Advances in Pediatrics 67 (2020) 183–196

ADVANCES IN PEDIATRICS

New Developments in
Diagnosis, Treatment, and
Management of Duchenne Muscular
Dystrophy
Maria Gieron-Korthals, MDa,*, Raymond Fernandez, MDb,c
a
Department of Pediatrics, Division of Child Neurology, University of South Florida, Morsani
College of Medicine, 17 Davis Boulevard, Suite 200, Tampa, FL 33606, USA; bPediatric Neurology
Associates, 4150 North Armenia Avenue, Suite 103, Tampa, FL 33607, USA; cMuscular Dystro-
phy Association Care Center, Shriners Hospital for Children, Tampa, FL, USA

Keywords
 Duchenne  Dystrophin gene and protein  Exon skipping  Gene transfer
Key points
 Duchenne muscular dystrophy (DMD) is an X-linked, recessive, lethal disease
characterized by progressive loss of muscle strength and function. Becker
muscular dystrophy is less severe, although there is phenotypic overlap with
DMD.
 Mutations in the dystrophin gene cause absence of or an insufficiently functional
dystrophin protein that destabilizes the muscle fiber membrane.
 Respiratory, cardiac, orthopedic, and other comorbidities contribute to disability
and shorten life span.
 The clinical course and survival time of patients with DMD are changing because
of advances in diagnostic testing, management of comorbidities, and evolving
molecular and genetic treatments, such as exon skipping and gene transfer, in
addition to corticosteroids.
 Neonatal screening is feasible but not yet being performed. Earlier diagnosis will
become more critical as treatments improve.

HISTORICAL REVIEW
The dystrophin gene was cloned in 1987 [1]. The dystrophin gene was found
to be on the X chromosome at the Xp21 site based on a cytogenetic study of

*Corresponding author. E-mail address: mgieron@usf.edu

https://doi.org/10.1016/j.yapd.2020.03.002
0065-3101/20/ª 2020 Elsevier Inc. All rights reserved.
184 GIERON-KORTHALS & FERNANDEZ

girls with the Duchenne muscular dystrophy (DMD) phenotype and X-auto-
some translocation [2], by linkage analysis [3] and by a cytogenetic study of
a boy with DMD and 3 additional mutations, all within a large deletion in
the Xp21 band [4]. The identification of the gene product, dystrophin, was
accomplished in 1987 [5]. Subsequent work focused on refining techniques
for precise genetic diagnosis and more detailed information on dystrophin.
It is important to realize that before the availability of DMD gene analysis,
the diagnosis of DMD/Becker muscular dystrophy (BMD) was based on his-
tory (including family history), physical examination, serum creatine kinase
(CK) level, and muscle biopsy histopathology, all of which may not result in
a specific diagnosis. It was sometimes learned later that the reasonably estab-
lished diagnosis of DMD/BMD was not correct because there is phenotypic
mimicry caused by mutations in other genes. However, diagnostic errors are
now uncommon.

DYSTROPHIN, THE DUCHENNE MUSCULAR DYSTROPHY GENE

PRODUCT
Dystrophin is an intracellular muscle fiber protein in close proximity to the in-
ner surface of the muscle fiber membrane. Its primary function is to stabilize
the membrane during muscle contraction. This stabilization is accomplished
by a series of direct connections to other intracellular and transmembrane pro-
teins and then by indirect extension to extracellular proteins that provide base-
ment membrane integrity.
There are 4 functional units of the dystrophin gene (Fig. 1):
1. The N terminus or actin-binding domain, which binds with the muscle contractile
protein, actin [6].
2. The central rod domain made up of 24 spectrinlike repeat units with 4 inter-
spersed hinge units that provide flexibility during muscle contraction [7].
3. The cysteine-rich domain, which connects dystrophin to the transmembrane
protein, beta-dystroglycan, which in turn connects to other transmembrane pro-
teins, including sarcospan and the tightly knit sarcoglycan proteins within the
muscle fiber membrane. Beta-dystroglycan connects to alpha-dystroglycan via its
extracellular extension providing a link to laminin-2, a significant component of
the extracellular basement membrane [8].
4. The carboxy-terminus, which connects dystrophin with the intracellular proteins,
dystrobrexin and syntrophins, that function in neuromuscular synaptic mainte-
nance and also function to stabilize neuronal nitric oxide synthase (nNOS) to the
muscle fiber membrane. nNOS is an enzyme that catalyzes nitric oxide forma-
tion, a signaling molecule that modulates vascular tone. If nNOS is not attached
to the muscle fiber membrane because of lack of dystrophin, functional ischemia
occurs as the result of blood vessel constriction.

