Muscular Dystrophy

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Continuing Education Activity

Muscular dystrophy comprises a group of genetic disorders characterized by progressive muscle weakness and wasting, with a global incidence of approximately 1 in 5,000 individuals. While it can manifest at any age, it is most commonly diagnosed in childhood. The root cause of muscular dystrophy lies in mutations affecting genes responsible for muscle structure and function, leading to the gradual degeneration and loss of muscle fibers.

Clinicians participating in this activity gain a comprehensive understanding of muscular dystrophy, including the global incidence, manifestation across ages, and the genetic basis involving mutations in muscle structure and function genes. The CE activity explores distinct hereditary patterns, emphasizing specific gene alterations leading to diverse manifestations. Participants learn about the impact on skeletal and cardiac muscles, disease progression, and associated complications, enhancing diagnostic and management skills for optimal patient care.

Objectives:

  • Identify the diverse pathophysiological mechanisms underlying various types of muscular dystrophy to enhance accurate and timely diagnoses.

  • Differentiate between different forms of muscular dystrophy, considering their unique patterns of inheritance, onset timing, and rates of muscle degeneration.

  • Implement a comprehensive multidisciplinary approach to care, integrating the expertise of different healthcare professionals for optimal patient management.

  • Coordinate care efficiently, considering the unique needs and challenges associated with muscular dystrophy, to provide comprehensive and patient-centered support.

       

Introduction

Muscular dystrophy constitutes a group of genetic disorders characterized by progressive muscle weakness and wasting. Muscular Dystrophy affects approximately 1 in 5,000 individuals worldwide and can manifest at any age, although it is most frequently diagnosed during childhood. The cause of muscular dystrophy is mutations affecting genes responsible for muscle structure and function, resulting in progressive degeneration and loss of muscle fibers.

The term "muscular dystrophy" encompasses a spectrum of hereditary disorders leading to progressive and widespread muscle disease due to inadequate or absent glycoproteins in the muscle cell plasma membrane.[1] Muscular dystrophy is a noncommunicable disorder with numerous variations exhibiting unique patterns of inheritance, onset timing, and rate of muscle degeneration.[2] Distinct alterations in specific genes cause different manifestations of this disease.

Muscular dystrophy affects skeletal and cardiac muscles. The progression of the condition varies depending on the type and severity of the disease but generally follows a pattern of progressive muscle weakness, reduced mobility, and the potential development of respiratory and cardiac complications.

Etiology

Muscular dystrophy can result from mutations in various genes and may be inherited in an X-linked, autosomal dominant, or autosomal recessive manner.[3] Changes in the X-linked gene DMD, which encodes dystrophin, are the most frequent cause of muscular dystrophy.[4] This is why the phenotype is manifested in hemizygous males, as they have only a single copy of the X chromosome.[5] It is important to note that mutations in dystrophin also create allelic heterogeneity.[6] Mutations in the DMD gene, for example, may give rise to either Duchenne or the less severe Becker muscular dystrophy, depending on the extent of the lack of protein.[7] 

Muscular dystrophy most often results from defective or absent glycoproteins in the muscle membrane.[1] Various types of muscular dystrophy are associated with distinct gene deletions or mutations, giving rise to diverse enzymatic or metabolic defects.[8] Notably, the dystrophin gene is the largest in the human genome, with 79 exons.[9] Due to its immense size (>2 x 106 bases), the dystrophin gene is prone to a high rate of spontaneous mutations.[10]

Insufficient levels of dystrophin result in damaged and ultimately dying muscle fibers, causing progressive muscle weakness, wasting, and fibrosis. This degenerative process can occur throughout the body, affecting various muscle groups and giving rise to different symptoms and complications.

While the genetic mutations causing muscular dystrophy may differ, the underlying mechanism of muscle degeneration and loss remains similar across all types of the disease. Early diagnosis, genetic testing, and appropriate management can help to improve outcomes and enhance the quality of life for individuals and families affected by muscular dystrophy.

