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Neuromuscular Disorders 101: The Progression of Muscular Dystrophy

Foreword


Neuromuscular disorders cause major changes in an individual's daily function and independence. Its broad term encompasses a large variety of diseases with different presentations. As healthcare evolves, so does clinical research updating disease diagnostic criteria and treatment options for neuromuscular disorders. This series will discuss neuromuscular disorders from a health science point of view concerning the etiology, pathophysiology, and treatment of neuromuscular disorders. The series will also discuss in depth the types of disorders and their etiology, diagnosis criteria, and medical rehabilitation management.


The series is divided into the following eight chapters:

  1. Neuromuscular Disorders 101: Living with Peripheral Neuropathy

  2. Neuromuscular Disorders 101: The Progression of Muscular Dystrophy

  3. Neuromuscular Disorders 101: The Effects of Amyotrophic Lateral Sclerosis

  4. Neuromuscular Disorders 101: The Break Down of Polymyositis

  5. Neuromuscular Disorders 101: Charcot-Marie-Tooth Disease: Effects on Childhood to Adulthood

  6. Neuromuscular Disorders 101: The Dysfunction of Multiple Sclerosis

  7. Neuromuscular Disorders 101: In the Face of Myasthenia Gravis

  8. Neuromuscular Disorders 101: Infection to Impairment: Guillain-Barre Syndrome


Duchenne Muscular Dystrophy (DMD) is a neuromuscular disorder that results in the degeneration of skeletal muscles (Crisafulli et al., 2020). Symptoms start to become evident in childhood as early as three years old. Impairments of DMD include cardiac, respiratory, and muscular disorders. A portion of patients also suffers from cognitive and behavioral impairments which include mental disability and autism spectrum disorder. DMD progresses very quickly as most children become wheelchair-bound by ages 8 to 14 years old (Crisafulli et al., 2020; Ryder et al., 2017; Yiu & Kornberg, 2008). This article will discuss in-depth the pathophysiology, diagnostic criteria, and medical management of DMD.


Genetics of DMD


DMD has a genetic origin and is stated as an X-linked disorder (“Duchenne muscular dystrophy,” 2021). X-linked describes the gene’s location on the sex “X” chromosome. Sex chromosomes are involved in the determination of one’s sex (“Sex chromosome,” 2023), and consist of X and Y chromosomes. Humans contain two sex chromosomes: females have two X chromosomes and males have one X and one Y. DMD is caused when the gene, dystrophin, is mutated or flawed to cause disease (“Duchenne muscular dystrophy,” n.d.). Dystrophin is a protein that assists in making muscle fibers strong and cohesive to prevent injury and maintain function. In DMD, dystrophin is mutated, or becomes non-functional on an X-recessive chromosome, causing muscle degeneration. Women are the most common carriers of the disease as they have two X chromosomes and pass along one X chromosome to males. If a female has a disease variant gene present on one chromosome, the disease is usually not evident as the mutation-carrying X chromosome is usually suppressed. However, men only have one X chromosome, so when an abnormal X chromosome is passed from a female to her child, he will develop DMD (“Muscular dystrophy, becker,” n.d.). It is estimated that 50% of women that carry the disease variant will have sons with DMD (“Duchenne muscular dystrophy,” 2021).


Figure 1: Dystrophic arm muscle. (“Duchenne and becker muscular dystrophy,” 2016)

