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Current and emerging therapies for Duchenne muscular dystrophy

and spinal muscular atrophy

Mohsan Iftikhar, Justin Frey, Md. Jasimuddin Shohan, Sohail

Malek, Shaker A. Mousa

PII: S0163-7258(20)30250-3
DOI: https://doi.org/10.1016/j.pharmthera.2020.107719
Reference: JPT 107719

To appear in: Pharmacology and Therapeutics

Please cite this article as: M. Iftikhar, J. Frey, M.J. Shohan, et al., Current and emerging
therapies for Duchenne muscular dystrophy and spinal muscular atrophy, Pharmacology
and Therapeutics (2020), https://doi.org/10.1016/j.pharmthera.2020.107719

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© 2020 Published by Elsevier.

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PT #23690

Current and Emerging Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy

Mohsan Iftikhar1, Justin Frey1, Md.Jasimuddin Shohan1, Sohail Malek2, Shaker A. Mousa1,* Shaker.mousa@acphs.edu
1
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144
2

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Department of Pediatric Neurology, Albany Medical Center, Albany, NY 12208
*

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Corresponding author at: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery

Drive, Rensselaer, NY 12144

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Abstract

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Many neuromuscular diseases are genetically inherited or caused by mutations in motor function proteins. Two of the most prevalent

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neuromuscular diseases are Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA), which are often diagnosed

during the early years of life, contributing to life-long debilitation and shorter longevity. DMD is caused by mutations in the

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dystrophin gene resulting in critical muscle wasting, with cardiac or respiratory failure by age 30. Lack of dystrophin protein is the

leading cause of degeneration of skeletal and cardiac muscle. Corticosteroids and artificial respirators remain as the gold-standard

management of complications and have significantly extended the life span of these patients. Additionally, drug therapies including

eteplirsen (EXONDYS 51®), golodirsen (VYONDYS 53™), and viltolarsen (VILTEPSO®) have been approved by the FDA to treat

specific types of DMD. SMA is defined by the degeneration of the anterior horn cells in the spinal cord and destruction of motor
neuron nuclei in the lower brain-stem caused by SMN1 gene deletion. Loss of SMN1 protein is partly compensated by SMN2 protein
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synthesis with disease severity being affected by the success of SMN2 gene synthesis. Evidence-based recommendations for SMA are

directed towards supportive therapy and providing adequate nutrition and respiratory assistance as needed. Treatment and prevention

of complications of muscle weakness are crucial for reducing the phenotype expression of SMA. Furthermore, drug therapies

including injectables such as onasemnogene abeparvovec-xioi (ZOLGENSMA®), nusinersen (SPINRAZA®), and an oral-solution,

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risdiplam (EVRYSDI™), are medications that have been FDA-approved for the treatment of SMA. This review discusses the current

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and emerging therapeutic options for patients with DMD and SMA.

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Keywords:

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Duchenne muscular dystrophy, Spinal muscular atrophy, SMN1 gene, dystrophin protein, autosomal-recessive disorder.

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Table of Contents
1. Introduction
2. Duchenne Muscular Dystrophy (DMD)
2.1 Pathophysiology
2.2 Prevalence
2.3 Diagnosis
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2.4 Current evidence-based recommendations
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2.4.1 Cardiac symptoms and treatment

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2.4.2 Pulmonary symptoms and treatment
2.4.3 Orthopedic symptoms and treatment
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2.4.4 Nutritional interventions
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2.4.5 Psychosocial and pharmacological interventions

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2.5 Physical management
2.6 Therapeutic management
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2.7 Gene therapy
2.8 Limitations
3. Spinal Muscular Atrophy (SMA)
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3.1 Pathophysiology
3.2 Prevalence
3.3 Subtype prevalence
3.4 Diagnosis
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3.5 Evidence-based recommendations

3.5.1 Pulmonary function
3.5.2 Nutrition and gastrointestinal
3.5.3 Orthopedic and musculoskeletal
3.5.4 Physical management
3.6 Future directions
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4. Conclusion
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Abbreviations
AAV Adeno-associated virus
ACE Angiotensin converting enzyme
ARB Angiotensin receptor blocker
BMD
CGH
Becker’s muscular dystrophy
Comparative genomic hybridization
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CK Creatine kinase
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CNV Copy number variation

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DMD
GMFM66
Duchenne muscular dystrophy
Gross Motor Function Measure 66
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HFMS
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Hammersmith Functional Motor Scale for spinal muscular atrophy
LVEF Left ventricular ejection fraction

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MLPA
NGS
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Next-generation sequencingr
Multiplex ligation-dependent probe amplification

pCO2
rAAV
SMA
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pressure of carbon dioxide in the blood
Recombinant adeno-associated virus
Spinal muscle atrophy
SNP Single nucleotide polymorphisms
SPO2 Blood oxygen saturation with pulse oximetry
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1. Introduction

Many neuromuscular diseases are genetically inherited or caused by mutations in motor function proteins. Two of the most prevalent

neuromuscular diseases are Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), which are often diagnosed

during the early years of life, contributing to life-long debilitation and shorter longevity. DMD is an autosomal-recessive disorder on

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the X chromosome that is defined by mutations in the dystrophin gene, leading to deficiency in dystrophin protein (NIH U.S. National

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Library of Medicine). The prevalence of DMD is 1/5000. Because DMD is inherited in an autosomal recessive manner on the X

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chromosome, it is more common in males than in females because men have only one X chromosome, and women are protected

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because they have 2X chromosomes (Falzarano, Scotton, Passarelli, & Ferlini, 2015). SMA is an autosomal-recessive disorder that

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involves degeneration of anterior horn cells in the spinal cord and destruction of motor neuron nuclei in the lower brain-stem. Survival

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motor neuron 1 (SMN1) is a gene that encodes the SMN protein in humans (Lefebvre, et al., 1995). The deletion of the SMN1 gene is

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solely pertinent to SMA patients, typically presenting the onset of disease in infants with non-existent motor function. The incidence

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of SMA is 1/6,000-10,000, and incidence is also higher in males than in females (Verhaart, et al., 2017). The common features of

motor paralysis and debilitation remain a problem in DMD and SMA. This review will discuss both disease states, their unique

features, and emphasize the current and emerging therapeutic options available for patients with DMD and SMA.