Although the phenotypic characteristics of certain muscular dystrophies are well-defined, the spectrum produced by mutations in various genes overlap, leading to nonallelic heterogeneity.[11] Recognizing nonallelic heterogeneity is crucial for several reasons: 

  1. The capacity to recognize disease loci in linkage studies is decreased by introducing subjects with associated phenotypes but separate genetic disorders.[12]
  2. Genetic testing becomes more complex as multiple distinct genes need analysis along with the likelihood of unique mutations in each candidate gene.[12]
  3. Understanding how genes or proteins interact provides valuable insights into cell molecular physiology.[12] 

Phenocopies can arise when nongenetic diseases simulate the symptoms of a genetic disorder.[13] For instance, features of virus- or toxin-induced neurologic symptoms may resemble those observed in muscular dystrophy. Like nonallelic heterogeneity, phenocopies pose challenges in linkage studies and genetic testing.[13] However, careful consideration of patient history and accurate differentiation in phenotype can usually render signs that distinguish these disorders from similar genetic diseases. It is important to note that muscular dystrophy exhibits variable expressivity and incomplete penetrance, contributing to its manifestations across a phenotypic spectrum in different affected individuals, highlighting the concept of variable expressivity.[14]  

Modes of Inheritance  

Muscular dystrophy exhibits various modes of inheritance, including autosomal dominant, autosomal recessive, and X-linked patterns, with specific subtypes:

  • Autosomal dominant, autosomal recessive, X-linked: 
    • Emery-Dreifuss 
  • Autosomal dominant, autosomal recessive
    • Limb-Girdle (Dysferlinopathy, Erb)
    • Pelvifemoral
    • Scapulohumeral
  • Autosomal dominant: 
    • Facioscapulohumeral (Landouzy-Dejerine)
    • Late-onset distal (older than 40)
    • Myotonic
    • Oculopharyngeal
    • Scapuloperoneal
  • Autosomal recessive: 
    • Congenital
    • Early onset distal (younger than 40)
  • X-linked: 
    • Becker (benign pseudohypertrophic)
    • Duchenne (pseudohypertrophic)

Autosomal dominant, autosomal recessive, X-linked:

Emery-Dreifuss muscular dystrophy: Attributed to an X-linked recessive defect in the nuclear protein emerin at the Xq27-28 position.[15] This variant can also arise from an autosomal recessive or autosomal dominant defect in inner nuclear lamina proteins lamin A/C on chromosome 1.[16]

Autosomal dominant, autosomal recessive inheritance: 

Limb-Girdle Muscular Dystrophy: Primarily exhibits an autosomal recessive inheritance pattern but can also occur in an autosomal dominant manner.[17] The age of onset varies, and the distribution of involved muscles includes the limbs and trunk, often displaying a heterogeneous phenotype.[17] The recessive form of the disease tends to have an earlier onset and a more rapid progression, while the dominant form follows a slower and more variable course.[3] 

Multiple genes have been implicated in this disease, with deficiencies identified in proteins such as sarcoglycan, calpain, dystroglycan, and dysferlin.[18] There is also potential involvement of telethonin, lamin A/C, myotilin, and caveolin-3 (see Table. Limb-Girdle Muscular Dystrophy Subtype and Gene Abnormality).[19] 

Table 1. Limb-Girdle Muscular Dystrophy Subtype and Gene Abnormality

Limb-Girdle Muscular Dystrophy Subtype Gene Deletion/Mutation
1A Myotilin deletion [20] 
1B Lamin A/C gene deletion [21] 
1C Caveolin 3 gene deletion [22]
2A Calpain gene mutation [23] 
2B Dysferlin gene deletion [24] 

2C

2D

2E

2F

 Sarcoglycan gene deletion [25][26][27][28]
2G Telethonin gene mutation [29]
2H TRIM32 (tripartite motif-containing) gene 32 mutation [30] 
2I  

Fukutin-related protein gene deletion.[31]

 

Autosomal dominant inheritance:

Facioscapulohumeral muscular dystrophy: Attributed to an autosomal dominant deletion of a 3.3 kb repeat on chromosome 4.[32] Approximately 95% of cases result from a mutation in the D4Z4 region, leading to facioscapulohumeral muscular dystrophy 1.[33] Other areas, such as the SMCHD1 region in the type 2 subtype, can also cause this disease.[34] The age of onset is between 10 and 30 years, and the distribution of affected muscles involved includes the face, neck, and shoulders.[33]