The pathology of dystrophin deficiency is multifaceted. Primarily, the integ-

rity of the muscle fiber membrane is compromised because of breakdown dur-
ing muscle fiber contraction allowing leakage of toxic substances into muscle
fibers, notably calcium. Another factor is the loss of membrane nNOS, causing
DEVELOPMENTS IN DMD 185

Fig. 1. Dystrophin and the dystrophin-associated glycoprotein complex (DAGC). (Top) Dystro-
phin protein. The N-terminal and C-terminal regions contain functionally important binding
sites, whereas the rod domain acts as a linker. (Bottom) Dystrophin connects the cytoskeleton
to the sarcolemma via components of the DAGC, a large multiprotein complex that includes
laminin, sarcoglycans, a-dystroglycan and b-dystroglycan, sarcospan, dystrobrevin, and a1-
syntrophin and b1-syntrophin, as well as associated proteins such as nitric oxide synthase.
nNOS, neuronal nitric oxide synthase. (From Douglas AG, Wood MJ. Splicing therapy for
neuromuscular disease. Mol Cell Neurosci. 2013; 56: 169–185; with permission.)

vasoconstriction and muscle ischemia and muscle fiber necrosis. This loss
causes inflammation, resulting in further damage and replacement of muscle fi-
bers by fat and fibrous tissue. Increase in oxidative stress and recruitment of
muscle fiber satellite cells are also implicated in dystrophin deficiency [9–13].

CLINICAL MANIFESTATIONS OF DUCHENNE MUSCULAR

DYSTROPHY
DMD affects 1 in approximately 3600 to 6000 male births. The pathology of
the disease, progressive muscle fiber breakdown at an accelerated pace, begins
186 GIERON-KORTHALS & FERNANDEZ

in utero, as shown by serum CK level increases detectable at birth [14]. How-

ever, there is a delayed onset of clinical symptoms and signs that typically be-
gins early, although it is not always distinct. Without a high level of suspicion,
the diagnosis of DMD is often not established until about 4 to 5 years of age.
Although motor delay and weakness are the hallmarks of DMD, many boys
show early cognitive and behavioral abnormalities that are sometimes more
obvious and of more significance. This finding should not shift attention
away from the possibility of underlying muscle disease; it should reinforce
the likelihood of DMD because many boys simultaneously show early speech,
language, and cognitive delays as well as behaviors suggestive of autism spec-
trum disorder [15]. A simple and sensitive but nonspecific serum CK measure-
ment serves as a reliable screen for DMD because it is always increased.
With a focus mainly on motor development, early differences in young boys
with DMD compared with typically developing peers are common [16]. Note
that these differences are not always thought to be significant, because young
boys with DMD usually show functional motor improvement that can
continue to 5 to 6 years of age, at which time they plateau and typically begin
to decline by age 7 years.
The more obvious signs of muscle weakness that are abnormal at any age
include the Gower maneuver when shifting position against gravity; difficulty
climbing stairs; waddling gait, indicating hip girdle weakness; and bulky mus-
cle groups, especially calves (pseudohypertrophy). These signs should lead to
the measurement of serum CK level. Nonspecific clumsiness and toe walking
in the absence of muscle weakness should also prompt serum CK
measurement.
A common scenario is detection of increased serum transaminases, alanine
transaminase (ALT) and aspartate transaminase (AST) levels, when a compre-
hensive metabolic panel is ordered for a variety of reasons, often not because of
suspected muscle disease. This finding often triggers a referral to a gastroenter-
ologist because of the increase in liver enzyme levels. However, in the absence
of clinically evident liver disease, the finding of increased transaminase levels
should be followed by serum CK measurement, which is not on the routine
comprehensive metabolic panel. The CK level will be increased to a signifi-
cantly higher degree than ALT and AST, leading to muscle disease as the
source. This finding saves time and unnecessary testing, which is sometimes
invasive and expensive.
Boys with DMD can experience improvement in motor function until the
age of approximately 4 to 6 years. Following this, they enter the plateau stage
of their disease, which can be as short as a few months to possibly 1 year, at
which time they invariably decline relentlessly. Identification of these stages
is important because it guides management, which becomes more complex
as the disease advances.
Female carriers may have varying degrees of muscle pain or weakness.
Symptoms occur in up to 10% of female carriers and become more frequent
with advancing age. Rarely, girls experience symptoms during childhood.
DEVELOPMENTS IN DMD 187

Even less common are girls with the severe DMD phenotype, as is seen in boys
[17]. The presence or absence of symptoms are both determined by random
inactivation of an X chromosome, which occurs early in embryogenesis. Car-
riers are at risk of developing cardiomyopathy, although the natural history has
not been well characterized. Occult abnormalities can be found by echocardio-
gram and by cardiovascular MRI. Cardiac assessment of asymptomatic carriers
is recommended every 3 to 5 years, beginning in young adulthood, or more
often if symptomatic [18].

