. 2019
  • Onasemnogene abeparvovec gene-replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): Global pivotal phase 3 study program (STR1VE-US, STR1VE-EU, STR1VE-AP) Mercuri, E., Baranello, G., Day, J. W., Bruno, C., Corti, S., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Masson, R., Pena, L. M., Baldinetti, F., Schultz, M., Shieh, P. B., Smith, E. C., Saito, K., Scoto, M., Spector, S. A., Truncated, A., Sproule, D. M., Mendell, J. R., Muntoni, F. ELSEVIER. 2019
  • The restore registry: A resource for measuring and improving spinal muscular atrophy outcomes Servais, L., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Droege, M., Dabbous, O., Khan, F., Anderson, F. A., Finkel, R. S. ELSEVIER. 2019
  • The revised Hammersmith scale (RHS) for spinal muscular atrophy: longitudinal trajectories in a large international cohort of patients with type 2 and 3 SMA Ramsey, D., Scoto, M., Mayhew, A., Lofra, R., Main, M., Milev, E., Mazzone, E., Montes, J., Glanzman, A., Pasternak, A., Duong, T., Civitello, M., Coratti, G., Straub, V., Day, J., Darras, B., De Vivo, D., Finkel, R., Mercuri, E., Muntoni, F. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S131
  • Onasemnogene Abeparvovec Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 1 (SMA1): Pivotal Phase 3 Study (STR1VE) Update Day, J., Chiriboga, C., Crawford, T., Darras, B., Finkel, R., Connolly, A., Iannaccone, S., Kuntz, N., Pena, L., Schultz, M., Shieh, P., Smith, E., Feltner, D., Ogrinc, F., Shah, A., Ouyang, H., Macek, T., Kernbauer, E., L'Italien, J., Sproule, D., Kaspar, B., Mendell, J. WILEY. 2019: S118–S121
  • Adeno-Associated Virus Serotype 9 (AAV9) Antibodies in Patients With Spinal Muscular Atrophy (SMA) Screened for Treatment With Gene-Replacement Therapy (GRT) Onasemnogene Abeparvovec Day, J., Finkel, R., Mercuri, E., Swoboda, K., Kernbauer, E., Ogrinc, F., Menier, M., Sproule, D., Feltner, D., Mendell, J. WILEY. 2019: S121
  • The clinical outcome study for dysferlinopathy: pregnancy in dysferlinopathy Moore, U., James, M., Jacobs, M., Mayhew, A., Spuler, S., Day, J., Bharucha-Goebel, D., Stojkovic, T., Mendell, J., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S104
  • RAINBOWFISH: A study of risdiplam (RG7916) in newborns with pre-symptomatic spinal muscular atrophy (SMA) Bertini, E., Day, J., Muhaizea, M., Xiong, H., Servais, L., Prufer, A., Tichy, M., Yeung, W., Gorni, K. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S187
  • A clinical outcome study for dysferlinopathy: biobanking samples collected through a collaborative international multisite study Hilsden, H., Moore, U., Cox, D., Day, J., Jones, K., Bharucha-Goebel, D., Pestronk, A., Walter, M., Stojkovic, T., Bravver, E., Mendell, J., Rufibach, L., Paradas, C., Diaz-Manera, J., Pegoraro, E., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S98
  • Measuring what matters in dysferlinopathy - linking functional ability to patient reported outcome measures Mayhew, A., James, M., Hilsden, H., Sutherland, H., Jacobs, M., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz Manera, J., Pegoraro, E., Mendell, J., Rufibach, L., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S100
  • Intrathecal administration of onasemnogene abeparvovec gene-replacement therapy (GRT) for spinal muscular atrophy type 2 (SMA2): phase 1/2a study (STRONG) Finkel, R., Day, J., Darras, B., Kuntz, N., Connolly, A., Crawford, T., Butterfield, R., Shieh, P., Tennekoon, G., Iannaccone, S., Ogrinc, F., Kavanagh, S., Kernbauer, E., Whittle, J., L'Italien, J., Kaspar, B., Sproule, D., Spector, S., Feltner, D., Mendell, J. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S207
  • JEWELFISH: safety and pharmacodynamic data in patients with spinal muscular atrophy (SMA) receiving treatment with risdiplam (RG7916) that have previously been treated with nusinersen Chiriboga, C., Mercuri, E., Fischer, D., Day, J., Kraus, D., Yeung, W., Kletzl, H., Gerber, M., Cleary, Y., Gorni, K. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S187
  • Functional progression in dysferlinopathy: results of a 3-year natural history study Jacobs, M., James, M., Mayhew, A., Hilsden, H., Sutherland, H., Spuler, S., Day, J., Jones, K., Bharucha-Goebel, D., Salort-Campana, E., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz Manera, J., Pegoraro, E., Mendell, J., Rufibach, L., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S102
  • Onasemnogene abeparvovec gene-replacement therapy (GRT) for spinal muscular atrophy Type 1 (SMA1): Pivotal phase 3 study (STR1VE) update Day, J., Chiriboga, C., Crawford, T., Darras, B., Finkel, R., Connolly, A., Iannaccone, S., Kuntz, N., Pena, L., Schultz, M., Shieh, P., Smith, E., Feltner, D., Ogrinc, F., Ouyang, H., Macek, T., Kernbauer, E., Sproule, D., Mendell, J. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S183
  • FIREFISH Part 1: 16-month safety and exploratory outcomes of risdiplam (RG7916) treatment in infants with type 1 spinal muscular atrophy Baranello, G., Servais, L., Day, J., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y., El-Khairi, M., Seabrook, T., Czech, C., Gerber, M., Nguyen, C., Gelblin, K., Gorni, K. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S184
  • The RESTORE registry: a resource for measuring and improving spinal muscular atrophy (SMA) outcomes Servais, L., Day, J., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P., Tizzano, E., Droege, M., Dabbous, O., Khan, F., Anderson, F., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S195
  • Trajectories of disease progression in ambulant and non ambulant SMA: 12 month follow-up Mercuri, E., Coratti, G., Pera, M., Scoto, M., Goemans, N., Pane, M., D'amico, A., Sansone, V., Messina, S., Nascimiento, A., Bertini, E., Finkel, R., Darras, B., De Vivo, D., Day, J., Muntoni, F. PERGAMON-ELSEVIER SCIENCE LTD. 2019: S131
  • Long-term Outcomes After Low Power, Slower Movement versus High Power, Faster Movement Irrigated-Tip Catheter Ablation for Atrial Fibrillation. Heart rhythm Bunch, T. J., May, H. T., Bair, T. L., Crandall, B. G., Cutler, M. J., Mallender, C., Weiss, J. P., Osborn, J. S., Day, J. D. 2019