Myotonic muscular dystrophy: Myotonic muscular dystrophy, or myotonic dystrophy, results from impaired dystrophia myotonica protein kinase (DMPK) expression.[35] It is caused by an autosomal dominant, abnormally expanded CTG trinucleotide repeat sequence located in the 3′ untranslated region of the DMPK gene.[36] Due to the expansion of trinucleotide repeat sequences (CTG), a phenomenon known as amplification and anticipation occurs, where family members develop the disease at progressively earlier ages across generations.[37]  Clinical severity increases with the number of nucleotide repeats, with some cases involving thousands of repeats.[38] The age of onset is approximately 10 to 15 years, and the distribution of affected muscles includes the face and extremities. This defect is classically associated with chromosome 19; however, a second form can occur on chromosome 3q.[39][40]

Oculopharyngeal muscular dystrophy: Typical onset around 30 to 40 years, with affected muscles including the extraocular and pharyngeal muscles. This condition is caused by an autosomal dominant GCG trinucleotide repeat, resulting in deficient mRNA transfer from the nucleus.[41]

Autosomal recessive inheritance:

Congenital muscular dystrophy: Caused by a mutation of the sarcolemmal protein merosin gene. Additionally, deficiencies or mutations in laminin-alpha 2, collagen type VI, integrin-alpha 7, and glycosyltransferases can contribute to the manifestation of this disorder.[42]

X-linked inheritance:

Becker Muscular Dystrophy: Caused by a mutation in the muscle protein dystrophin gene, which codes for the protein dystrophin and is notably the largest in humans with 79 exons.[8] The gene is transmitted in an X-linked re­cessive manner, located on the X chromosome's small arm (p) at the Xp21 locus position.[8][43] In the absence of dystrophin, muscle cells deteriorate or die. The age of onset is 10 to 20 years, and the distribution of involved muscles is generalized.[1] 

Duchenne muscular dystrophy: Caused by a dystrophin gene mutation located on the small arm of the X chromosome at the Xp21 position.[8] A spontaneous mutation occurs in a third of cases, while X-linked maternal-fetal transmission accounts for two-thirds of cases.[44][45] This mutation results in a nonfunctional dystrophin protein, leading to effects similar to those observed in Becker muscular dystrophy. The age of onset is typically around 3 to 5 years, and the distribution of involved muscles is generalized.[42] 

In females with Duchenne muscular dystrophy, an error in somatic cells leads to the inactivation of 1 X-chromosome at an early stage, creating a mosaic representation of heterozygous X-linked genes. While this condition generally protects female heterozygotes from X-linked disorders affecting males, X-inactivation in the female carrier with an X-autosome translocation can sometimes create a lethal genetic imbalance in half of the body's cells, causing cell death. Consequently, the same X-chromosome is expressed in every cell, and if it carries a disease allele, the individual can express the X-linked disease similarly to males. This phenomenon explains some cases of Duchenne muscular dystrophy in females.[46]

Epidemiology

Muscular dystrophy is a relatively rare condition, affecting an estimated 1 in every 5,000 to 10,000 individuals worldwide. In the US, approximately 250,000 individuals are estimated to be living with muscular dystrophy or a related neuromuscular disorder. However, obtaining accurate prevalence estimates is challenging due to factors such as the wide range of disease severity, variations in the age of onset, and the complexity of genetic testing required for diagnosis. Furthermore, the prevalence of the disease varies depending on the specific type of muscular dystrophy and the characteristics of the population being studied.

Duchenne muscular dystrophy is the most common type of muscular dystrophy observed in children, affecting approximately 1 in every 3,500 to 5,000 male births worldwide. Primarily affecting boys, the onset of Duchenne muscular dystrophy typically occurs between the ages of 3 and 5 years. The condition is progressive and ultimately fatal, with most individuals with Duchenne muscular dystrophy surviving into their late teens or early 20s.

Becker muscular dystrophy is a milder form resulting from mutations in the same DMD gene. This condition affects approximately 1 in every 18,000 to 30,000 individuals worldwide, predominantly males. Becker muscular dystrophy typically has a later onset and milder course than Duchenne muscular dystrophy, with individuals often able to maintain ambulation into adulthood.