2. Duchenne Muscular Dystrophy

2.1 Pathophysiology
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Mutations in the dystrophin gene result in critical muscle wasting, with cardiac or respiratory failure by age 30 (Findlay, et al., 2015).

The lack of dystrophin protein is the leading cause of degeneration of skeletal and cardiac muscle. The size of the dystrophin gene is

one of the largest in humans, leading to difficulties for gene-replacement pharmacotherapy. The full-length mRNA strands remain

mainly expressed in skeletal and cardiac muscle. Integrating a full-length messenger RNA (mRNA) strand of the dystrophin gene into

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a vehicle used for gene therapy is unlikely to be successful due to its length, and it is not able to fit into multiple administration routes

(Muntoni, Torelli, & Ferlini, 2003).

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Patients with DMD typically progress to a severe cardiomyopathic condition at 10 years of age. The disease manifests in a

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rapidly progressive manner, requiring patients to be in a wheelchair by age 10 (Wu, et al., 2014). Novel drug therapies including

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eteplirsen (EXONDYS 51®) (Sarepta Therapeutics Inc., 2020), golodirsen (VYONDYS 53™) (Sarepta Therapeutics Inc., 2019), and

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viltolarsen (VILTEPSO®) (NS Pharma Inc., 2020) have been recently approved by the FDA to treat patients with DMD. Due to the

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various genetic mutations that exist in patients with DMD, options remain limited with respect to curing or treating all patients. More

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pharmacotherapies that target restoration of dystrophin production are needed to further improve the treatment of DMD.

2.2 Prevalence

TREAT-NMD, a worldwide academic organization studying neuromuscular diseases and approaches to new therapies for patients,

reports figures representing epidemiological research for DMD. One study estimated the number of patients per country in the national

DMD registry with the point prevalence calculated (Bladen, et al., 2015). In France, USA, UK, and Canada, the point prevalence was
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calculated as 10.9, 1.9, 2.2, and 6.1 per 100,000 males, respectively. Another study of point prevalence of dystrophin mutations in

Canadian patients from a 2006 consensus reported a point prevalence of 10.3 per 100,000 males aged 0 to 24 years (Ryder, et al.,

2017). Romitti and colleagues found the population-based prevalence estimates for DMD and Becker’s muscular dystrophies (BMD),

an X-linked autosomal recessive disorder characterized by progressive weakness often in the legs and pelvis. The prevalence’s of

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these disease states were gathered from a total of 6 US states using the Muscular Dystrophy Surveillance, Tracking, and Research

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Network (MD STARnet) formed by the Centers for Disease Control and Prevention (Romitti, et al., 2015). The diagnosis of DMD

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was formed on clinical symptoms, age of onset, creatine kinase value, muscle biopsy reports, dystrophin mutation genetic analysis

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testing, and family history. The point prevalence was 10.2 per 100,000 males aged 5 to 24 years in 2010. A study by Norwood and

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colleagues presented a point prevalence of 8.3 per 100,000 males in 2007 based on 124 cases in northern England (Norwood, et al.,

2009).

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2.3 Diagnosis
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Clinical symptoms for DMD are not present at birth; the average age of diagnosis is typically at 4 years and the first appearance of

symptoms include weakness in the proximal muscles before distal muscles, weakness in the lower extremities, decreased endurance,

decreased head control, and overall motor function impairment (Birnkrant, Bushby, Bann, Apkon, Blackwell, Brumbaugh, et al.,

2018). Various methods are used when diagnosing DMD. Molecular quantitative analysis, including gene analysis, remains as the

most widely used method of diagnosing DMD (Falzarano, et al., 2015). Gene analysis defines the molecular defect in the DMD genes,

where deletions of one or more exons are present in 65% of patients. The remaining patients have duplication of exons or small
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mutations or rearrangements. Multiplex ligation-dependent probe amplification (MLPA) tests the 79 exons of the DMD gene

simultaneously, indicating the copy number variation (CNV) in a multiplex polymerase chain-based reaction (Falzarano, et al., 2015).

A similar method that uses a quantitative full-gene approach is the oligonucleotide-based array comparative genomic

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hybridization (CGH), which searches for the presence of CNVs in the full genomic region of the DMD gene. This method has been

adjusted to map the CNVs in the DMD gene completely, allowing a deeper diagnosis, detecting complex arrangements and intronic

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alterations to more accurately indicate mutation break-points in the DMD gene (Ferlini, 2014). The high density of probes in the array

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allows the detection of mutations by multiple probes, considerably reducing the potential of false positives due to single nucleotide

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polymorphisms (SNP) (Bovolenta, et al., 2008; Hegde, et al., 2008).

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Emerging technologies are leading to the sequencing of the entire coding region of the dysfunctional DMD gene, allowing

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detection of small mutations such as small deletions or insertions, single base change, and splicing mutations. Next-generation

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sequencing (NGS) examines the sequencing of millions of DNA fragments simultaneously, reducing the time and cost for genetic

diagnosis while increasing the DNA sequencing output. The innovative development and utilization of NGS has potential to become a

unique diagnostic method for complete genomic sequencing. Currently, diagnosing DMD is still confirmed via molecular diagnosis to

detect CNVs, CGH genomic sequencing to detect mutations, and emerging strategies including NGS (Ankala, et al., 2015).

2.4 Current evidence-based recommendations

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Corticosteroids and artificial respirators remain as the gold-standard management of complications of DMD and have significantly

extended the life span of DMD patients (Wein, Alfano, & Flanigan, 2015). The mortality of DMD patients is between 19 and 25 years

of age (Schram, et al., 2013). Corticosteroids are among the agents with evidence-based benefits as they prolong disease progression

(Escolar, et al., 2011). The two most commonly utilized corticosteroids are prednisone/prednisolone and deflazacort. Typical doses

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used to treat DMD are 0.75 mg/kg per day of prednisone or 0.9 mg/kg per day of deflazcort (Escolar, et al., 2011). In addition to

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glucocorticoid use, the FDA has recently approved 3 different treatment options for DMD including EXONDYS 51, VYONDYS 53,

and VILTEPSO.
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Multidisciplinary care is a required intervention to optimize function and quality of life for patients with DMD. The

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coordination of multiple specialists to receive adequate care for this condition is common and essential to maximize therapy. Common

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problems that are managed with multidisciplinary care include cardiac, pulmonary, orthopedic, nutritional, and psychosocial

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behaviors. Physical therapy, occupational therapy, and language therapy should be individualized based on each patient’s needs to

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provide optimal care (Birnkrant, Bushby, Bann, Apkon, Blackwell, Brumbaugh, et al., 2018; Narayanaswami, et al., 2015).