    Abstract

    BACKGROUND: High power, shorter duration (HPSD) ablation strategies have been advocated to increase efficacy and minimize posterior wall deep tissue thermal injury during atrial fibrillation (AF) ablation.OBJECTIVE: Determine the long-term outcomes of arrhythmia free-survival from AF and atrial flutter (AFL) between HPSD and low power, longer duration (LPLD) ablation strategies.METHODS: Of a total of 1,333 first time AF ablation with 3 years of follow up, propensity-matched populations for baseline risk factors were created comprising of 402 patients treated with low power LPLD (30 W for 5 seconds: posterior wall, 30 W for 10-20 seconds: anterior wall) and 402 patients treated with HPSD (50 W for 2-3 seconds: posterior wall and 50 W for 5-15 seconds: anterior wall). AF/AFL outcomes after a 90-day blacking period were assessed.RESULTS: HPSD ablation was associated with shorter procedures and fluoroscopy times (p<0.0001 for both). Recurrence of AF at 1 (12.9% vs 16.2%, p=0.19) and 3 years (26.5% vs 30.7%, p=0.23) was similar between LPLD and HPSD, respectively. AFL was higher at 1 (7.2% vs 11.2%, p=0.03) and 3 years (16.1% vs 21.8%, p=0.06, p=0.04 after multivariate adjustment) with HPSD ablation. Patients with a LPLD approach had lower rates of need for a repeat ablation (21% vs 30%, p=0.002).CONCLUSIONS: Long-term freedom from AF rates were not significantly different between both approaches. A HPSD ablation strategy compared to a LPLD approach was associated with an increased risk of AFL and need for repeat ablation, but lowered procedure times.