Limb-girdle muscular dystrophy is a group of inherited muscular dystrophies that primarily impact the muscles of the hip and shoulder girdles. Presently, there are over 30 subtypes of limb-girdle muscular dystrophy, each arising from gene mutations. The prevalence of limb-girdle muscular dystrophy varies based on the specific subtype, but it is estimated to be approximately 1 in every 14,500 to 123,000 individuals worldwide.

Facioscapulohumeral muscular dystrophy is another type of muscular dystrophy that affects approximately 1 in every 20,000 individuals worldwide. Facioscapulohumeral muscular dystrophy typically presents with a later onset and slower progression than other types of muscular dystrophy, with symptoms often emerging in the teenage or adult years. This condition is caused by mutations in the DUX4 gene, which results in inappropriate expression of a toxic protein in muscle cells.

Muscular dystrophy more commonly affects males than females, as many genetic mutations responsible for the condition are on the X chromosome. However, some forms of muscular dystrophy, such as limb-girdle muscular dystrophy, exhibit an equal prevalence in both males and females. This is outlined below as follows:

Muscular dystrophy

  • Most common childhood muscular dystrophy: Duchenne 
  • Most common adult muscular dystrophy: Myotonic [47] 
  • Prevalence of muscular dystrophy (general population): 16 to 25.1 per 100,000 [48][49] 
  • Frequency of muscular dystrophy (general population): 1 per 3,000 to 8,000 [50][51] 
  • Incidence of muscular dystrophy (male births): 1 per 5,000 or 200 per 1,000,000 [52]

Becker muscular dystrophy 

  • Prevalence (general population): 4.78 per 100,000 [53]
  • Frequency (live male births): 1 per 18,000 [54] 
  • Incidence (live male births): 1 per 5618 [54]

Congenital muscular dystrophy 

  • Prevalence (general population): 0.99 per 100,000 [53] 
  • Prevalence (children): 0.82 Per 100,000 [53] 
  • Prevalence (general population-Italy): 1 per 16,000 [55] 
  • Incidence (general population-Italy): 0.563 per 100,000 [56]

Duchenne muscular dystrophy 

  • Prevalence (general population): 4.78 per 100,000 [53]  
  • Frequency (general population): 13 to 33 per 100,000 [57] 
  • Frequency (males): 1 per 3,500 [4] 
  • Incidence (live male births): 1 per 5,136 [52] 

Emery-Dreifuss muscular dystrophy

  • Prevalence (general population): 0.39 per 100,000 [53] 
  • Prevalence (children): 0.22 per 100,000 [53]

Facioscapulohumeral muscular dystrophy 

  • Prevalence (general population): 3.95 per 100,000 [53]
  • Prevalence (children): 0.29 per 100,000 [53]

Limb-Girdle muscular dystrophy

  • Prevalence (general population): 1.63 per 100,000 [53] 
  • Prevalence (children): 0.48 per 100,000 [53]

Myotonic muscular dystrophy 

  • Prevalence (general population): 8.26 per 100,000 [53] 
  • Prevalence (Children): 1.41 per 100,000 [53]

Oculopharyngeal muscular dystrophy 

  • Prevalence (general population): 0.13 per 100,000 [58]

*US, England, Australia, & Canada unless otherwise specified* 

Pathophysiology

There are several types of muscular dystrophy, each characterized by its unique genetic mutation and pathophysiology. Nevertheless, all forms of muscular dystrophy share a common feature: the progressive loss of muscle mass and strength.

In addition to the absence of dystrophin, the pathophysiology of muscular dystrophy involves a cascade of events that lead to muscle fiber damage and loss. The lack of dystrophin causes increased membrane permeability in muscle fibers, enabling calcium ions to enter the cell and activate enzymes that degrade the muscle fiber structure. This inflammation and degeneration of muscle fibers initiate a regeneration process by satellite cells. However, over time, this regeneration becomes less efficient, contributing to progressive muscle fiber loss and the development of fibrosis.