Epidemiology and Clinical Manifestations


It is estimated that DMD affects 15.9 to 19.5 per 100,000 live births and has a prevalence of 1 in every 5,000 males (5 to 9 years old) (“MD STARnet Data,” 2022; Ryder et al., 2017). Approximately at 2.5 years old, parents or caregivers are able to notice initial signs and symptoms of DMD with the average age of diagnosis at 5 years old. Young children with the disease present symptoms of motor deficit such as abnormal gait between ages 3 to 5 years old (Yiu & Kornberg, 2008). Scoliosis (abnormal curvature of the spine) is very common in most children with DMD as well as acute bone injuries due to children sustaining falls as a result of motor impairment. Acute bone injury such as fracture occurs in 21% to 44% of children and causes 20% to 40% of children to lose the ability to walk (Yiu & Kornberg, 2008). This prevalence can be explained as children with DMD might begin to develop osteoporosis (decrease in bone mineral and mass) in their early ambulatory years. Cardiac impairment is also diagnosed in one-third of children by 14 years old and in all children over 18 years old (Yiu & Kornberg, 2008). Studies have shown that younger patient populations born after 1990 have a life expectancy of about 28 years old, whereas patients born before that only have a life expectancy of 22 years old (Broomfield et al., 2021). Furthermore, respiratory difficulty is experienced with DMD owing to decreasing vital capacity, i.e., the total amount of air exhaled after maximum inhalation, by 8% to 12% per year after 10 years old (David & Sharma, 2022; Yiu & Kornberg, 2008). Intellectual disability has been estimated to occur in 30% of boys in DMD with an increase in incidence of attention deficit hyperactive disorder (ADHD).


Difficulty in large motor movements such as running, stair climbing, and jumping becomes evident in the early stages of DMD (Crisafulli et al., 2020). A child usually suffers from frequent falls and develops a waddling gait pattern due to motor delay (Yiu & Kornberg, 2008). Gowers sign, a movement strategy where a child with DMD climbs up their lower extremities with their hands when transitioning from a sit to a stand position from the floor, is a hallmark sign of DMD (Shrestha & Munakomi, 2022). This demonstrates a compensation movement pattern due to weakness in the pelvis and proximal lower extremity muscles. Because of the lack of functional dystrophin, DMD also causes cardiac impairment by weakening the musculature of the heart (“Duchenne muscular dystrophy,” n.d.). Cardiac involvement is shown in 25% of children under the age of 6 with cardiomyopathy being reported in patients 18 years old and over (“Duchenne muscular dystrophy,” n.d.; Yiu & Kornberg, 2008). Cardiomyopathy is a broad term used to define conditions that affect the pumping mechanism of the heart (“Cardiomyopathy,” 2019). Weakening of the cardiac muscle causes a decrease in overall blood flow and is considered life-threatening if not monitored and treated (Ryder et al., 2017). Poor respiratory function is also a result of DMD due to weakness in the diaphragm and other associated respiratory musculature, resulting in decreased oxygen supply and increased risk of respiratory illness (e.g., pneumonia). In addition, it is estimated that approximately one-third of males with DMD are diagnosed with a learning disability (“Duchenne muscular dystrophy,” n.d.). Healthcare providers postulate that the mutated dystrophin has an effect on cognition as learning difficulties are seen in attention, memory, verbal learning, and emotion regulation.


Figure 2: Signs and symptoms of muscular dystrophy (“Duchenne muscular dystrophy,” 2022)

Diagnosis and Treatment Options


There are a variety of diagnostic tests and assessments for DMD (“Duchenne Muscular Dystrophy,” n.d.). Genetic testing through blood tests is performed to show a gene mutation affecting dystrophin in children with suspected DMD. These tests also inform providers of the location of the gene mutation. It is emphasized that genetic testing can not only confirm a DMD diagnosis more accurately, but is very beneficial in assisting clinicians and patients with prognosis and treatment options (Aartsma-Rus, 2016). Muscle biopsies, where a small sample of muscle is extracted for medical evaluation, may also be performed. Upon examination of a biopsy, medical providers can identify degenerative changes to the musculature. This testing measure has long been considered the gold standard of DMD diagnosis, but ever since the advancements in genetic blood testing, muscle biopsies are only conducted if genetic testing is negative (Yiu & Kornberg, 2008). An electrocardiogram (EKG) is also utilized to identify abnormal heart rate rhythms that generally occur with DMD.