    View details for DOI 10.1016/j.hrthm.2019.08.001

    View details for PubMedID 31398477

  • Nusinersen experience in teenagers and young adults with spinal muscular atrophy (SMA): Results from CS2/CS12 and SHINE Deconinck, N., Darras, B. T., Day, J. W., Chiriboga, C. A., Iannaccone, S. T., Swoboda, K. J., Finkel, R. S., Tulinius, M., Saito, K., Montes, J., Mignon, L., Sun, P., Bhan, I., Gheuens, S., Bevernage, S. P., Farwell, W., De Vivo, D. C. WILEY. 2019: 143–44
  • Avxs-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): pivotal phase 3 study (STR1VE) update Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Farrar, M., Feltner, D. E., Ogrinc, F. G., Macek, T. A., Kernbauer, E., Muehring, L. M., L'Italien, J., Sproule, D. M., Kaspar, B. K., Mendell, J. R. BMJ PUBLISHING GROUP. 2019
  • FIREFISH Part 1: survival, ventilation and swallowing ability in infants with type 1 spinal muscular atrophy (SMA) treated with risdiplam (RG7916) Vlodavets, D., Servais, L., Baranello, G., Day, J. W., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y., El-Khairi, M., Seabrook, T., Czech, C., Gerber, M., Nguyen, C., Gelblin, K., Gorni, K., Khwaja, O. WILEY. 2019: 310–11
  • The RESTORE Registry: a resource for measuring and improving Spinal Muscular Atrophy (SMA) outcomes Servais, L., Day, J. W., De Vivo, D. C., Kirschner, J., Mercuri, E., Muntoni, F., Shieh, P. B., Tizzano, E., Droege, M., Dabbous, O., Khan, F., Anderson, F. A., Finkel, R. S. WILEY. 2019: 437
  • RAINBOWFISH: a study of risdiplam (RG7916) in infants with pre-symptomatic spinal muscular atrophy (SMA) Bertini, E., Day, J. W., Al Muhaizea, M., Xiong, H., Servais, L., Prufer, A., Buchbjerg, J., Yeung, W. Y., Gorni, K., Khwaja, O. WILEY. 2019: 445
  • AVXS-101 gene replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): pivotal studies clinical update (STR1VE-EU and STR1VE) Mercuri, E., Baranello, G., Day, J. W., Bruno, C., Corti, S., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Masson, R., Pena, L. D., Schultz, M., Shieh, P. B., Smith, E. C., Feltner, D. E., Ouyang, H., Lavrov, A., Truncated, A., L'italien, J., Sproule, D. M., Mendell, J. R., Muntoni, F. WILEY. 2019: 224–25
  • Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy. Journal of pharmacokinetics and pharmacodynamics Conrado, D. J., Larkindale, J., Berg, A., Hill, M., Burton, J., Abrams, K. R., Abresch, R. T., Bronson, A., Chapman, D., Crowther, M., Duong, T., Gordish-Dressman, H., Harnisch, L., Henricson, E., Kim, S., McDonald, C. M., Schmidt, S., Vong, C., Wang, X., Wong, B. L., Yong, F., Romero, K., Duchenne Muscular Dystrophy Regulatory Science Consortium (D-RSC), Vishwanathan, V., Chidambaranathan, S., Douglas Biggar, W., McAdam, L. C., Mah, J. K., Tulinius, M., Cnaan, A., Morgenroth, L. P., Leshner, R., Tesi-Rocha, C., Thangarajh, M., Duong, T., Kornberg, A., Ryan, M., Nevo, Y., Dubrovsky, A., Clemens, P. R., Abdel-Hamid, H., Connolly, A. M., Pestronk, A., Teasley, J., Bertorini, T. E., Webster, R., Kolski, H., Kuntz, N., Driscoll, S., Bodensteiner, J. B., Gorni, K., Lotze, T., Day, J. W., Karachunski, P., Henricson, E. K., Abresch, R. T., Joyce, N. C., McDonald, C. M., McDonald, C. M., Campbell, C., Torricelli, R. E., Finkel, R. S., Flanigan, K. M., Goemans, N., Heydemann, P., Kaminska, A., Kirschner, J., Muntoni, F., Osorio, A. N., Schara, U., Sejersen, T., Shieh, P. B., Sweeney, H. L., Topaloglu, H., Tulinius, M., Vilchez, J. J., Voit, T., Wong, B., Alfano, L. N., Eagle, M., James, M. K., Lowes, L., Mayhew, A., Mazzone, E. S., Nelson, L., Rose, K. J., Abdel-Hamid, H. Z., Apkon, S. D., Barohn, R. J., Bertini, E., Bloetzer, C., deVaud, L. C., Butterfield, R. J., Chabrol, B., Chae, J. H., Jongno-Gu, D. R., Comi, G. P., Darras, B. T., Dastgir, J., Desguerre, I., Escobar, R. G., Finanger, E., Guglieri, M., Hughes, I., Iannaccone, S. T., Jones, K. J., Karachunski, P., Kudr, M., Lotze, T., Mah, J. K., Mathews, K., Nevo, Y., Parsons, J., Pereon, Y., de Queiroz Campos Araujo, A. P., Renfroe, J. B., de Resende, M. B., Ryan, M., Selby, K., Tennekoon, G., Vita, G., Abdel-Hamid, H., Apkon, S., Barohn, R., Belousova, E., Bertini, E., Brandsema, J., Bruno, C., Burnette, W., Butterfield, R., Byrne, B., Campbell, C., Carlo, J., Chae, J. H., Chandratre, S., Comi, G., Connolly, A., De Groot I, I., Deconinck, N., Dooley, J., Dubrovsky, A., Durigneux, J., Finanger, E., Finkel, R., Frank, L. M., Goemans, N., Harper, A., Hattori, A., Herguner, O., Iannaccone, S., Janas, J., Jong, Y. J., Kirschner, J., Komaki, H., Kuntz, N., Lee, W. T., Leung, E., Mah, J., Mathews, K., McDonald, C. M., Mercuri, E., McMillan, H., Mueller-Felber, W., de Munain A, L., Nakamura, A., Niks, E., Ogata, K., Pascual, S., Pegoraro, E., Pereon, Y., Renfroe, B., Sanka, R. B., Schallner, J., Schara, U., Selby, K., Sendra, I. I., Servais, L., Smith, E., Sparks, S., Topaloglu, H., Victor, R., Vilchez, J. J., Wicklund, M., Wilichoswki, E., Wong, B., Abresch, R. T., Carter, G. T., Henricson, E., McDonald, C. M. 2019