Typical findings in muscular dystrophy include muscle weakness and wasting, particularly in the proximal muscles of the lower limbs, pelvic girdle, and shoulders. Individuals affected by the condition may encounter challenges in movement, including running, jumping, and climbing stairs, along with muscle cramps and stiffness. With disease progression, respiratory and cardiac complications may arise due to the engagement of muscles responsible for breathing and heart function.

Muscle Contraction

It is crucial to grasp the fundamental physiology of muscle cell function initially. The sliding filament model represents muscle tension as a function dependent on the contraction of the muscle filaments. This contraction is facilitated by calcium released from the sarcoplasmic reticulum, leading to muscle depolarization. Intracellular calcium binds to the anionic charge of troponin C, causing the displacement of tropomyosin from the G-actin site. Once exposed, a myosin head attaches to the exposed G-actin site, initiating a pivot that requires energy from adenosine triphosphate (ATP). This pivot allows actin filaments to slide past myosin filaments, resulting in muscle shortening, transmitted to the muscle cell's glycoprotein-rich cytoskeleton.

Dystrophin 

Dystrophin is localized to the cytoplasmic surface of the muscle fiber plasma membrane, forming connections between the internal cytoskeleton and the extracellular matrix through glycoproteins that traverse the plasma membrane.[8] This cytoskeletal protein provides structural stability to a protein (dystroglycan) complex within cell membranes.[59] Specifically, dystrophin anchors the actin cytoskeleton to the basement membrane within a membrane-glycoprotein complex.[59] Dystrophin, laminin, and other proteins constitute this cytoskeletal framework.[8] Dystrophin interacts with F-actin and β-dystroglycan, binding to α-dystroglycan and laminin within the extracellular matrix.[8][60] The primary role of dystrophin is to secure the cytoskeleton to the extracellular matrix,[8] and any dysfunction in dystrophin alters tension transmission in contracting muscles.[1] 

When dystrophin is not functioning correctly, the contractile actin and myosin proteins, which generally shorten during muscle contraction, lead to both muscle weakness and injury to the cell membrane. This damage causes creatine kinase (CK) to leak from every damaged muscle cell, resulting in abnormally high levels of CK in the plasma.[61] The release of CK incites an inflammatory response, promoting scar tissue formation and leading to the classic pseudohypertrophy of calf muscles associated with muscular dystrophy.[62] Despite the appearance of hypertrophied muscles, there is a deficiency in functioning contractile filaments in the tissue, creating weak muscles.[1] The­ deficit is present from fetal development onwards.[63] Phago­cytosis of the damaged muscle cells by inflammatory cells further contributes to scar­ring and impaired muscle function.[1]

Dystrophin-Glycoprotein Complex

This protein meshwork formed by dystrophin and associated proteins appears to strengthen the sarcolemma.[64] The loss of 1 component of this network may trigger changes in other elements. For instance, the initial loss of dystrophin may result in the breakdown of sarcoglycans, including dystroglycan.[65] The weakened membrane ultimately leads to muscle cell death.[1] Fat and connective tissue gradually replace skeletal muscle, resulting in significant muscle atrophy.[66] This skeletal muscle deterioration leads to deformities in the skeleton, causing gradual immobility. Car­diac and smooth muscle in the gastrointestinal tract commonly undergo fibrosis.[67] The brain may exhibit structural abnormalities with no consistent pattern.[67]

Toxicokinetics

The toxicokinetics of muscular dystrophy involve complex interactions among genetic, environmental, and immune factors, resulting in muscle weakness and degeneration. Additional research is needed to fully understand these mechanisms and develop more effective treatments for this debilitating condition.

Environmental Factors

Physical activity and nutrition could potentially influence the toxicokinetics of muscular dystrophy. Increased physical activity may elevate oxidative stress and inflammation, potentially worsening muscle damage in individuals with muscular dystrophy. Conversely, proper nutrition, with adequate protein and essential nutrients, might contribute to maintaining muscle mass and function.

Inflammation

Chronic inflammation has the potential to activate immune cells, release inflammatory cytokines, and promote muscle damage and degeneration. In some cases, the accumulation of abnormal proteins in muscle cells may trigger inflammation.