CARRIER DETECTION
Approximately two-thirds of mothers of boys with DMD are carriers. Carrier
testing can be targeted in mothers and other at-risk women in the family, look-
ing for the mutation in the proband. If a woman is a somatic cell line carrier,
recurrence risk in future pregnancies is 50% for the disease in boys and 50% for
girls to be carriers [19]. If a woman is not a somatic cell line carrier, the recur-
rence risk is low, but not zero. Parents must understand that recurrence is a
possibility because of germ cell line mosaicism, with risk as high as 15%.
Germ cell line mosaicism means that the mutation is present in some of the
eggs in the woman’s ovaries, and this cannot be detected by genetic testing
before fertilization. This situation should be carefully explained so that parents
can pursue all options regarding family planning and prevention of DMD in
future pregnancies, both the disease and carrier state.
Carrier detection should be offered to all adult women within a family who
are potential carriers. Children should be tested only if there is a medically
compelling reason to do so, such as childhood onset of symptoms suspicious
of muscle disease or cardiomyopathy.
Asymptomatic children who are potential carriers should not be tested.
However, testing should be offered promptly when they reach the age of con-
sent and are capable of making their own decisions regarding reproductive is-
sues. Parents might request carrier detection in their young children because
they are concerned about the possibility and simply want to know. This reason
is not compelling, and clinicians are not obligated to comply.
Referral to a genetic counselor is recommended for advice, given the
complexity of the issues involved.

GENETIC TESTING
Approximately 70% of DMD mutations are single-exon or multiexon deletions
or duplications. The remainder are subexonic, including small deletions (as
small as a single nucleotide), small insertions, nonsense mutations, and
missense mutations, which are rarely pathogenic [20].
The diagnosis of DMD should be established by genetic testing, which has
become more readily available and usually affordable with reasonable turn-
around time. If affordability is an issue, funding sources are usually available
and easily accessed in the multispecialty care center (MCC) setting.
188 GIERON-KORTHALS & FERNANDEZ

The preferred initial testing method is next-generation sequencing (NGS) us-

ing a single-step method of data collection [21,22]. This method is generally be-
ing used in place of earlier 2-step methods involving multiplex ligation-
dependent probe amplification or whole-genome microarray to look for
exon-level deletions or duplications and, if necessary, followed by Sanger
sequencing analysis to look for sequence abnormalities. If a mutation is de-
tected by NGS and the data are convincing based on stringent criteria, confir-
mation by another method is not necessary.
If the clinical suspicion of DMD is high, targeted DMD gene analysis should
be performed as the initial test. If targeted DMD gene analysis is negative, an
appropriately expanded multigene panel should then be analyzed [23].
In contrast, if there is a reasonable degree of uncertainty regarding the diag-
nosis of DMD, an expanded gene panel that includes the DMD gene should be
the initial diagnostic step [24]. Rarely, in less than 1% of boys with DMD, the
genetic abnormality cannot be detected and a muscle biopsy is necessary. The
biopsy specimen should be processed by a well-equipped laboratory and inter-
preted by an experienced muscle pathologist.
The algorithm for genetic testing is outlined in Fig. 2.

NEWBORN SCREENING FOR DUCHENNE MUSCULAR

DYSTROPHY
DMD newborn screening is not yet being performed but is possible by mea-
surement of CK level on a dried blood spot obtained shortly after birth. If
the CK level is greater than 2000 IU/L, genetic testing is necessary [14]. If
less than 2000 IU/L, CK measurement should be repeated in several weeks.