    Abstract

    Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

    View details for DOI 10.1007/s10928-019-09642-7

    View details for PubMedID 31127458

  • Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease. Genetics in medicine : official journal of the American College of Medical Genetics Kishnani, P. S., Gibson, J. B., Gambello, M. J., Hillman, R., Stockton, D. W., Kronn, D., Leslie, N. D., Pena, L. D., Tanpaiboon, P., Day, J. W., Wang, R. Y., Goldstein, J. L., An Haack, K., Sparks, S. E., Zhao, Y., Hahn, S. H., Pompe ADVANCE Study Consortium 2019

    Abstract

    PURPOSE: To characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date.METHODS: Patients aged ≥1 year with confirmed Pompe disease previously receiving 160L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments.RESULTS: Of 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n=23), c.-32-13T>G (n=13), and c.525delT (n=12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean±SD, median, range): overall 46.3±33.0% (47.9%, 0.0-100.0%), IOPD 41.6±31.64% (38.9%, 0.0-99.7%), LOPD: 61.8±33.2 (70.9%, 0.0-100.0%).CONCLUSION: ADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.

    View details for PubMedID 31086307

  • Transcriptome alterations in myotonic dystrophy skeletal muscle and heart HUMAN MOLECULAR GENETICS Wang, E. T., Treacy, D., Eichinger, K., Struck, A., Estabrook, J., Olafson, H., Wang, T. T., Bhatt, K., Westbrook, T., Sedehizadeh, S., Ward, A., Day, J., Brook, D., Berglund, J., Cooper, T., Housman, D., Thornton, C., Burge, C. 2019; 28 (8): 1312–21