Malignant Hyperthermia

This is a unique and life-threatening myopathy that can occur in genetically susceptive individuals following exposure to triggering factors, typically halogenated anesthetic gases like halothane, isoflurane, sevoflurane, and desflurane.[68] Additionally, exposure to succinylcholine can also induce this condition.[69] In individuals with dystrophinopathies, the administration of these agents can lead to rhabdomyolysis, prompting many experts to advocate for the exclusive use of nontriggering agents.

Malignant hyperthermia occurs due to abnormal calcium regulation associated with dystropinopathies. Dysregulated calcium release of the sarcoplasmic reticulum, coupled with anesthetic-induced interference in calcium reuptake, results in persistent muscle contraction, prolonged aerobic and anaerobic metabolism, increased carbon dioxide production, elevated end-tidal carbon dioxide, and tachycardia in these individuals who are unable to increase their alveolar minute volume adequately. This hypermetabolism generates an exponentially dangerous amount of heat, overwhelming the body's capacity to dissipate it effectively.

History and Physical

The onset of muscular dystrophy usually occurs in the third to fourth decades of life.[47] However, it may also become apparent in infancy or undergo accelerated deterioration near onset.[39] Parents of affected individuals may express concerns about their child's walking ability compared to peers of the same age.[70][71] The child may encounter difficulties in activities like kicking a ball due to muscle weakness.[72] Pseudo-drop events resulting from weakness of the quadriceps muscle may also be observed.[73] Notably, both parents could be in good health.[74] 

During a physical examination, individuals affected by muscular dystrophy typically exhibit pronounced calf muscle enlargement along with weakness in the proximal muscles of the lower limbs.[75] Consequently, affected individuals often rely on their arms and hands for assistance when rising from a seated position.[76] Other complaints include a history of delayed ambulation, toe walking, calf hypertrophy, and proximal hip girdle muscle instability.[77] 

Presentations may also include asymptomatic elevation of serum creatine kinase (CK), exertion intolerance, dilated cardiomyopathy, malignant hyperthermia, quadriceps myopathy, language delay, and in rare cases, Turner syndrome in X chromosome monozygotic females with Duchenne muscular dystrophy.[78] In some individuals with subclinical muscular dystrophy, the diagnosis may initially be suspected based on family history or the presence of elevated liver enzymes. However, the underlying cause of these enzyme elevations is not always clear.[79] These enzymes may include alanine aminotransferase and aspartate aminotransferase.[79] 

Given the X-linked inheritance pattern of muscular dystrophy, the overwhelming majority of patients are male.[4] Symptomatic disease in daughters can be explained by factors such as Turner syndrome, skewed X chromosome inactivation, translocation of the mutated gene to an autosome, or uniparental disomy (both copies of a chromosome set originating from one parent).[80] Typically, symptomatic females present in infancy with proximal muscle weakness.[81] Reports exist of increased weakness in adulthood, myalgias, spasms, and lethargy as initial manifestations.[75] Scoliosis and sustained alveolar hypoventilation can cause severe problems for every child with muscular dystrophy.[82]

Cardiovascular Findings

Arrhythmias

Cardiac arrhythmias have greater significance in individuals with muscular dystrophy. The typical electrocardiogram (ECG) shows increased net RS in lead V1, deep and narrow Q waves in the precordial leads, and tall right precordial R waves in V1.[83] Cardiac disturbances are commonly observed in patients with Duchenne muscular dystrophy type 1.[84] 

Myotonic dystrophy also affects the heart muscle, causing arrhythmias and heart block.[85] ECG abnormalities include first-degree heart block and more extensive conduction system involvement. A complete heart block and sudden death can occur.[86]

Congestive heart failure 

Congestive heart failure is rare in muscular dystrophy, typically occurring only in cases of severe stress, such as pneumonia.[87] Infrequent instances of congestive heart failure may result from cor pulmonale secondary to respiratory failure.[88] Additionally, mitral valve prolapse is a common occurrence in individuals with muscular dystrophy.[88]

Dilated cardiomyopathy

Genetic dilated cardiomyopathies, accounting for 30% to 40% of nonischemic dilated cardiomyopathies, are associated with some cases of muscular dystrophy.[89] In the skeletal myopathies, an ECG will reveal a dominant R wave in lead V1 (indicative of prominent posterior wall involvement).[90] While the presence of cardiomyopathy is prevalent in almost all patients with muscular dystrophy, a cardiac cause of death is not always certain.[91] The incidence of cardiac involvement in Duchenne muscular dystrophy is as high as 95%.[92] Chronic heart failure may occur in 50% of children.[93]