The standard treatment methods for DMD include corticosteroid therapy and extensive physical rehabilitation (Falzarano et al., 2015; Yiu & Kornberg, 2008). Corticosteroids are a common treatment approach to help delay the progression of DMD. A typical corticosteroid used for DMD treatment is prednisone. Studies have revealed that prednisone can improve muscle strength while causing less clinically severe adverse effects (e.g., weight gain, metabolic disorder, osteoporosis, gastrointestinal symptoms) (Falzarano et al., 2015). Although the exact mechanism of action is not fully understood, Researchers believe that corticosteroids in DMD cause an anti-inflammatory response in the musculature and inhibit muscle breakdown, stimulate muscle repair, and stabilize muscle fibers from degeneration (Carvalho, 2022). Prednisone has been demonstrated to prolong a child’s life expectancy and delay respiratory dysfunction. Gene therapy including exon skipping (production of a partially functional dystrophin protein) and gene transfer (restoration of normal gene expression) could restore dystrophin at low levels (Chung Liang et al., 2022) and potentially become a promising treatment option for DMD. However, this treatment approach continues to require further research to determine the efficacy and limitations of gene therapy in patients with DMD.


Figure 3: Overall description of DMD (“Duchenne muscular dystrophy illustrations,” n.d.)

A Case Example of DMD


Sinha et al. (2017) once provided a case report detailing a DMD diagnosis of a 12-year-old male patient with an initial complaint of toothache. His medical history includes experiencing symptoms of multiple falls, muscle weakness, and the inability to climb stairs despite no history of muscular pain and nerve impairments. The authors noted on physical examination: the patient demonstrated difficulty with standing, walking, and standing from a sitting position. Muscular strength assessment revealed proximal body/limb weakness, muscle contracture in the hamstring muscle, and a positive Gower’s sign. The patient’s oral examination showed signs of an enlarged tongue, tooth decay, and poor hygiene. Further assessment including electromyographic testing and muscle biopsy indicated a DMD diagnosis for the patient. The authors highlighted symptoms of motor impairment as a clinical hallmark presentation of DMD, suggesting that the patient was displaying signs of delayed motor development. Interestingly, the patient’s oral symptoms are also indicative of DMD since the misalignment of teeth in patients can be associated with developmental abnormalities in orofacial muscles. It was also noted that the patient had high levels of creatine, which served as a confirmation of DMD diagnosis. Repeated muscular contractions in DMD patients can cause increased permeability of the sarcolemma (sheath that encloses muscle fibers), which results in leakage of creatine kinase (CK), elevating levels of CK in the system.


Rehabilitation for Patients with DMD


Conservative rehabilitation plays a huge role in the management of DMD to maintain mobility function. Orthoses, or braces, are used to support the lower extremities of children to aid mobility and decrease the chances of muscular contractures that occur with DMD (Muscular Dystrophy Association, n.d.). Standing frames are also used in progressive DMD patients to promote circulation, bone health, and alignment in the spine that support standing activity, despite children generally losing the ability to walk at ages 10 to 12 years old (Arora, 2019). New methods such as virtual reality technology within physical therapy treatment have shown remarkable results in improving functional outcomes associated with DMD. A systematic study conducted by Baeza-Barragán et al. (2020) concluded that virtual reality used in seven clinical trials for upper extremity rehabilitation improved the function, quality of life, and motivation in patients with DMD. Methods of virtual reality technology included musical games, virtual ball mazes, and catching cubes that utilized a variety of devices/interfaces like computers, webcams, kinetic sensors, and video game consoles. Besides, exercise therapy has been shown to improve muscular endurance and function in patients with DMD. Research has reported that participation in a six-week exercise program of respiratory muscle exercise significantly improves inspiratory muscle endurance. Moderate exercise increases adiponectin levels in the body, which provides anti-inflammatory properties in skeletal muscle beneficial for patients with DMD (Su & Song, 2022). Exercise can also improve cardiac function by increasing contractile protein concentration and maintaining heart rate variability.


In conclusion, DMD is a progressive neuromuscular disease that results in severe debility in young children, markedly males. Treatments aim to preserve muscular function and retain independence in mobility, thereby improving patients’ quality of life. Signs and symptoms of DMD arise at a very young age and often begin by displaying difficulty with basic mobility. It is crucial for parents or caregivers to seek medical attention for a child showing signs of DMD so that the progression of the disease can be delayed.