    View details for DOI 10.1093/hmg/ddy432

    View details for Web of Science ID 000467482600007

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy Day, J., Wolford, C., MacPherson, C., Martens, W., McDermott, M., Darras, B., De Vivo, D., Cunningham, Z., Finkel, R., Zeineh, M., Sampson, J., Hagerman, K., Duong, T. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Phase 1 Study of Intrathecal Administration of AVXS-101 Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 2 (SMA2) (STRONG) Finkel, R. S., Day, J. W., Darras, B. T., Kuntz, N. L., Connolly, A. M., Crawford, T., Butterfield, R. J., Shieh, P. B., Tennekoon, G., Iannaccone, S. T., Meriggioli, M., Spector, S. A., Ogrinc, F. G., L'Italien, J., Wells, C., Kaspar, B., Sproule, D. M., Feltner, D. E., Mendell, J. R. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy Through Newborn Screening Glascock, J., Sampson, J., Haidet-Phillips, A., Connolly, A., Darras, B., Day, J., Finkel, R., Howell, R., Klinger, K., Kuntz, N., Prior, T., Shieh, P., Crawford, T., Kerr, D., Jarecki, J. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • AVXS-101 Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 1 (SMA1): Pivotal Phase 3 Study (STR1VE) Update Day, J. W., Chiriboga, C. A., Crawford, T. O., Darras, B. T., Finkel, R. S., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Feltner, D. E., Ogrinc, F. G., Macek, T. A., Wells, C., Muehring, L. M., L'Italien, J., Sproule, D. M., Kaspar, B. K., Mendell, J. R. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • FIREFISH Part 1: Survival, Ventilation and Swallowing Ability in Infants with Type 1 SMA Receiving Risdiplam (RG7916) Servais, L., Baranello, G., Day, J. W., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y., El-Khairi, M., Seabrook, T., Czech, C., Gerber, M., Nguyen, C., Gelblin, K., Gorni, K., Khwaja, O. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • FIREFISH Part 1: 1-Year Results on Motor Function in Babies with Type 1 SMA Baranello, G., Servais, L., Day, J. W., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y., El-Khairi, M., Seabrook, T., Czech, C., Gerber, M., Nguyen, C., Gelblin, K., Gorni, K., Khwaja, O. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study. Journal of neuromuscular diseases Tao, F., Beecham, G. W., Rebelo, A. P., Blanton, S. H., Moran, J. J., Lopez-Anido, C., Svaren, J., Abreu, L., Rizzo, D., Kirk, C. A., Wu, X., Feely, S., Verhamme, C., Saporta, M. A., Herrmann, D. N., Day, J. W., Sumner, C. J., Lloyd, T. E., Li, J., Yum, S. W., Taroni, F., Baas, F., Choi, B., Pareyson, D., Scherer, S. S., Reilly, M. M., Shy, M. E., Zuchner, S., Inherited Neuropathy Consortium 2019

    Abstract

    BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.OBJECTIVE: We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.METHODS: We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study.RESULTS: The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91*10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08*10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63*10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14*10-7, beta = 3.014).CONCLUSIONS: While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.

    View details for PubMedID 30958311

  • Revised upper limb module for spinal muscular atrophy: 12 month changes MUSCLE & NERVE Pera, M., Coratti, G., Mazzone, E. S., Montes, J., Scoto, M., De Sanctis, R., Main, M., Mayhew, A., Lofra, R., Young, S., Glanzman, A. M., Duong, T., Pasternak, A., Ramsey, D., Darras, B., Day, J. W., Finkel, R. S., De Vivo, D. C., Sormani, M., Bovis, F., Straub, V., Muntoni, F., Pane, M., Mercuri, E., Bettolo, C., Civitiello, M., Mirek, E., Salazar, R., Forcina, N., Norcia, G., Carnicella, S., Antonaci, L., ISMAC Consortium Grp 2019; 59 (4): 426–30

    View details for DOI 10.1002/mus.26419

    View details for Web of Science ID 000461232700011

  • Variation in SIPA1L2 is correlated with phenotype modification in Charcot- Marie- Tooth disease type 1A ANNALS OF NEUROLOGY Tao, F., Beecham, G. W., Rebelo, A. P., Svaren, J., Blanton, S. H., Moran, J. J., Lopez-Anido, C., Morrow, J. M., Abreu, L., Rizzo, D., Kirk, C. A., Wu, X., Feely, S., Verhamme, C., Saporta, M. A., Herrmann, D. N., Day, J. W., Sumner, C. J., Lloyd, T. E., Li, J., Yum, S. W., Taroni, F., Baas, F., Choi, B., Pareyson, D., Scherer, S. S., Reilly, M. M., Shy, M. E., Zuechner, S., Lewis, R., Acsadi, G., Finkel, R., Fridman, V., Ramchandren, S., Walk, D., Logigian, E., Stanton, M., Eichinger, K., Guntrum, D., Gibson, C., Burns, J., Moroni, I., Pisciotta, C., Laura, M., Muntoni, F., Sowden, J. E., Mountain, J., Bai, Y., Bacon, C., Gutmann, L., Grider, T., Phetteplace, J., Seyedsadjadi, R., Houlden, H., Cortese, A., Pandraud, A., Calabrese, D., Saveri, P., Richardson, J., Dankwa, L., Lee, D., Siskind, C., Maciel, R., Bis, D., Inherited Neuropathy Consortium 2019; 85 (3): 316–30