Fig. 2. A proposed algorithm for genetic testing for highly and less highly suspected DMD.
dx, diagnosis.
DEVELOPMENTS IN DMD 189

GENOTYPE-PHENOTYPE CORRELATION
Most mutations that cause DMD are deletions that shift the translational
reading frame of messenger RNA (mRNA), referred to as frameshift or out-
of-frame deletions. In-frame deletions typically cause the milder BMD pheno-
type. Phenotypic expression largely depends on whether or not the mRNA
reading frame is shifted at the deletion site [25].
A frameshift occurs when the number of nucleotides deleted is not a multiple
of 3 [20]. Codons are nucleotide triplets that encode an amino acid during RNA
translation in ribosomes. If the number of nucleotides deleted is not a multiple
of 3, codons that are upstream from the mutation site encode normal amino
acids up to the mutation site. However, codons downstream from the mutation
site are out of frame and encode amino acids that are foreign to the remaining
portion of the dystrophin protein. The result is the formation of unstable or
virtually absent dystrophin, which causes the DMD phenotype.
In-frame deletions occur when the number of nucleotides deleted is a multi-
ple of 3. Codons that are both upstream and downstream from the mutation
site encode amino acids that are typically present and in proper sequence
except for those deleted. This condition results in the formation of an internally
truncated dystrophin protein that is semifunctional, causing the milder BMD
phenotype.
There is an approximately 90% correlation between a frameshift deletion
and the DMD phenotype [26]. However, there are exceptions to the reading
frame rule to be considered when discussing possible clinical severity in young
children. In-frame mutations predicting a milder phenotype are less certain.
Also, it is difficult, if not impossible, to predict clinical severity caused by du-
plications [20].
Notable exceptions to the reading frame rule occur in boys with mutations
before exon 6. This condition is caused by alternate translation initiation sites
within ribosomes that become activated [27]. Reliable predictions within this
region of the gene are difficult and families should be counseled accordingly.
Another exception to the reading frame rule are boys that have frameshift de-
letions that are amenable to exon 44 skipping, often causing a milder DMD
phenotype that resembles BMD [28]. This condition is probably caused by
spontaneous skipping of exon 44, which restores the mutation to being in
frame.
Boys with nonsense mutations that cause the formation of a premature stop
codon typically show the DMD phenotype. Nonsense mutations result in an
aberrantly located stop codon that stops dystrophin production prematurely,
which triggers a process referred to as nonsense-mediated decay, and dystro-
phin is virtually absent. Although the DMD phenotype is often predicted
accurately, there are exceptions, and a milder DMD phenotype may result.
This condition is caused by spontaneous skipping of the exon that contains
the premature stop codon, enabling the production of partially functional dys-
trophin [29].
190 GIERON-KORTHALS & FERNANDEZ

Missense mutations result in single-nucleotide substitutions and are typically

well tolerated, especially if within the dystrophin rod–encoding region of the
gene. However, missense mutations can occur within vital gene regions such
as splice sites, promoter regions, or within the cysteine-rich encoding region;
these mutations are of greater consequence [30].

MODERN MANAGEMENT AND TREATMENT IN THE ERA OF

STEROIDS AND BEYOND
The natural history of DMD before and after the introduction of steroids is
shown in Fig. 3. Before treatment in the 1960s, loss of ambulation occurred
in many boys by 9 to 10 years of age, and the mean survival age was
17.7 years. The introduction of surgical management of scoliosis and nonin-
vasive ventilation did not alter motor function but significantly lengthened
survival to a mean age of 27.9 years. Contemporary treatment that included
the addition of corticosteroid treatment and improved cardiac management
beginning in the 1980s lengthened the time of ambulation by 2 to 3 years
and extended survival into the third decade. Prospective data from The
Cooperative International Neuromuscular Research Group support
continued corticosteroid treatment across the life span, even after the loss
of ambulation [31].

Fig. 3. Natural history of DMD. (Top arrow) 1960s: before treatment. (Middle arrow) 1970 to
1990: spinal surgery and ventilation added. (Bottom arrow) 1980 to present: steroid and cardiac
management. Top arrow from McDonald C. Natural history of DMD/BMD: What is clinically
meaningful? Oral presentation at The Cooperative International Neuromuscular Research
Group; June, 2013; London, UK; middle and bottom arrows from McDonald CM, Henricson
EK, Abresch RT, et al. The cooperative international neuromuscular research group Duchenne nat-
ural history study–a longitudinal investigation in the era of glucocorticoid therapy: design of pro-
tocol and the methods used. Muscle & Nerve 2013 July; 48(1):32–54; with permission.
DEVELOPMENTS IN DMD 191