Bibliographical References

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Arora H. (2019). Duchenne muscular dystrophy: still an incurable disease. Neurology India, 67(3), 717–723. https://doi.org/10.4103/0028-3886.263203


Baeza-Barragán, M. R., Labajos Manzanares, M. T., Ruiz Vergara, C., Casuso-Holgado, M. J., & Martín-Valero, R. (2020). The use of virtual reality technologies in the treatment of Duchenne muscular dystrophy: systematic review. JMIR mHealth and uHealth, 8(12), e21576. https://doi.org/10.2196/21576


Broomfield, J., Hill, M., Guglieri, M., Crowther, M., & Abrams, K. (2021). Life expectancy in Duchenne muscular Dystrophy: reproduced individual patient data meta-analysis. Neurology, 97(23), e2304–e2314. https://doi.org/10.1212/WNL.0000000000012910


Cardiomyopathy. (2019). Centers for Disease Control and Prevention. https://www.cdc.gov/heartdisease/cardiomyopathy.htm


Carvalho, T. (2022). Prednisone. Retrieved January 13, 2023 from https://musculardystrophynews.com/prednisone/


Chung Liang, L., Sulaiman, N., & Yazid, M. D. (2022). A decade of progress in gene targeted therapeutic strategies in Duchenne muscular dystrophy: a systematic review. Frontiers in Bioengineering and Biotechnology, 10, 833833. https://doi.org/10.3389/fbioe.2022.833833


Crisafulli, S., Sultana, J., Fontana, A., Salvo, F., Messina, S., & Trifirò, G. (2020). Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis. Orphanet Journal of Rare Diseases, 15(1), 141. https://doi.org/10.1186/s13023-020-01430-8


David, S., Sharma, S. (2022). Vital capacity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541099/


Duchenne muscular dystrophy. (n.d.). John Hopkins Medicine. https://www.hopkinsmedicine.org/health/conditions-and-diseases/duchenne-muscular-dystrophy


Duchenne muscular dystrophy - about the disease. (2021). Genetic and rare diseases information center, national center for advancing translational sciences. Retrieved January 10, 2023 from https://rarediseases.info.nih.gov/diseases/6291/duchenne-muscular-dystrophy


Falzarano, M. S., Scotton, C., Passarelli, C., & Ferlini, A. (2015). Duchenne muscular dystrophy: from diagnosis to therapy. Molecules (Basel, Switzerland), 20(10), 18168–18184. https://doi.org/10.3390/molecules201018168


MD STARnet data and statistics. (2022). Centers for Disease Control and Prevention. Retrieved January 11, 2023 from https://www.cdc.gov/ncbddd/musculardystrophy/data.html


Muscular Dystrophy Association. (n.d.) Duchenne muscular dystrophy. Retrieved January 11, 2023 from https://www.mda.org/disease/duchenne-muscular-dystrophy


Muscular dystrophy, becker. (Updated 2008). National Organization for Rare Disease. https://rarediseases.org/rare-diseases/muscular-dystrophy-becker/?filter=Causes


Ryder, S., Leadley, R. M., Armstrong, N., Westwood, M., de Kock, S., Butt, T., Jain, M., & Kleijnen, J. (2017). The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet Journal of Rare Diseases, 12(1), 79. https://doi.org/10.1186/s13023-017-0631-3


Sex chromosome. (Updated 2023). National Human Genome Research Institute. https://www.genome.gov/genetics-glossary/Sex-Chromosome


Shrestha. S., & Munakomi, S. (2022) Gower sign. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 January. Available from: https://www.ncbi.nlm.nih.gov/books/NBK540973/


Sinha, R., Sarkar, S., Khaitan, T., & Dutta, S. (2017). Duchenne muscular dystrophy: case report and review. Journal of Family Medicine and Primary Care, 6(3), 654–656. https://doi.org/10.4103/2249-4863.222015


Su, Y., & Song, Y. (2022). The new challenge of "exercise + X″ therapy for Duchenne muscular dystrophy-individualized identification of exercise tolerance and precise implementation of exercise intervention. Frontiers in Physiology, 13, 947749. https://doi.org/10.3389/fphys.2022.947749


Yiu, E. M., & Kornberg, A. J. (2008). Duchenne muscular dystrophy. Neurology India, 56(3), 236–247. https://doi.org/10.4103/0028-3886.43441

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