    View details for DOI 10.1002/ana.25426

    View details for Web of Science ID 000459920600003

  • Variation in SIPA1L2 is Correlated with Phenotype Modification in CMT Type 1A. Annals of neurology Tao, F., Beecham, G. W., Rebelo, A. P., Blanton, S. H., Moran, J. J., Lopez-Anido, C., Svaren, J., Morrow, J. M., Abreu, L., Rizzo, D., Kirk, C. A., Wu, X., Feely, S., Verhamme, C., Saporta, M. A., Herrmann, D. N., Day, J. W., Sumner, C. J., Lloyd, T. E., Li, J., Yum, S. W., Taroni, F., Baas, F., Choi, B., Pareyson, D., Scherer, S. S., Reilly, M. M., Shy, M. E., Zuchner, S., Inherited Neuropathy Consortium 2019

    Abstract

    OBJECTIVE: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of eight years. CMT1A is caused in most patients by a uniformly sized 1.5Mb duplication event involving the gene PMP22.METHODS: We genotyped DNA samples from 971 CMT1A patients on Illumina beadchips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal induced proliferation associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve and our functional studies identified and confirmed interacting proteins using co-immunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation.RESULTS: We identified significant association of four SNPs (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (P < 1*10-7 ). Co-immunoprecipitation and mass-spectroscopy studies identified beta-actin and MYH9 as SIPA1L2 binding partners. Further, we show that SIPA1L2 is part of a myelination-associated co-expressed network regulated by the master transcription factor SOX10. Importantly, in vitro knock-down of SIPA1L2 in Schwannoma cells lead to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development.INTERPRETATION: offers a new pathway to therapeutic interventions. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30706531

  • Assessment of disease progression in dysferlinopathy: A 1-year cohort study NEUROLOGY Moore, U., Jacobs, M., James, M. K., Mayhew, A. G., Fernandez-Torron, R., Feng, J., Cnaan, A., Eagle, M., Bettinson, K., Rufibach, L. E., Lofra, R., Blamire, A. M., Carlier, P. G., Mittal, P., Lowes, L., Alfano, L., Rose, K., Duong, T., Berry, K. M., Montiel-Morillo, E., Pedrosa-Hernandez, I., Holsten, S., Sanjak, M., Ashida, A., Sakamoto, C., Tateishi, T., Yajima, H., Canal, A., Ollivier, G., Decostre, V., Mendez, J., Praxedes, N., Thiele, S., Siener, C., Shierbecker, J., Florence, J. M., Vandevelde, B., DeWolf, B., Hutchence, M., Gee, R., Pruegel, J., Maron, E., Hilsden, H., Lochmueller, H., Grieben, U., Spuler, S., Rocha, C., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Harms, M., Pestronk, A., Krause, S., Schreiber-Katz, O., Walter, M. C., Paradas, C., Hogrel, J., Stojkovic, T., Takeda, S., Mori-Yoshimura, M., Bravver, E., Sparks, S., Diaz-Manera, J., Bello, L., Semplicini, C., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V., Arrieta, A., Hwang, E., Lee, E., Illa, I., Gallardo, E., Belmonte Jimeno, I., Llauger Rossello, J., Harwick, B., Sykes, J., Yetter, B., Smith, M., Lapeyssonie, B., Bendahan, D., Le Fur, Y., Shahram, A., Albane, T., Coppenrath, E. M., Harris, E., Guglieri, M., Evangelista, T., Murphy, A., Moat, D., Hodgson, T., Wallace, D., Ward, L., Galley, D., Calore, C., Stramare, R., Rampado, A., Gidaro, T., Turk, S., Servais, L., Theis, C., Diabate, O., Schimmoeller, L., Foster, G., Carbonell, P., Cabrera, M., Morgado, Y., Gala, S., Perez, J., Sawyer, A., Clarke, N. F., Sandaradura, S., Ghaoui, R., Cornett, K., Miller, C., Foster, S., Peduto, A., Sato, N., Tamaru, T., Kobayashi, Y., Ashida, A., Nakayama, T., Segawa, K., Ohtaguro, S., Nakamura, H., Ohhata, M., Kimura, E., Endo, M., Brody, N., Leach, M. E., Toles, A., Fricke, S. T., Otero, H. J., Jain COS Consortium 2019; 92 (5): E461–E474
  • Revised Upper Limb Module for Spinal Muscular Atrophy: 12 month changes. Muscle & nerve Pera, M. C., Coratti, G., Mazzone, E. S., Montes, J., Scoto, M., De Sanctis, R., Main, M., Mayhew, A., Muni Lofra, R., Dunaway Young, S., Glanzman, A. M., Duong, T., Pasternak, A., Ramsey, D., Darras, B., Day, J. W., Finkel, R. S., De Vivo, D. C., Sormani, M. P., Bovis, F., Straub, V., Muntoni, F., Pane, M., Mercuri, E., iSMAC Consortium Group 2019