Musculoskeletal Findings

Research findings suggest that the gracilis, semimembranosus, semitendinosus, and sartorius muscles can be affected in patients with muscular dystrophy.[94] Additionally, individuals may exhibit an equinovarus feet deformity,[95] pelvic tilting,[73] and contractures throughout the body.[96] Furthermore, spinal deformities may lead to conditions such as lordosis or scoliosis,[97] and ocular issues like cataracts and bilateral ptosis can also occur.[98]

Contractures

Most patients with muscular dystrophy experience joint contractures of varying degrees, affecting the elbows, hips, knees, and ankles. Arthrogryposis, or joint contractures present at birth, can occur. Contractures of the heel cords and iliotibial bands manifest by age 6, accompanied by toe walking and a lordotic posture. Prolonged sitting worsens joint contractures, particularly in the hips, knees, elbows, and wrists.[99] Contractures become fixed, contributing to muscular atrophy, skeletal deformities, and the development of progressive scoliosis often associated with pain.[3][99] 

Duchenne muscular dystrophy leads to complications such as muscle weakness, contractures of the knees, hips, and other joints, and scoliosis.[100] The contractures and skeletal deformities that develop from facioscapulohumeral muscular dystrophy are less frequent and less prominent than Duchenne muscular dystrophy.[101] Clinical findings like foot drop and depressed or absent muscle stretch reflexes may be present.[102]

Delayed motor milestones

Duchenne muscular dystrophy is usually diagnosed in children at around the age of 3 when parents observe slow motor development.[103] Clinical symptoms commonly emerge between 5 and 15 years, marked by developmental delays in sitting, standing, and walking.[103] Children affected by Duchenne muscular dystrophy often exhibit clumsiness, frequent falls, and difficulties climbing stairs.[103] In contrast, individuals with Becker muscular dystrophy remain ambulatory into their teens and early 20s, with the average age for wheelchair necessity reported as 25 in one study.[77] The key distinction is that patients with Becker dystrophy can walk beyond age 15, while those with Duchenne dystrophy typically use a wheelchair by age 12.[103]

Expressionless facies 

A characteristic feature noted from early childhood is the inability to close the eyes fully. The expression on the face is often described as expressionless, and the weakening of facial muscles results in a "drooping expression." In myotonic dystrophy, the face takes on a hatchet-shaped appearance due to facial wasting and weakness, accompanied by bilateral partial ptosis. While bilateral facial palsy is rare, it is crucial to rule out other possible diagnoses for facial weakness, including upper and lower motor neuron disorders, through thorough diagnostic tests.[104]

Fractures 

Muscle weakness and inactivity, particularly in individuals using a wheelchair full time, contribute to the development of osteoporosis and an increased risk of pathologic fractures. Bisphosphonates may be considered to enhance bone strength in cases of fractures, although there is a lack of long-term studies on the safety of bisphosphonates in this population.[105]

Gait instability 

The affected individuals, particularly boys, frequently stumble and struggle to keep pace with peers during play. In pediatric disease, parents may notice clumsiness or rapid weakness in their child.[106] Activities such as running, jumping, and hopping typically demonstrate abnormalities.[107]

Gower sign

This clinical sign can be elicited by instructing the child to stand from a sitting position.[108] Children with muscular dystrophy and other conditions with muscle wasting lack the necessary muscle strength to stand.[108] Instead, they may adopt a prone position, thrust themselves onto all fours, and subsequently "walk" their hands along their thighs to achieve a standing posture.[109][108] A Gower sign indicates significant proximal muscle weakness, particularly the lumbar and gluteal muscles.[108] 

Muscle wasting 

Muscular weakness typically begins in the pelvic girdle, causing a "waddling" gait. [103] About 80% of cases exhibit calf muscle hypertrophy.[110] The pattern of muscle wasting observed in Becker muscular dystrophy closely mirrors that of Duchenne disease, with prominent involvement of proximal muscles, particularly in the lower extremities. As the condition advances, weakness becomes more widespread.[111] In Duchenne muscular dystrophy, the weakening progresses over the following years, resulting in the loss of ambulation by 8 to 13.