2.4.1 Cardiac symptoms and treatment

Current recommendations rely on early diagnosis and treatment of cardiomyopathy in patients with DMD, which can prolong survival

(Birnkrant, Bushby, Bann, Alman, et al., 2018; McNally, et al., 2015). Guidelines suggest a baseline assessment of cardiac function at

the time of DMD diagnosis consisting of an electrocardiogram, noninvasive imaging with echocardiography or cardiac magnetic
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resonance imaging that should be repeated annually for asymptomatic individuals (Birnkrant, Bushby, Bann, Alman, et al., 2018).

Referral to a cardiologist may be appropriate for the frequency of cardiac monitoring based on the assessment of any abnormalities

that present. As the disease progresses, the risk of cardiac arrythmia is increased, which leads to further surveillance in late ambulatory

stage and inclusion of a periodic 24-hour Holter monitoring as directed by the specialist.

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Initiation of angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) for males with DMD is

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recommended beginning at 10 years of age (Birnkrant, Bushby, Bann, Alman, et al., 2018; McNally, et al., 2015). ACE inhibitors

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have been evaluated for the preventative efficacy of slowing heart disease in children with DMD who are within the range of normal

left ventricular ejection fraction (LVEF).

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Results from a retrospective observational study suggested that early diagnosis and

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treatment of dilated cardiomyopathy in patients with DMD and BMD may lead to ventricular remodeling (Jefferies, et al., 2005).

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Among 69 affected boys, ACE inhibitors (enalapril, captopril, or lisinopril) were started in 27 patients with DMD and 4 patients with

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BMD after the first abnormal echocardiogram indicative of dilated cardiomyopathy (eg, LVEF <55 percent or left ventricular

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dilation); the mean age was 15 years. A beta-blocker (carvedilol or metoprolol) was added after 3 months if echocardiography showed

no improvement. At a mean follow-up of 3.3 years among 29 of the 31 patients who had repeat echocardiography, left ventricular size

and function showed normalization, improvement, or stabilization in 19, 8, and 2 patients, respectively. In addition, the mean LVEF

increased from 36 to 53 percent and there was evidence of reduced structural changes to the heart.

2.4.2 Pulmonary symptoms and treatment

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Patients with DMD require serial monitoring of vital capacity initiated at ages 5-6 and yearly thereafter following the ambulatory

stage (Birnkrant, Bushby, Bann, Alman, et al., 2018). As the disease progresses and ambulation is lost, every 6 months the patients

should be monitored for seated vital capacity, maximum respiratory pressure, maximum expiratory pressure, peak cough flow, blood

oxygen saturation with pulse oximetry (SPO2), and end-tidal or transcutaneous partial pressure of carbon dioxide in the blood (pCO2).

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If a patient has excessive weight gain, a sleep study should be considered at any stage for the patient in order to exclude sleep apnea as

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an associated symptom. Implementation of respiratory support is more common after loss of ambulation (Birnkrant, Bushby, Bann,

Alman, et al., 2018).

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Guidelines recommend interventions for core respiratory therapy including lung volume recruitment, assisted coughing,

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nocturnally assisted ventilation, and daytime ventilation (Birnkrant, Bushby, Bann, Alman, et al., 2018). These interventions have

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been linked with prolonged survival (Bach & Martinez, 2011; Eagle, et al., 2002; Gomez-Merino & Bach, 2002; Ishikawa, et al.,

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2011). Lung volume recruitment is essential and is done by using a self-inflating manual ventilation bag or mechanical

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insufflation/exsufflation once or twice daily when vital capacity is less than 60% of predicted. Manual and mechanically assisted

cough techniques are suggested when vital capacity is less than 50% of predicted, peak cough flow is less than 270 L/min, or

maximum expiratory pressure is less than 60 cm water (Birnkrant, Bushby, Bann, Alman, et al., 2018). Nocturnal ventilation is

indicated when signs of insufficient pulmonary function are exhibited during sleep. Implementation is characterized by a pCO2 of 10

mmHg above the awake baseline for greater than or equal to 2 % of sleep, an SPO2 of less than or equal to 88% for greater than or

equal to 2% of sleep time or for at least 5 minutes uninterrupted. Initiation of nocturnal ventilation can be considered when the apnea-
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hypopnea index is greater than or equal to 5 events per hour. Assisted daytime ventilation is initiated regardless of nocturnal

ventilation if the SPO2 is less than 95%, pCO2 is greater than 45 mmHg, or symptoms of awake dyspnea are present (Birnkrant,

Bushby, Bann, Alman, et al., 2018).

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The need for immunizations is more common after the loss of ambulation in a patient. It is suggested that all patients receive

yearly immunizations with inactivated influenza and pneumococcal vaccines due to the patients’ immunosuppressive condition.

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(Centers for Disease Control and Prevention, 2017) The decision of a tracheostomy is considered based on the patient’s preference,

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severity of condition, inability to use noninvasive ventilation successfully, multiple failed extubating attempts during critical illness

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despite use of noninvasive ventilation and mechanically assisted coughing, or no benefit from noninvasive cough assisting methods to

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prevent aspirations or secretions into the lungs (Katz, et al., 2013; McKim, Griller, LeBlanc, Woolnough, & King, 2013; Rodger, et

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al., 2015).

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In terms of respiratory infections, antibiotic therapy may be considered in the late non-ambulatory stage of acute respiratory

illness. Guidelines suggest the use of antibiotics when there are 3 or more symptoms present associated with pneumonia including

fever, elevated white blood cell count or C-reactive protein (CRP), sputum production, pulmonary infiltrate on chest radiography, and

hypoxemia or respiratory distress (Birnkrant, Bushby, Bann, Alman, et al., 2018). During respiratory infection, the frequent use of a

home pulse oximeter is suggested to monitor the need for further use of ventilation techniques.