    Abstract

    INTRODUCTION: The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3.METHODS: Longitudinal 12 month data was collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module.RESULTS: The 12 month changes ranged between -7 and 9 (mean: -0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (-0.45 in type 2, -0.23 in non-ambulant type 3 and -0.34 in ambulant type 3, p=0.96) and the relationship between 12 month change and age classes was not significantly different among the three types of SMA patients.DISCUSSION: Our results confirm that the Module explores a wide range of functional abilities and can be used in ambulant and non-ambulant patients of different ages in conjunction with other functional scales. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30677148

  • Assessment of disease progression in dysferlinopathy: A 1-year cohort study. Neurology Moore, U., Jacobs, M., James, M. K., Mayhew, A. G., Fernandez-Torron, R., Feng, J., Cnaan, A., Eagle, M., Bettinson, K., Rufibach, L. E., Lofra, R. M., Blamire, A. M., Carlier, P. G., Mittal, P., Lowes, L. P., Alfano, L., Rose, K., Duong, T., Berry, K. M., Montiel-Morillo, E., Pedrosa-Hernandez, I., Holsten, S., Sanjak, M., Ashida, A., Sakamoto, C., Tateishi, T., Yajima, H., Canal, A., Ollivier, G., Decostre, V., Mendez, J. B., Sanchez-Aguilera Praxedes, N., Thiele, S., Siener, C., Shierbecker, J., Florence, J. M., Vandevelde, B., DeWolf, B., Hutchence, M., Gee, R., Prugel, J., Maron, E., Hilsden, H., Lochmuller, H., Grieben, U., Spuler, S., Tesi Rocha, C., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Harms, M., Pestronk, A., Krause, S., Schreiber-Katz, O., Walter, M. C., Paradas, C., Hogrel, J., Stojkovic, T., Takeda, S., Mori-Yoshimura, M., Bravver, E., Sparks, S., Diaz-Manera, J., Bello, L., Semplicini, C., Pegoraro, E., Mendell, J. R., Bushby, K., Straub, V., Jain COS Consortium 2019

    Abstract

    OBJECTIVE: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.METHODS: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.RESULTS: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.CONCLUSION: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.CLINICALTRIALSGOV IDENTIFIER: NCT01676077.

    View details for PubMedID 30626655

  • AVXS-101 Gene Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 1 (SMA1): Pivotal Phase 3 Study (STR1VE) Update Shell, R., Day, J., Chiriboga, C., Crawford, T. O., Darras, B. T., Finkel, R., Connolly, A. M., Iannaccone, S. T., Kuntz, N. L., Pena, L. M., Schultz, M., Shieh, P. B., Smith, E. C., Feltner, D. E., Ogrinc, F. G., Macek, T. A., Wells, C., Muehring, L. M., L'Italien, J., Sproule, D. M., Kaspar, B. K., Mendell, J. R. AMER THORACIC SOC. 2019
  • Perspectives on Spinraza (Nusinersen) Treatment Study: Views of Individuals and Parents of Children Diagnosed with Spinal Muscular Atrophy. Journal of neuromuscular diseases Pacione, M., Siskind, C. E., Day, J. W., Tabor, H. K. 2018

