""

What is DMD?

DMD Is a Rare, X-linked, Fatal, Degenerative Neuromuscular Disorder1,2

 Caused by mutations in the dystrophin gene (DMD) located on the X chromosome2

Occurs in approximately 1 in every 3500 to 5000 males born worldwide3,4

More than 90% will be nonambulant by their 2nd decade of life5

DMD is a dystrophinopathy caused by genetic changes or mutations in the 79-exon DMD gene coding for dystrophin.2,6 These genetic changes, most commonly the deletion of one or more exons, prevent the body from producing enough or any functional dystrophin.2,6

exon map

 

The large size (2.4 million base pairs) and structure of the DMD gene makes it susceptible to a relatively high rate of mutations, with a clustering of deletion mutations observed around the 5' region of the gene (exons 2-20) as well as the central region of the gene (exons 45-55).7,8 Duchenne muscular dystrophy results from DMD gene mutations leading to disruption in the normal transcript reading frame or production of a premature stop codon.7,8

Dystrophin is one of a group of proteins that work together to strengthen muscle fibers and protect them from injury as muscles contract and relax.9 Although dystrophin exists in small amounts in the body (0.002% of total striated muscle protein),10 it plays a key structural role. Without it, muscle cells become damaged and are eventually replaced with fat and collagen.2

Disease Progression

Duchenne muscular dystrophy weakens the body’s muscles over time. And once muscle tissue is lost, it cannot be "fixed," which is why Duchenne is considered irreversible. However, some management options for Duchenne can help to slow disease progression. In the early stages of Duchenne, the disease primarily affects the muscles of the hips and thighs. This can lead to difficulty standing, climbing stairs, and maintaining balance.11

Note that the graphics show typical clinical and biological signs of DMD at various approximate age ranges. Also, DMD is a heterogeneous disease, and each child may progress differently.

0 to 4 Years

  • Inflammation soon after birth12,13
  • Muscle fibrosis seen as early as 1 year old12,13
  • Motor delays6
  • Other delays (eg, speech)6,14

5 to 7 Years

  • Progressive muscle weakness15
  • Enlarged calves6
  • Toe walking6
  • Standing-from-supine difficulty6,16
  • Fat accumulation in muscle17

8 to 11 Years

  • Motor milestone delays6,18
  • Decreased walking ability6,18
  • Part-time wheelchair use19

12 to 19 Years

  • Decreased upper limb, respiratory, and cardiac function20
  • Loss of ambulation19
  • Ventilatory support often required18
  • Unable to perform activities of daily living (ADL)21

Teens and beyond

  • Increasing cardiac dysfunction20
  • Heart failure18
  • Life expectancy severely reduced20

Common signs of DMD can be divided into motor and
non-motor signs:

 

Motor signs

Not walking until
~18 months old6,22

Walking on toes with legs apart, walking with belly pointed out, or both6,15

Falling down often2

Needing help getting up from floor, or using arms to walk body to standing position (Gower’s maneuver)6,15,20

Enlarged calves20

Fatigue23

Non-motor signs

Emotional/behavioral challenges24

Aggressive/noncompliant behavior, depressed/overcontrolled behavior

Cognitive impairment14,24

Intellectual disability, learning disability, delayed speech

Neuropsychiatric disorders24

ADHD, anxiety, autism spectrum disorder, epilepsy

Developmental delays can be a sign of neuromuscular disorders such as DMD.25

CONSIDER CK TESTING FOR NEUROMUSCULAR DISORDERS
REFERENCES
1. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al.; and the Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74:637-647. 2. Aartsma-Rus A, Ginjaar lB, Bushby K. The importance of genetic diagnosis for Duchenne muscular dystrophy. J Med Genet. 2016;53:145-151. 3. Emery AEH. Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord. 1991;1:19-29. 4. Crisafulli S, Sultana J, Fontana A, et al. Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis. Orphanet J. Rare Dis. 2020;15:141-161. 5. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2009;58:1119-1122. 6. Birnkrant DJ, Bushby K, Bann CM, et al; for the DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17:251-267. 7. Aartsma-Rus A, Van Deutekom JC, Fokkema IF, et al. Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule Muscle Nerve. 2006;34(2):135-144. 8. Fairclough RJ, Wood MJ, Davies KE. Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches. Nat Rev Genet. 2013;14:373-378. 9. Harper SQ. Molecular dissection of dystrophin identifies the docking site for nNOS. Proc Natl Acad Sci. 2013;110(2):387-388. 10. Hoffman EP, Brown RH, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51:919-928. 11. National Organization for Rare Disorders (NORD. Duchenne Muscular Dystrophy. Accessed September 30, 2021. hltgs://rarediseases.org/rare-diseases/duchenne-muscular-dystrophy/ 12. Chen Y-W, Nagaraju K, Bakay M, et al. Early onset of inflammation and later involvement of TGF in Duchenne muscular dystrophy. Neurol. 2005;65:826–834. 13. Klingler W, Jurkat-Rott K, Lehmann-Horn F, Schleip R. The role of fibrosis in Duchenne muscular dystrophy. Acta Myol. 2012;31(3):184-195. 14. Cyrulnik SA, Fee RJ, De Vivo, DC, Goldstein E, Hinton VJ. Delayed developmental language milestones in children with Duchene’s muscular dystrophy. J Pediatr. 2007;150:474-478. 15. Peverelli L, Testolin S, Villa L. Histologic muscular history in steroid-treated and untreated patients with Duchenne dystrophy. Neurology. 2015;85:1886-1893. 16. Chang RF, Mubarak SJ. Pathomechanics of Gowers' sign: a video analysis of a spectrum of Gowers' maneuvers. Clin Orthop Relat Res. 2012;470(7):1987-91. 17. Wilcocks RJ, Rooney WD, Triplett WT, et al. Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large duchenne muscular dystrophy cohort. Ann Neurol. 2016;79:535-547. 18. Niks EH, Aartsma-Rus A. Exon skipping: a first in class strategy for Duchenne muscular dystrophy. Expert Opin Biol Ther. 2017;17:225-236. 19. Ryder S, Leadley RM, Armstrong N, Westwood M, de Kock S, Butt T, Jain M, Kleijnen J. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J Rare Dis. 2017;12(1):79. 20. Emery AEH. The muscular dystrophies. Lancet. 2002;359:687-695. 21. Parent Project Muscular Dystrophy website. Stages of DMD. Accessed October 29, 2021. https://parentprojectmd.org/care/care-guidelines/by-stage/early-non%20ambulatory/ 22. Lurio JG, Peay HL, Mathews KD. Recognition and management of motor delay and muscle weakness in children. Am Fam Physician. 2015;91:38-44. 23. El-Aloul B, Speechley KN, Wei Y, Wilk P, Campbell C. Fatigue in young people with Duchenne muscular dystrophy. Dev Med Child Neurol. 2020;62:245-251. 24. Ricotti V, Mandy WPL, Scoto M, et al. Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations. Dev Med Child Neurol. 2016;58:77-84. 25. Ciafaloni E, Fox DJ, Pandya S, et al. Delayed diagnosis in Duchenne muscular dystrophy: data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). J Pediatr. 2009;155:380-385.