2.4.3 Orthopedic symptoms and treatment

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Interventions for patients with DMD include physical therapy to assist in mobility and prevent or reduce risk of contractures. Physical

therapy methods range from passive stretching exercise at locations including ankles, knees and hips 4 to 6 times a week (Birnkrant,

Bushby, Bann, Apkon, Blackwell, Brumbaugh, et al., 2018; Glanzman, Flickinger, Dholakia, Bonnemann, & Finkel, 2011). Stretching

of these areas assists in the prevention of contractures of the Achilles tendons, iliotibial bands, and flexors of the hip. As the disease

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progresses in severity, stretching may be necessary at the wrists, hands, or neck (Birnkrant, Bushby, Bann, Apkon, Blackwell,

Brumbaugh, et al., 2018).

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Orthopedic evaluations are performed as needed to monitor for scoliosis and associated complications or necessary surgical

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interventions. Monitoring for scoliosis by visual evaluation of the spine should be considered annually in ambulatory stage and every

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6 months in the nonambulatory stage (Birnkrant, Bushby, Bann, Alman, et al., 2018; Birnkrant, Bushby, Bann, Apkon, Blackwell,

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Brumbaugh, et al., 2018). A spine radiography is suggested to be done every 6 months to one year if a spinal curve is seen. If the

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curve is greater than 20 degrees, the patient should be referred to an orthopedic surgeon for stabilization or correction by surgical

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intervention (Birnkrant, Bushby, Bann, Alman, et al., 2018). The correction of scoliosis can improve the quality of life, may improve

function, sitting balance and tolerance, and patient comfort. However, the evidence for correction of scoliosis must still be evaluated

for patients with DMD (Cheuk, Wong, Wraige, Baxter, & Cole, 2015).

Patients with DMD in either ambulatory or nonambulatory stages should consider gentle exercise including swimming,

cycling, and low-resistance strength training (Alemdaroglu, Karaduman, Yilmaz, & Topaloglu, 2015; Bushby, et al., 2010; Jansen,
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van Alfen, Geurts, & de Groot, 2013). Exercise should be implemented with caution because overexertion of muscles may cause

possible complications to fragile muscles in dystrophinopathy, a collective term grouping X-linked muscle weakness conditions

(Abresch, Carter, Han, & McDonald, 2012; Bushby, et al., 2010). Various exercise programs including whole-body vibration therapy

are being evaluated for significance in increased motor function and muscle strength (Moreira-Marconi, et al., 2017; Vry, et al., 2014).

2.4.4 Nutritional interventions

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From the use of glucocorticoids, patients may suffer adverse effects associated with weight gain and malnutrition. Guidelines suggest

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evaluation of nutritional deficiencies by a dietician or nutritionist at every clinic visit, beginning at first diagnosis. Goals for patients

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revolve around preventing obesity, malnutrition, and promoting a healthy diet with protein, fluids, and micronutrients including

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calcium and vitamin D (Birnkrant, Bushby, Bann, Apkon, Blackwell, Brumbaugh, et al., 2018). Calcium supplementation is

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recommended for children with insufficient intake of calcium-containing foods or for patients with less than the recommended intake

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of the dietary limit. Vitamin D supplementation is recommended if the serum concentration of vitamin D is less than 30 ng/mL

(Hollis, 2005; Munns, et al., 2016).

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Patients who experience symptoms associated with gastrointestinal complications should be referred to a gastroenterologist.

Symptoms include constipation, gastroesophageal reflux, gastrointestinal motility, and dysphagia. If dysphagia is present, the referral

to a speech and language therapist for a swallow assessment should be considered. (Birnkrant, Bushby, Bann, Apkon, Blackwell,
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Brumbaugh, et al., 2018). Surgical interventions can include a gastrostomy tube placement to prevent complications of weight loss,

dehydration, aspiration, and moderate or severe dysphagia.

2.4.5 Psychosocial and pharmacological interventions

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Consistency of psychosocial care for DMD is needed with ongoing support from psychiatrists or psychologists. Patients with DMD

have a higher rate of intellectual disability including learning disorders, autism spectrum disorders, and attention deficit hyperactivity

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disorder (ADHD) (Hendriksen & Vles, 2006, 2008; Pane, et al., 2012). Increased risks of anxiety and depression have been observed

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in DMD patients. (Banihani, et al., 2015). Patients are recommended to have neuropsychological evaluations and receive therapeutic

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interventions when problems associated with developmental, behavioral, or emotional problems are present. Routine assessments of

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mental health of the patient and family at every visit is suggested coupled with recommendations for standard cognitive behavioral

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therapy or pharmacological intervention if deemed necessary. Educational and vocational support is important to improve the care of a

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patient who needs psychosocial intervention. (Birnkrant, Bushby, Bann, Apkon, Blackwell, Colvin, et al., 2018). Developing and

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using a formal education plan that is updated annually based on a patient’s needs should be done to continue supporting the patient

(Narayanaswami, et al., 2015). Planning and education for adult caregivers are suggested to aid in patient care to provide the optimal

psychological support.

Pharmacotherapy for symptoms including anxiety and depression is typically managed by using selective serotonin reuptake

inhibitors (SSRIs) such as fluoxetine and sertraline. For behavioral issues associated with aggression or emotional dysregulation,
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alpha-adrenergic agonists are considered first-line therapy and atypical antipsychotic drugs such as olanzapine and risperidone are

second-line therapy. Stimulants or alpha-adrenergic agonists may be used for management of cognitive and executive deficits

including ADHD (Birnkrant, Bushby, Bann, Apkon, Blackwell, Colvin, et al., 2018). Pharmacotherapy should be carefully utilized for

these patients because of the risk of adverse effects, which can further deteriorate cardiovascular symptoms with the use of stimulants,

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antipsychotic agents, and specific antidepressants. Although current pharmacotherapy used for DMD has been shown to benefit

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patients, these agents do not upregulate the production of dystrophin protein. Palliative care must be sensitively engaged in for the

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patient when discussing treatment options, advanced care planning, and end of life events. Future directions lead towards promising

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physical and therapeutic management options for these patients, including new leads on genetic therapy and comprehensive exercising

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training programs (Moreira-Marconi, et al., 2017; Vry, et al., 2014).