    Abstract

    BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder characterized by muscle loss. In December 2016 the FDA approved the first and only treatment drug for SMA: Spinraza (nusinersen). Despite excitement and optimism, there are no published data on the perceptions of individuals with SMA and their families about the benefits, risks, and challenges associated with treatment.OBJECTIVE: This qualitative interview study sought to characterize the perspectives of patients/families with SMA who did not want, or were unsure about, receiving this new innovative treatment for a previously untreatable and often fatal condition.METHODS: Individuals and families were recruited via advertisements on Facebook groups related to SMA and through the Stanford Neuromuscular Contact Registry. Participants completed a demographic questionnaire and participated in a semi-structured interview via voice conferencing. Interview questions focused on: 1) experiences with SMA, 2) opinions about Spinraza treatment, and 3) factors considered in decisions regarding treatment.RESULTS: Thirteen people were interviewed: ten adults with SMA (ages 27- 48, nine with Type II) and three parents of minor children with SMA (one each of Types I, II and III). Qualitative content analysis identified a range of opinions about Spinraza treatment: five were uninterested (2 adults, 3 parents), four adults were still deciding whether to pursue treatment, three adults were interested or in the process of pursuing treatment, and one adult was currently receiving the drug after overcoming significant reluctance. Participants described several key factors influencing their treatment decisions, including: concerns about risk factors and side effects, high cost, insurance coverage, time involvement, and lack of data about efficacy. Participants reported learning about most of these factors through parent/patient testimonials on SMA-specific social media groups.CONCLUSIONS: Participants reported basing decisions about pursuing Spinraza on a variety of practical and value-based considerations. They described carefully weighing the perceived potential benefits and risks of treatment through the lens of their current quality of life and prognosis. These findings suggest that providers should be aware that some patients and parents, especially those with Types II-IV, may approach treatment decisions differently than parents of children with SMA I. Informed treatment decisions can be supported through: 1) the collection and dissemination of better data on Spinraza treatment in these populations; 2) clear communication about risks, side effects and eligibility; 3) improved access to payment and treatment facilities; and 4) facilitation of discussions between providers and patients/families about identity and disability in the context of goals of care and other life and support challenges.

    View details for PubMedID 30594933

  • Transcriptome alterations in myotonic dystrophy skeletal muscle and heart. Human molecular genetics Wang, E. T., Treacy, D., Eichinger, K., Struck, A., Estabrook, J., Olafson, H., Wang, T. T., Bhatt, K., Westbrook, T., Sedehizadeh, S., Ward, A., Day, J., Brook, D., Berglund, J. A., Cooper, T., Housman, D., Thornton, C., Burge, C. 2018

    Abstract

    Myotonic dystrophy (dystrophia myotonica, DM) is a multi-systemic disease caused by expanded CTG or CCTG microsatellite repeats. Characterized by symptoms in muscle, heart, and central nervous system, among others, it is one of the most variable diseases known. A major pathogenic event in DM is the sequestration of Muscleblind-like proteins by CUG or CCUG repeat-containing RNAs transcribed from expanded repeats, and differences in the extent of MBNL sequestration dependent on repeat length and expression level may account for some portion of the variability. However, many other cellular pathways are reported to be perturbed in DM, and the severity of specific disease symptoms varies among individuals. To help understand this variability and facilitate research into DM, we generated 120 RNASeq transcriptomes from skeletal and heart muscle derived from healthy and DM1 biopsies and autopsies. A limited number of DM2 and Duchenne Muscular Dystrophy samples were also sequenced. We analyzed splicing and gene expression, identified tissue-specific changes in RNA processing, and uncovered transcriptome changes strongly correlating with muscle strength. We created a web resource at http://DMseq.org that hosts raw and processed transcriptome data and provides a lightweight, responsive interface that enables browsing of processed data across the genome.

    View details for PubMedID 30561649

  • Consensus-based care recommendations for adults with myotonic dystrophy type 1 NEUROLOGY-CLINICAL PRACTICE Ashizawa, T., Gagnon, C., Groh, W. J., Gutmann, L., Johnson, N. E., Meola, G., Moxley, R., Pandya, S., Rogers, M. T., Simpson, E., Angeard, N., Bassez, G., Berggren, K. N., Bhakta, D., Bozzali, M., Broderick, A., Byrne, J. B., Campbell, C., Cup, E., Day, J. W., De Mattia, E., Duboc, D., Duong, T., Eichinger, K., Ekstrom, A., van Engelen, B., Esparis, B., Eymard, B., Ferschl, M., Gadalla, S. M., Gallais, B., Goodglick, T., Heatwole, C., Hilbert, J., Holland, V., Kierkegaard, M., Koopman, W. J., Lane, K., Maas, D., Mankodi, A., Mathews, K. D., Monckton, D. G., Moser, D., Nazarian, S., Nguyen, L., Nopoulos, P., Petty, R., Phetteplace, J., Puymirat, J., Raman, S., Richer, L., Roma, E., Sampson, J., Sansone, V., Schoser, B., Sterling, L., Statland, J., Subramony, S. H., Tian, C., Trujillo, C., Tomaselli, G., Turner, C., Venance, S., Verma, A., White, M., Winblad, S., Myotonic Dystrophy Fdn 2018; 8 (6): 507–20

    Abstract

    Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit.The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations.The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.

    View details for DOI 10.1212/CPJ.0000000000000531

    View details for Web of Science ID 000456290100016

    View details for PubMedID 30588381

    View details for PubMedCentralID PMC6294540