Progressive functional motor decline begins in most boys by about 6 to

7 years of age. Coincident with a progressive decline, there is progressive multi-
system involvement requiring multispecialty care. Because management only
becomes more complicated with advancing age, early referral to a neurologist,
physiatrist, or to an MCC is advised. MCCs are able to provide direct services
by care center staff in attendance or by prompt referral to specialists not regu-
larly present in the care center setting. This management approach has led to
improved survival rates [32].
DMD care considerations published in 2018 [33–35] include management
strategies in the following areas. The appropriate health care professionals
who should be in attendance are indicated:
1. Neuromuscular management
 Neurologist or physiatrist: establish diagnosis, monitor disease trajectory,
steroid treatment management, Eteplirsen treatment of those eligible, keep
abreast of on-going clinical trials, carrier detection
2. Respiratory
 Pediatric pulmonologist: basic pulmonary function tests (mainly forced vital
capacity), advise on use of noninvasive respiratory support (cough assist,
mask ventilation)
3. Nutrition
 Neuromuscular specialist and nutritionist: refer to a gastroenterologist for
inadequate oral caloric intake
4. Cardiac
 Pediatric cardiologist: interpret electrocardiogram and echocardiogram,
cardiac MRI when necessary, prophylaxis and treatment of cardiomyopathy
5. Orthopedic
 Pediatric orthopedist: monitor for scoliosis and joint contractures, ensure
radiograph capability at the time of visit
6. Psychosocial
 A social worker: provide and coordinate referrals and support to patients and
families, psychological or psychiatric referral as needed
7. Rehabilitation
 A physical therapist: assist with functional assessments, occupational and
speech therapy availability, orthotics, and seating
8. Bone health
 Neuromuscular specialist: monitor for adverse effects of limited weight
bearing and steroid treatment, monitor vitamin D3 intake, monitor for bone
fragility by spine radiograph
9. Endocrinology
 Endocrinologist: referral for management of complex bone health problems
requiring intravenous (IV) bisphosphonate, monitoring of pubertal develop-
ment as needed
10. Primary and emergency care settings
 Overall health maintenance, including immunizations, emergency depart-
ment for emergencies
11. Transitional care across the lifespan
 Early planning and referral
192 GIERON-KORTHALS & FERNANDEZ

A critical aspect of care that applies to almost every boy is steroid treatment.
The exact age at which to begin steroids is not precisely defined, but a reason-
able age range is 4 to 6 years, typically the plateau stage of DMD [33]. If the
DMD phenotype is considered to be unusually severe, earlier treatment can
be recommended. In contrast, if the phenotype is milder, parents might not
be receptive to early treatment, and discussion of steroid treatment at each visit
is necessary.
Whether to prescribe prednisone or prednisolone (0.75 mg/kg/d) or deflaza-
cort (0.9 mg/kg/d) is controversial. Also, initiating treatment at a lower dose
and gradually increasing it to the recommended maximum daily dose depend-
ing on response and tolerability is reasonable and often advised.
It is well established that steroids extend ambulation for an average duration
of approximately 2 years or more compared with untreated boys [36]. Steroid
treatment has also been shown to reduce the likelihood of scoliosis [37] that will
require surgical intervention, and it prolongs upper limb and respiratory func-
tion for a variable period of time compared with untreated boys [38].
Deflazacort probably causes less weight gain and less behavior change than
prednisone or prednisolone, but careful monitoring for all side effects is neces-
sary for either steroid [38].
A clinical trial directly comparing prednisone with deflazacort is in progress
with estimated completion in late 2019. It is hoped that the results of this trial
will enable clinicians to make a more informed decision when prescribing either
prednisone or deflazacort and also result in better dosing schedules.
Access to nongeneric deflazacort became a significant problem in the
United States after the drug was granted US Food and Drug Administration
(FDA) approval in February 2017. Thus far, deflazacort is manufactured
by only 1 US pharmaceutical firm, and it can no longer be imported at a
reasonable cost. Securing payment by patients’ insurance carriers has been
difficult.