2.5 Physical management

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Due to the truncated dystrophin proteins and malfunctional dystrophin gene, physical management is limited to a supplementary role

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of care for DMD patients (Falzarano, et al., 2015). Roles in health maintenance include nutrition, management of adrenal

insufficiency, orthopedic, cardiac, respiratory, and psychosocial care. Exercise cannot change the absence of dystrophin protein or

alter the progression of the disease. However, it can act as supportive care to further improve symptoms such as muscle weakness,

respiration, and reduced endurance. Moreover, studies involving exercise therapy in DMD patients have reported significant

improvements in motor function. For example, one study reported the effect of high-resistance weight training in 16 patients with

neuromuscular disorders. The muscle performance was quantified by measuring patients’ maximum force (muscle strength), the force-
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time integral--area under force-time plot during 60 seconds of sustained maximum force (work done), and the fatigue index--

percentage reduction in maximum force (Milner-Brown & Miller, 1988). Overall, the subjects’ muscle strengths ranged from 2% to

75% normal before the program. In patients having markedly to moderately weak muscles, maximum force increased by 80% ± 48%,

force-time integral increased by 132% ± 93%, and mean fatigue index was significantly reduced from 53% ± 18% to 34% ± 7.7%.

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This showed that high-resistance weight training was a way to significantly increase muscle performance of patients with

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neuromuscular disease if the disease progression was slow and initial muscle strength was greater than 15% normal. Although this

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study showed significant improvements in muscle strength, the outcomes of safety for exercise implementation were not studied.

2.6 Therapeutic management

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Currently, there are multiple strategies being studied as therapeutic options that target restoration of dystrophin production. The aim is

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to preserve muscle mass and mitigate the symptoms presented. Pharmacological strategies under investigation are diverse in their

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mechanism of action in order to provide better treatment for these patients.

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VBP15 is a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) inhibitor that has been used in muscular

dystrophy model (mdx) mice to study the effects of skeletal muscle cells’ repair and relief of symptoms (Heier, et al., 2013). NF-kB is

a protein complex that controls transcription of DNA, cytokine production, and cell survival (Gilmore, 2006). NF-kB activation occurs

when mechanical stress is present due to deficiency of dystrophin. Symptoms that result from activation include muscle inflammation,

fibrosis, and further muscle degeneration. Edasalonexent (CAT-1004) is a small molecule orally administered and created to inhibit
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NF-kB (Finanger, et al., 2018), which is activated from infancy in DMD and is central to critical muscle wasting and preventing

muscle regeneration. A phase 1/2 trial with 17 male patients given edaslonexent for 1 week showed inhibition of NF-kB pathways

while being well-tolerated (Finanger, et al., 2018). Future studies will provide additional efficacy and safety data to further assess the

drug and its role in DMD. Moreover, givinostat, a histone deacetylase inhibitor consisting of anti-inflammatory, anti-angiogenic, and

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antineoplastic qualities, targets the downstream signaling pathway of the genetic defect seen in DMD (Colussi, et al., 2008; Consalvi,

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et al., 2013). Givinostat shows hope in promoting transcription of numerous factors that upregulate muscle regeneration, including

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follistatin. The drug has counteracted muscle degeneration in mdx mice and has been studied to assess the safety, tolerability, PK , and

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effects on histology, and similar laboratory-related data in 20 ambulant children with DMD (Bettica, et al., 2016).

2.7 Gene therapy

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Gene therapy offers potential for treatment for most patients with DMD. The possibility of restoring the dystrophin truncated protein

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is in development and hopefully leading to a therapeutic effect in skeletal and cardiac muscle. However, the size of the dystrophin

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gene remains too large to fit in a recombinant adeno-associated virus (rAAV), the targeted vector for dystrophin gene delivery

(Guiraud, et al., 2015; Seto, Bengtsson, & Chamberlain, 2014). This is due to the persistence of rAAV in muscle and the lack of

pathogenicity (Guiraud, et al., 2015; Seto, et al., 2014). This leads to trying to find alternate methods of using a smaller-size

dystrophin gene in aspiration to provide a milder phenotype for patients with DMD.
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Approximately 15% of patients with DMD possess premature stop codons that terminate protein translation early, resulting in

truncated and dysfunctional proteins. An anti-bacterial class used in gram negative infections, named aminoglycosides, attach to the

decodings site of ribosomal RNA, disrupting the stop codon sequence and allowing the production of functional, full-length

dystrophin protein (Scully, Pandya, & Moxley, 2013). Although promising, the potential for ototoxicity and renal toxicity remains a

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concern for chronic use at high dosages. This result led to an alternative drug, Ataluren (Translarna™), that continues to interfere with

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the stop codon sequence seen in DMD patients and lacks antibacterial properties. Ataluren is a non-aminoglycoside drug that has been

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developed to have read-through activity and antibiotic characteristics (Bushby, et al., 2014). It is the first FDA-approved drug for the

underlying cause of DMD (Korinthenberg, 2018).

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Antisense oligonucleotides and exon skipping mechanisms have played a role in contemporary treatment options. The actions

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are based on using splicing therapy to skip mutated exons within pre-mRNA transcripts. 2′O-methyl phosphorothioate (2′OMePS,

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named PRO051/Drisapersen and developed by Prosensa/GSK) and the phosphorodiamidate morpholino oligomer named EXONDYS

51 (developed by Sarepta Therapeutics) are emerging therapies that restore the dystrophin protein after local injection. Drisapersen

was being evaluated in clinical trials but was denied approval by the FDA due to failure in a phase III trial with 186 patients

(GlaxoSmithKline, 2014). Eteplirsen (EXONDYS 51) (Sarepta Therapeutics Inc., 2020) received accelerated approval by the FDA in

2016, resulting in the first drug that was approved in patients with DMD. EXONDYS 51 is indicated for the treatment of DMD in

patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. The approval of EXONDYS 51 was
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controversial in that some studies indicated no difference in patients with DMD versus placebo during a 6-minute walking

examination. Nevertheless, the potential hope it generated in helping these patients with unmet needs led to its approval. With respect

to approaching treatment options for DMD, RNA remains the most well-studied target for development and antisense oligonucleotides

remain as the most-implemented molecules for RNA modulation in patients with DMD and SMA.

