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Editorial
July 25, 2018

Precious SMA natural history data
A benchmark to measure future treatment successes

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August 21, 2018 issue
91 (8) 337-339

Abstract

Classic chromosome 5q spinal muscular atrophy (SMA) is one of the most common neuromuscular conditions in childhood and the most common fatal genetic disease in infants. Byers and Banker1 first described the variability of this disease in terms of clinical onset and phenotypic severity of SMA and introduced us to the clinical spectrum of “infantile SMA.” They suggested that SMA was a progressive disease. Others, however, favored a static clinical course after an initial period of deterioration. This debate has continued to the present. Most accept that a continual gradient in phenotypic severity exists, meaning every patient with SMA is truly unique. The modern classification of SMA, established in 1992, is therefore based on age at symptom onset and best motor performance achieved.2 SMA type I, also known as Werdnig-Hoffmann disease, exhibits subtypes of differing severity and, therefore, has been further divided into IA, IB, and IC, based on age at clinical onset. Dubowitz3 proposed a decimal classification system based on a continual rather than a discrete variable (e.g., SMA type 1.1, 1.5, and 1.9) to better capture the graded severity of the clinical phenotypes.

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References

1.
Byers RK, Banker BQ. Infantile muscular atrophy. Arch Neurol 1961;5:140–164.
2.
Darras BT, Markowitz JA, Monani UR, De Vivo DC. Spinal muscular atrophies. In: Darras BT, Jones HRJ, Ryan MM, De Vivo DC, editors. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician's Approach. San Diego: Academic Press; 2015:117–145.
3.
Dubowitz V. Chaos in classification of the spinal muscular atrophies of childhood. Neuromuscul Disord 1991;1:77–80.
4.
Darras BT, Finkel RS. Natural history of spinal muscular atrophy. In: Sumner CJ, Paushkin S, Ko CP, editors. Spinal Muscular Atrophy: Disease Mechanisms and Therapy. San Diego: Academic Press; 2017:399–421.
5.
Pane M, Palermo C, Messina S, et al; on behalf of the Italian EAP Working Group. An observational study of functional abilities in infants, children, and adults with type 1 SMA. Neurology 2018;91:e696–e703.
6.
Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy: clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol 1995;52:518–523.
7.
Leaffer EB, Hinton VJ, Salazar R, et al. Spinal muscular atrophy type I: cases of normal cognitive function despite having limited motor function and physical-environmental interaction. Poster presented at the annual meeting of the National Academy of Neuropsychology; November 4–7, 2015; Austin, TX.
8.
Glascock J, Sampson J, Haidet-Phillips A, et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis 2018;5:145–158.