TREATMENTS BEYOND STEROIDS

Therapies based on RNA modulation: antisense oligonucleotides
Eteplirsen is a phosphorodiamidate morpholino oligomer [39]. It is the only
approved RNA modulating treatment that partially restores dystrophin expres-
sion. It is a synthetic strand of 30 morpholino rings, each serving as the back-
bone for a single nucleotide. The strand of 30 nucleotides attaches only to a
specific complementary site on exon 51 of pre-mRNA near the exon 51–intron
51 junction. Eteplirsen is classified as an antisense oligonucleotide (ASO)
because it attaches to the sense strand of pre-mRNA, hence antisense, and it
is a short nucleotide strand, hence oligo, meaning few or small.
Eteplirsen partially restores dystrophin expression only in boys with frame-
shift DMD gene deletions that can be transformed to in-frame deletions by
skipping (eliminating) exon 51 when pre-mRNA undergoes splicing. Amenable
frameshift deletions must include exon 50 from the upstream direction or exon
52 downstream, and exon 51 must be present.
DEVELOPMENTS IN DMD 193

Removal of exon 51 expands the deletion size by an additional exon. How-

ever, the expanded deletion is transformed to an in-frame deletion because the
total number of nucleotides deleted becomes a multiple of 3, as opposed to the
original nucleotide number. The end result is an internally truncated but semi-
functional dystrophin molecule produced from end to end that can be incorpo-
rated into the muscle protein cascade shown in Fig. 1. Even though truncated
dystrophin production is limited, there is an increase in dystrophin-containing
fibers that seems to be of some clinical benefit [40,41].
Accelerated approval was based on the surrogate end point of dystrophin
production in treated boys, albeit in small quantities, but nevertheless reason-
ably likely to predict some degree of clinical benefit in an otherwise untreatable
lethal disease [42]. Accelerated approval was granted with the understanding
that the continuation of phase III studies is necessary to confirm the benefits
after 2 additional years of treatment. Analysis of these data should soon be
available.
Post–FDA eteplirsen approval studies showed an increase in dystrophin
production after 180 weeks of treatment [43]. Additional studies showed
slower rates of decline of respiratory function and use of upper extremities
[44–46].

SYSTEMIC GENE TRANSFER (TRANSGENE THERAPY)

Mendell and colleagues [47] reported the results of 4 boys with DMD treated
by single-dose IV delivery of microdystrophin (full-length gene is too large
for viral vector) transgene with the MHCK7 promoter via an adeno-associ-
ated viral vector. The viral vector has high skeletal and cardiac muscle affin-
ity, a low level of prior immunity, and it is not pathogenic in humans even
though it easily enters muscle cells. The MHCK7 promoter drives gene
expression selectively in skeletal and cardiac muscle. The microdystrophin
transgene contains only the essential DMD gene components necessary for
encoding a small but functional dystrophin protein. Boys ranged in age
from 4 to 7 years, and had different mutation types between exons 18 and
58, no viral vector antibodies, below-average times on the 100-m walk test,
CK levels greater than >1000 IU/L, and a stable steroid dose for at least
3 months before study entry. An additional daily steroid dose greater than
their standard DMD dose was started 1 day before treatment and continued
for about 30 days posttreatment [47].
Robust microdystrophin expression was shown by Western blot and by
immunohistochemistry at 90 days. All clinical end points were met and CK
levels decreased significantly. The duration of a single IV transgene infusion
remains to be determined but, thus far, there is benefit up to 9 months. The
transgene is found in muscle satellite cells, which should prolong the duration
of action. Whether or not doses can be repeated will depend on immune
responses.
This treatment is not mutation dependent and, if successful, will be available
to most boys with DMD depending on the presence of viral antibody.
194 GIERON-KORTHALS & FERNANDEZ

TREATMENTS IN DEVELOPMENT
 Two additional ASO skipping sites for exon 53 and 45 (in clinical trials)
 Second-generation ASOs with better skeletal and cardiac muscle penetration
 Ataluren for nonsense mutation readthrough
 Vamorolone, a dissociative steroid, with fewer side effects than glucocorticoids
 Nuclear factor-jB inhibition of inflammation and fibrosis
 B4GALNT2 (Beta-1,4-N-Acetyl-Galactosaminyltransferase 2) gene over-
expression for modulation of muscle protein other than dystrophin

With the implementation of comprehensive DMD care consideration updated

in 2018, further improvement in general health, motor function, quality of life,
and survival is anticipated. Genetically based treatments, those approved and
in clinical trials, should provide even more significant benefits.

Acknowledgments
The authors thank Elizabeth Kociolek for preparation of the text and figures
for this article and Dr Jane Carver for critical review of the article.

Disclosure
Dr M. Gieron-Korthals does not have any commercial or financial conflicts of
interest or any funding sources. Dr R. Fernandez served as a consultant for Sar-
epta’s Regional Advisory Board. He does not have any financial or commercial
conflicts of interest or funding sources.

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