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In December 2019, an antisense oligonucleotide named golodirsen (VYONDYS 53) (Sarepta Therapeutics Inc., 2019) was

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approved by the FDA and indicated for the treatment of DMD in patients who have a confirmed mutation of the DMD gene that is

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amenable to exon 53 skipping (FDA, 2019b). This indication was approved under accelerated approval based on an increase in

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dystrophin production in skeletal muscle observed in patients. It was based on a two-part study; part 1 was a double-blind, placebo-

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controlled, dose-titration study in 12 DMD patients, and part 2 was a 168-week, open-label study assessing the efficacy and safety of

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Vyondys 53 at a dose of 30 mg/kg/week in the 12 patients enrolled in part 1, plus 13 additional treatment-naive patients with DMD

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amenable to exon 53 skipping. Continued approval for this drug’s current indication may be contingent upon verification of a clinical

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benefit in confirmatory trials. This recent release of VYONDYS 53 to the neuromuscular community shows promise. However, this

type of gene therapy must be monitored closely to assess long-term safety and efficacy.

In August 2020, another antisense oligonucleotide named viltolarsen (VILTEPSO) (NS Pharma Inc., 2020) was approved by

the FDA for the treatment of DMD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.

This indication is currently approved under accelerated approval based on an increase in dystrophin production in skeletal muscle
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observed in patients treated with VILTEPSO. Continued approval for this indication may be contingent on verification and description

of clinical benefit in a confirmatory trial. The approval was based on one study (clinicaltrials.gov identifier: NCT02740972) that was a

randomized, open-label, multicenter, 2-period, dose-finding study in males with DMD who were 4 years to less than 10 years of age

and on a stable corticosteroid regimen for at least 3 months. Patients were randomized into two arms: the VILTEPSO arm or placebo

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(n=8). Patients in the VILTEPSO arm received 20 weeks of 40 mg/kg once weekly (0.5 times the recommended dosage) or 80 mg/kg

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once weekly. In patients who received VILTEPSO 80 mg/kg weekly (n=8), mean dystrophin levels increased from 0.6% (SD 0.8) of

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normal at baseline to 5.9% (SD 4.5) of normal by week 25, with a mean change in dystrophin of 5.3% (SD 4.5) of normal levels

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(p=0.01) as assessed by validated Western blot (normalized to myosin heavy chain); the median change from baseline was 3.8%. All

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patients demonstrated an increase in dystrophin levels over their baseline values. Some of the common adverse reactions (reported in

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≥15%) of DMD patients treated with VILTEPSO 80 mg/kg once weekly were upper respiratory tract infection, injection site reaction,

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cough, and pyrexia (NS Pharma Inc., 2020). The approval of VILTEPSO adds another potential antisense oligonucleotide treatment

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option for patients with DMD who are amenable to exon 53 skipping. However, similar to VYONDYS 53, VILTEPSO should

continue to be monitored closely to determine the significance of the long-term safety and efficacy.

2.8 Limitations

Taking into consideration the large size of the dystrophin gene and the specificity involved with regulation in tissue expression, it is

difficult to approach genetic therapy for this condition. The RNA processing required for expression include a diverse regulation of

finely tuned editing and achieving full remission of this disease has not yet been achieved. Furthermore, the three FDA-approved
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treatments for DMD are not applicable to every patient due to the differences in mutations with the DMD gene. The current treatment

options that are universal for use in all patients with DMD remain limited in their potential benefits and most likely do not specifically

target dystrophin upregulation.

3. Spinal Muscular Atrophy (SMA)

3.1 Pathophysiology
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SMA is defined by the degeneration of anterior horn cells in the spinal cord and destruction of motor neuron nuclei in the lower brain-

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stem caused by the inheritance in an autosomal-recessive manner (Kolb & Kissel, 2015). SMN1 gene deletion is a characteristic in the

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genome of patients with SMA, and the onset of disease can present in infants at birth to later onset in adulthood (Ogino & Wilson,

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l
2002). The majority of patients with SMA have homozygous deletions (95%) of SMN1, and rare cases (5%) are caused by mutations

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in locations other than 5q13.2 (Darras, 2015; Kolb & Kissel, 2015). SMN2 is a centromeric homologue of the gene present in humans.

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The difference between SMN2 and SMN1 is the cytosine-to-thymine transition in exon 7 of the SMN2 gene, leading to production of a

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truncated, non-functional SMN protein from most of SMN2-derived mRNAs (Monani, et al., 1999). Although most production is non-

functional, about 10-15% of mRNAs from SMN 2 contain exon 7 and can produce few functional, full-length SMN protein

(Butchbach, 2016). As a result, loss of SMN1 protein is partly compensated by SMN2 protein synthesis. Such clinical presentations

and pathogenesis of SMA with possibilities of SMN2 protein transcription have directed the advancement of therapeutic methods

beyond symptomatic and supportive care.

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Disease severity of SMA inversely correlates with possession of SMN2 gene copy numbers, which can range from 0 to 8 in the

normal population (Butchbach, 2016; Kolb & Kissel, 2015). The presence of three or more copies of SMN2 is associated with a milder

phenotype. SMA currently is classified as types 0 through IV, and type 0 and type I are the most common and severe forms

(Butchbach, 2016). The different phenotypes of SMA categorize through age of onset and clinical course. Type 0 patients designate

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with prenatal onset, and type I patients typically present after birth but before 6 months of age (Arnold, Kassar, & Kissel, 2015). Type

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II patients typically have a less severe course, presenting within 3 and 15 months of age, and type III patients present typically from 18

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months of age to adulthood and have a progressively chronic path. (Arnold, et al., 2015). Type IV patients present with the least

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severe form of SMA, specific to onset in adulthood (Arnold, et al., 2015; Kolb & Kissel, 2015). Although the phenotype of SMA (type

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I to type IV) is largely associated with the number of SMN2 gene copies present in the patient population, the ideal number or

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concentration of SMN2 gene copies required for normal functionality is not fully understood. The different types of SMA and

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associated characteristics are listed in Table 1.

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3.2 Prevalence
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When all types of SMA are examined together, the prevalence remains at 1-2/100,000 persons, representing the most common

monogenic cause of infant mortality (Sugarman, et al., 2012; Verhaart, et al., 2017). Some studies concluded a higher prevalence rate

that may conclude regional differences in terms of genetics. Although this may indicate that the genetics of certain populations are

more prone to SMA, there are other factors to consider when understanding the higher prevalence observed. In Sweden, there has been

a higher number of neuromuscular disorders observed, which may be due to the high-quality health system and superior awareness
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education for these disorders (Verhaart, et al., 2017). The combination of these factors can explain the feasibility in identifying

patients with SMA and the higher prevalence rate.