Information & Authors

Information

Published In

Neurology®
Volume 91Number 8August 21, 2018
Pages: 337-339
PubMed: 30045956

Publication History

Published online: July 25, 2018
Published in print: August 21, 2018

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Disclosure

B. Darras has received royalties as the author of articles regarding neuromuscular diseases for UpToDate, Inc.; has served as consultant (ad hoc scientific advisory board member) for Sarepta Inc., AveXis Inc., BMS Inc., Cytokinetics Inc., Biogen Inc., Marathon Inc., Santhera Inc., Audentes Inc., PTC Therapeutics, and Hoffmann-La Roche Inc.; has been a consultant for Leerink Partners LLC, Cowen and Company, Guidepoint Global Consultation, Vertex Pharma, Clearview Healthcare Partners, Gerson Lehrman Group, Putnam Associates, WallachBeth Capital LLC, Frankel Group, Voyager Therapeutics, Noble Insights, Jefferies and Company, and Krog & Partners Inc.; has received speaker honoraria from Biogen; has served on the speakers bureau of Biogen; receives research support from PTC Therapeutics Inc., Summit Inc., Fibrogen Inc., Santhera Inc., Cyokinetics Inc., Biogen Inc., AveXis Inc., Roche Inc., Valerion Therapeutics, Ionis Pharmaceuticals, Sarepta Therapeutics, the NIH (NINDS), the SMA Foundation, Working on Walking Foundation, the Muscular Dystrophy Association, and the Slaney Family Fund for SMA (has no financial interests in these companies); presented a promotional talk regarding nusinersen (Biogen) at the AAN Annual Meeting in Boston, April 2017; and has presented 3 to 4 educational talks about administration of nusinersen (Biogen) to individual health care providers. Dr. Darras has no conflicts of interest regarding this editorial. D. De Vivo reports roles as advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals Inc., Ultragenyx Pharmaceuticals, Metafora, Roche, Sanofi, Sarepta, the SMA Foundation, the Pediatric Neurotransmitter Disease Association, the International Reye Syndrome Foundation, the Will Foundation, the Canavan Disease Foundation, the NYC Scientific Advisory Board, the Metafora Glut1 Deficiency Foundation, and the Grace Wilsey Foundation (no financial interests in these companies); has received a speaker honorarium from the American Academy of Neurology; has served on the editorial boards of Current Opinion in Neurology, MedLink in Neurology, and the Journal of Pediatric Neurology; holds a patent for Gene therapy for Glut1 Deficiency; receives publishing royalties from Elsevier and Lippincott; has provided expert witness for legal proceedings; and has received research support from Ionis Pharmaceuticals, Biogen, Ultragenyx Pharmaceuticals, Sarepta Therapeutics, the Department of Defense, Hope for Children Research Foundation, the NIH, the Colleen Giblin Foundation, the Will Foundation, the Pediatric Neurotransmitter Disease Association, the Glut1 Deficiency Foundation, and the SMA Foundation. Dr. De Vivo has no conflicts of interest regarding this editorial. Go to Neurology.org/N for full disclosures.

Study Funding

No targeted funding reported.

Authors

Affiliations & Disclosures

Basil T. Darras, MD
From the Department of Neurology (B.T.D.), Neuromuscular Program, Boston Children's Hospital, and Harvard Medical School, Boston, MA; and Pediatric Neurology Service at Columbia University Irving Medical Center (D.C.D.), New York, NY.
Disclosure
Scientific Advisory Boards:
1.
(1) Hoffman LaRoche (2) Cytokinetics, Inc. (3) Audentes, Inc (4) Sarepta Therapeutics (5) Biogen (6) PTC Therapeutics (7) AveXis
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Speaker honoraria from Biogen
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
(1) Various titles, UpToDate, 1999-present (2) 2 videotaped presentations,
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
(1) Leerink Partners, LLC (2) Cowen and Company (3) Guidepoint Global Consultation (4) Vertex Pharma (5) Clearview Healthcare Partners (6) Gershon Lehrman Group (7) Putnam Associates (8) Wallachbeth Capital, LLC (9) Frankel Group (10) Voyager Therapeutics (11) Noble Insights (12) Jefferies and Company (13) Krog & Partners, Inc.
Speakers' Bureaus:
1.
Biogen
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
(1) PTC Therapeutics (2) Valerion Therapeutics (MTM) (3) Ionis Pharmaceuticals (4) Sarepta Therapeutics (5) Biogen (6) Summit (7) AveXis (8) Roche
Research Support, Government Entities:
1.
(1) NIH/NIAMS, 2P01 NS040828-6A11, Co-PI, 2000-2012. (2) NIH/NINDS, 1U10NS077269, Site-PI/PD, 2011-2018. (3) NIH/NIAMS, 1R01AR060850, Co-PI, 2011-2015. (4) NIH/NINDS, 5U01NS061799, FOR-DMD, Site-PI, 2012-2016. (5) NIH/NINDS via Skulpt Inc., 5RNS073188, Site-PI, 2015- 2016.
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) SMA Foundation (2) Muscular Dystrophy Association (3) Slaney Family Fund for SMA
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Darryl C. De Vivo, MD
From the Department of Neurology (B.T.D.), Neuromuscular Program, Boston Children's Hospital, and Harvard Medical School, Boston, MA; and Pediatric Neurology Service at Columbia University Irving Medical Center (D.C.D.), New York, NY.
Disclosure
Scientific Advisory Boards:
1.
SMA Foundation. The Hope for Children Research Foundation. Pediatric Neurotransmitter Disease Association. International Reye Syndrome Foundation. The Will Foundation Chairman, Data Safety Monitoring Board, Cytokinetics Chairman, Canavan Disease Foundation Advisory Board, NYC Scientific Advisory Board, Metafora Glut1 Deficiency Foundation The Grace Wilsey Foundation
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Speaker Honorarium from the American Academy of Neurology
Editorial Boards:
1.
Current Opinion in Neurology, Editorial Board Medlink in Neurology, Editorial Board Journal of Pediatric Neurology Editorial Board (Turkish journal)
Patents:
1.
Gene therapy for Glut1 Deficiency patent International PCT Patent Application No. PCT/US2016/021810 Based on U.S. Provisional Patent Application Serial No.: 62/130,899 Title: RECOMBINANT GLUT1 ADENO-ASSOCIATED VIRAL VECTOR CONSTRUCTS AND RELATED METHODS FOR RESTORING GLUT1 EXPRESSION Filed: March 10, 2016 Our Ref.: 01001/003887-WO0
Publishing Royalties:
1.
Elsevier Publishers. Lippincott Publishers.
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Ionis Pharmaceuticals Biogen Pharmaceuticals Ultragenyx Pharmaceuticals
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Ionis Pharmaceuticals Biogen Pharmaceuticals Ultragenyx Pharmaceuticals Sarepta Therapeutics
Research Support, Government Entities:
1.
NIH, DOD
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
SMA Foundation. The Colleen Giblin Foundation. The Will Foundation The Pediatric Neurotransmitter Disease Association The Glut1 Deficiency Foundation
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
Expert witness.