3.3 Subtype prevalence

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Type I SMA has been stated to quantify up to half of all new SMA diagnoses, however prevalence studies have found type I indicates

0.04 to 0.28 per 100,000 (Verhaart, et al., 2017). This value is numerically lower than the given prevalence of 1-2/100,000 for all

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SMA subtypes. Due to the clinical manifestations and disease severity of type I, life expectancy is notably shorter compared to other

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e
types (Kolb, et al., 2017). More often, many patients do not survive during the study time, leading to the possible reason for this lower

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prevalence. Currently, the median age for life expectancy in type I SMA patients is approximately one year of age (Verhaart, et al.,

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2017).

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In the less severe forms of SMA, 75 to 93% of type II patients may survive beyond twenty years, and type III patients may live

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close to the expectancy of the normal population. For SMA types II and III, the prevalence is 1.5/100,000 when combined (Verhaart,

et al., 2017). Three studies have evaluated the prevalence, and two of them found higher prevalence of type III than type II patients

(Darin & Tulinius, 2000; Norwood, et al., 2009). A reasonable explanation may be as previously stated that the longer life expectancy

in SMA patients plays a role in evaluation of prevalence.

3.4 Diagnosis
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Previously, muscle biopsy and electrodiagnostic testing were standards for evaluation of SMA. However, molecular genetic testing is

readily available today and considered the standard diagnostic option for SMA. The efficiency of molecular testing and high

frequency of SMA in hypotonic infants leads to early consideration for any infant with muscle weakness or hypotonia (Arnold &

Flanigan, 2012). The significance of SMA relates to the homozygous deletion for both SMN1 copies, and genetic testing confirms the

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homozygous deletion in 95% of patients with SMA regardless of disease severity (Darras, 2015; Kolb & Kissel, 2015).

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Before the wide use of genetic molecular diagnostic testing, other diagnostic options were used to demonstrate the presence of

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denervation. Tools such as electrodiagnostic testing and muscle biopsies were used to evaluate potential SMA. Electrodiagnosis is

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considered for atypical patients who do not have both SMN1 deletion and SMN1 mutation. Muscle biopsy is no longer indicated

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because electrodiagnostic testing readily demonstrates denervation, allowing the avoidance of unnecessary and invasive testing for

a
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these patients (Arnold, et al., 2015). Molecular genetic testing plays a vital role in diagnosing typical SMA, and electrodiagnosis plays

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a critical role in diagnosing atypical patients resembling non-5q type SMA.

3.5 Evidence-based recommendations

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Evidence-based recommendations for SMA are directed towards supportive therapy, providing adequate nutrition and respiratory

assistance as needed. Treatment and prevention of complications of muscle weakness are crucial for reducing the phenotype

expression of SMA. Current recommendations are based on evaluations at baseline including respiratory function, sleep, daily life
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activities, orthopedic status, nutritional requirements, and feeding needs. It is recommended to have patients with SMA evaluated on a

6-month basis and more frequently for patients who express a more severe phenotype.

3.5.1 Pulmonary function

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Respiratory function should assist in clearing lower respiratory secretions and hypoventilation during sleep. Techniques used to clear

airway secretions are manual or mechanical chest physiotherapy including postural drainage and manual cough assistance or use of a

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mechanical insufflation/exsufflation device. A noninvasive approach is nasal ventilation as an alternative to a tracheostomy or

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conventional ventilator support. Early intervention of noninvasive nasal ventilation can improve the standard of living for patients

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with SMA type I. When noninvasive tactics become inadequate for care, initiating ventilator support should be considered based on

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patient characteristics.

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3.5.2. Nutrition and gastrointestinal
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Common features of respiratory dysfunction associated with deficient feeding, risk of aspiration, and failure to thrive are widely seen

with SMA type I. As the disease progresses, bulbar dysfunction can develop over time and be a concern for patients with SMA type II.

Non-ambulatory patients are the main group needing supportive nutritional and gastrointestinal care because their condition can

enhance adverse events including gastrointestinal reflux, delayed gastric emptying, and constipation. Ambulatory patients are less

likely to experience nutritional and gastrointestinal complications.

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Management tactics for nutritional deficiencies include altering food consistency to improve food intake and better escape

risks of aspiration. Surgical interventions including precutaneous endoscopic gastrostomy (PEG) can better assist in maintaining

proper nutrition and reduce the risk of aspiration for patients with SMA experiencing improper nutrition and gastrointestinal

complications.

3.5.3 Orthopedic and musculoskeletal

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Physical and pharmacotherapy interventions are used in combination to provide delays in muscle weakness. Spinal bracing may be

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used to further delay the development of progressive scoliosis as seen by deficiencies in muscle strength. However, the use of spinal

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bracing in patients with SMA type I and II significantly reduces expiratory tidal volume in the sitting position, further reducing

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respiratory function. The use of spinal bracing should be considered based on patient characteristics and be approached with caution.

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Surgical interventions involving the repair of scoliosis may be utilized, however the consensus on management is yet to be decided

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(Farrar, et al., 2017).
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One novel therapy that targets survival motor neuron is nusinersen (SPINRAZA®) (Neil & Bisaccia, 2019). Nusinersen is a

modified 18-mer antisense oligonucleotide (ASO) and is the first FDA-approved drug for all types of SMA. This medication is used

globally in Europe, Canada, Japan, Australia, and USA. The mechanism involves binding to the ISS-N1 regulatory motif in the intron

downstream of exon 7 on SMN2 pre-mRNA, allowing the inclusion of exon 7 to create full-length SMN2 mRNA, leading to a full-

length SMN protein (Singh & Singh, 2018). Nusinersen is administered intrathecally at equivalent 12 mg doses in 5 mL with the
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initial three loading doses 14 days apart, and the fourth loading dose is 30 days after last dose (FDA, 2019a). After the loading phase

is concluded, maintenance injections are given every 4 months. Studies have shown significant improvement in survival and motor

function for patients treated with nusinersen when compared to controls. The approval was based on the ENDEAR trial that indicated

improvement in motor milestones (head control, kicking, crawling, standing, walking) in 82 patients based on measurements on the

Hammersmith Infant Neurological Examination (HINE) scale (Finkel, et al., 2017).

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Medications like nusinersen play a crucial role in improving muscle strength and it is recommended for most infants with

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e
SMA. For children ages 2 to 12 years, treatment with nusinersen is suggested to improve the progressive muscle weakness (Neil &

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Bisaccia, 2019). Data is scarce when recommending nusinersen in older children and adults with more advanced forms of SMA. The

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uncertainty of long-term adverse effects associated with use and the lack of evidence for potential of treatment in more harsh forms of

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the disease leads to considering individualized treatment based on each patient’s characteristics.

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To date, there is no consensus recommendation from clinical practice guidelines that physical exercise or therapy services are

necessary to implement in patients with SMA. However, a study by Dunaway and colleagues provided the frequency, setting,

duration, and type of physical therapy services after interviewing patients with SMA and their caregivers (Dunaway, et al., 2016).

Results indicated that 86% of 105 patients with SMA received physical therapy services, and greater frequency was associated with

younger age and inability to walk. Another study of exercise benefits for treatment of SMA was a single-blind, randomized, controlled

clinical trial of a small number of participants (n=14) ages 10 to 48 years and divided into control and exercise groups. The exercise
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group received 6 months of intervention involving exercise therapy consisting of home-based cycling and strengthening, and

thereafter both groups received 12 months of intervention. The primary outcome was the distance walked during the six-minute walk

test. It was found that daily exercise was safe for ambulatory patients with SMA and should be encouraged (Montes, et al., 2015). The

study also documented reduction in oxidative capacity and blunted conditioning responses, which may represent vital information in

the underlying pathophysiological mechanism of SMA.

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3.5.4 Physical management
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Due to the genetic makeup of the disease, physical management is limited to a supplemental role concurrent with therapeutic

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management. The supplemental care for patients with SMA that may be used is physical therapy. Patients utilize physical therapy and

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other exercise therapies to increase muscle strength and motor function. Exercise programs involving resistance strength training have

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suggested potential benefits in improving or stabilizing muscle strength and motor function for patients with SMA. One study

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included 9 children with SMA who completed a 12-week (3 days/week), supervised, progressive training program (Lewelt, et al.,

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2015). The program was concluded to be feasible, safe, and well tolerated. Overall, further evaluation of the significance must be

considered before a definite recommendation can be made regarding PT or exercise therapy. Other studies have shown daily exercise

to be safe in ambulatory SMA and should be implemented if possible. In the same Montes et al. study described above, it was

concluded that there were no deleterious effects on strength, function, or fatigue. A reduction in oxidative capacity and a blunted

conditioning response to exercise was seen in these patients, allowing a deeper understanding of the pathophysiology of SMA.
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3.6 Future directions

Future directions for SMA include gene therapy as a direct way to elevate SMN protein levels. In SMA mouse models, AAV-

mediated SMN1 gene replacement resulted in a large-scale expression of SMN in the spinal cord, significantly increasing survival.

Other studies conducted with primates proved that AAV9-SMN1 crossed the blood brain barrier, creating transgene expression in the

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brain, spinal motor neurons, dorsal root ganglia, neurons and glial cells within the CNS. The expression further included the liver,

heart, and skeletal muscle.

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In May 2019, the FDA approval of onasemnogene abeparvovec-xioi (ZOLGENSMA®, manufactured by Novartis) (AveXis

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Inc., 2019) was based on data from the ongoing Phase 3 STR1VE trial and the completed Phase 1 START trial evaluated the efficacy

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and safety of a one-time IV infusion of ZOLGENSMA in patients with SMA type I who showed symptoms of SMA at <6 months of

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age, with one or two copies in the STR1VE trial or two copies in the START trial of the SMN2 backup gene and who have bi-allelic

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SMN1 gene deletion or point mutations. The approval of this drug makes this the first gene therapy targeted medication available on

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the market for SMA. In August 2019, the FDA released a statement on data manipulation and inaccuracy issues pertaining to the

production process for the product, which did not affect the efficacy and safety results from the human clinical trials, in turn requiring

no change in their review. Although the future for ZOLGENSMA is promising and it is used increasingly in the clinic, it must be

monitored closely to assess long-term safety and efficacy. In addition, ZOLGENSMA is a very costly treatment. At a price of over US

$2 million dollars/patient, ZOLGENSMA is considered the most expensive drug in the world.
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In August 2020, the FDA approved risdiplam (EVRYSDITM) (Genentech Inc., 2020) for the treatment of SMA in patients 2

months of age and older. Risdiplam is a survival of motor neuron 2 (SMN2)-directed RNA splicing modifier and the first oral solution

to be approved for treatment of SMA. The efficacy of risdiplam for the treatment of patients with infantile-onset and later-onset SMA

was evaluated in two clinical studies; Study 1 (NCT02913482) and Study 2 (NCT02908685). Study 1 evaluated use in patients with

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type I SMA, and study 2 evaluated use in patients with type II or type III. The overall findings of these studies support the

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effectiveness of risdiplam in SMA patients 2 months of age and older and appear to support the early initiation of treatment with

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risdiplam. The administration route and clinical efficacy established from the studies make risdiplam a promising drug treatment

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choice for patients with type I to III SMA. However, long-term safety and efficacy data will need to be assessed to further define the

role of this treatment.

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The role of physical therapy in supplemental care is being studied to examine whether the benefits are truly significant for

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patients with SMA. Currently the lack of data does not provide a definite recommendation that physical therapy must be implemented

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for these patients. However, different types of exercise programs are being implemented to consider the potential benefits in

improving muscle weakness and motor function.

4. Conclusion

The current therapeutic options for patients with DMD and SMA are expanding as new therapies that provide better outcomes for

patients become available. The introduction of gene therapy-based therapeutics is considered a major breakthrough in the improved
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treatment of DMD and SMA patients. Both pharmacological and non-pharmacological management are critical to improving patient

outcomes and quality of life. The topic of treating neurodegenerative disorders that decrease motor function is continuously being

studied, however, further studies on current and emerging therapies for DMD and SMA will need to be conducted before curative

treatments or regimens can be established.

Conflict of Interest Statement.

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The authors declare that there are no conflicts of interest.
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SMA Type No. of Copies of SMN2

- p Age of Onset

Type I (Werdnig-Hoffman Disease) 2

r e Before 6 months

Type II (Dubowitz Syndrome)

l P
3-4 6-18 months

Type III (Kugelberg-Welander Disease)

n a 3-4 Early childhood to early adulthood

Type IV
u r 4-8 Early to late adulthood (20-30+ years)

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Table 1: Classification of SMA Types, Characteristics, and Age of Onset