Notes

Correspondence Dr. Darras [email protected]
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.

Author Contributions

BTD/DCD: Drafting/revising the manuscript.

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Cited By
  1. Assessing the Assisted Six-Minute Cycling Test as a Measure of Endurance in Non-Ambulatory Patients with Spinal Muscular Atrophy (SMA), Journal of Clinical Medicine, 12, 24, (7582), (2023).https://doi.org/10.3390/jcm12247582
    Crossref
  2. Lung function decline preceding chronic respiratory failure in spinal muscular atrophy: a national prospective cohort study, Orphanet Journal of Rare Diseases, 18, 1, (2023).https://doi.org/10.1186/s13023-023-02634-4
    Crossref
  3. Childhood spinal muscular atrophy, Motor System Disorders, Part II: Spinal Cord, Neurodegenerative, and Cerebral Disorders and Treatment, (43-58), (2023).https://doi.org/10.1016/B978-0-323-98817-9.00030-2
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  4. Disease Modifying Therapies for the Management of Children with Spinal Muscular Atrophy (5q SMA): An Update on the Emerging Evidence, Drug Design, Development and Therapy, Volume 16, (1865-1883), (2022).https://doi.org/10.2147/DDDT.S214174
    Crossref
  5. Natural history of respiratory muscle strength in spinal muscular atrophy: a prospective national cohort study, Orphanet Journal of Rare Diseases, 17, 1, (2022).https://doi.org/10.1186/s13023-022-02227-7
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  6. Reply to: The 4‐Copy Conundrum in the Treatment of Infants with Spinal Muscular Atrophy, Annals of Neurology, 91, 6, (892-892), (2022).https://doi.org/10.1002/ana.26357
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  7. In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy, Brain Sciences, 11, 2, (194), (2021).https://doi.org/10.3390/brainsci11020194
    Crossref
  8. Nusinersen Treatment in Adults With Spinal Muscular Atrophy, Neurology Clinical Practice, 11, 3, (e317-e327), (2021)./doi/10.1212/CPJ.0000000000001033
    Abstract
  9. Intellectual abilities, language comprehension, speech, and motor function in children with spinal muscular atrophy type 1, Journal of Neurodevelopmental Disorders, 13, 1, (2021).https://doi.org/10.1186/s11689-021-09355-4
    Crossref
  10. Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1–3, Thorax, 77, 1, (40-46), (2021).https://doi.org/10.1136/thoraxjnl-2020-216564
    Crossref
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