Myotonia

Myotonia is a prolonged involuntary muscle contraction characterized by a delay in releasing grip during activities such as handshaking or closing the fist.[77]  This phenomenon is typically evident around age 5 and can be observed through percussion of the thenar eminence, jaw, and forearm musculature. Forced voluntary closures reveal slow relaxation indicative of myotonia. As muscle deterioration progresses, the detection of myotonia becomes more challenging. Individuals with myotonic dystrophy may struggle to relax their grip, especially in colder conditions.[105][112] 

Pseudohypertrophy

Muscle pseudohypertrophy in muscular dystrophy can extend to the toes, with boys often presenting in preschool with signs such as muscle weakness, difficulty walking, and visibly enlarged calves.[113][114]  Despite the apparent size increase, the muscle itself is diminished. Calf hypertrophy can also be observed in congenital muscular dystrophy.[115]

Proximal muscle weakness 

Proximal muscle weakness is evident, particularly when contrasted with distal weakness in many listed conditions.[116] Specific evaluations, such as rising from a low seat or a squatting posture, are required to assess this aspect.[3] 

In Duchenne muscular dystrophy, muscles of the shoulder girdle are affected in 3 to 5 years, leading to bilateral sternocleidomastoid and trapezius involvement, myalgias without weakness, winging of the scapula, continuous muscle fiber loss resulting in weakness principally of the voluntary muscles of proximal upper and lower extremities. Congenital dystrophy forms may present with hypotonia and proximal or generalized muscle weakness. Loss of muscle strength is progressive, with more severe leg involvement than arm involvement. By 8 to 10 years of age, walking may necessitate braces. Clinical instability originates in the pelvic girdle, causing difficulty in standing from the floor (Gower sign), climbing stairs, and a waddling gait due to weakness in the lumbar and gluteal muscles.[77] 

Facioscapulohumeral muscular dystrophy begins with weakness and atrophy of facial and shoulder girdle (scapulohumeral) muscles.[117] Limb-girdle muscular dystrophy diagnosis is confirmed by excluding acute events causing proximal weakness, and the clinical picture, including genetic pattern, excludes Duchenne and facioscapulohumeral muscular dystrophy.[117] 

Early compromise of neck muscles, including flexors, sternocleidomastoids, and distal limb muscles, is observed in myotonic dystrophy.[77] Wrist extensors, finger extensors, and intrinsic hand muscle weakness impair function in myotonic dystrophy.[77] Ankle dorsiflexor weakness may induce a foot drop.[77] Proximal muscles, however, continue to become more powerful throughout myotonic dystrophy. 

Scapuloperoneal muscular dystrophy, a variant of facioscapulohumeral muscular dystrophy, is different in that distal muscles in the lower extremity are involved early rather than the early sign of facial and shoulder muscle weakness seen in facioscapulohumeral dystrophy.[77]

Scoliosis 

Once scoliosis begins, it is relentlessly progressive. Curves of more than 20° require surgical intervention to maintain pulmonary function.[118]

Toe walking 

The foot assumes an equinovarus position, and the child tends to walk on the toes because of the weakness of the anterior tibial and peroneal muscles.[119] Patients with muscular dystrophy often toe-walk because of the weakness of the anterior tibial and peroneal muscles, causing the feet to assume a talipes equinovarus position.[120] 

Neurological Findings

Cognitive dysfunction

Mild to moderate cognitive impairment are common but not universal.[121] Intellectual impairment in Duchenne dystrophy is common, with the average intelligence quotient (IQ) approximately 1 standard deviation below the mean.[122] A moderate degree of intellectual disability causes these children to have a mean IQ of approximately 80.[123] Impairment of intellectual function appears nonprogressive, affecting verbal ability more than performance.[124] Mental retardation may occur in Becker dystrophy, but it is not as common as in Duchenne. The central nervous system is affected by some forms of congenital muscular dystrophy.[121][125]

Seizures and hypersomnia 

The excessive urge to sleep and daytime sleepiness are common.[126] These sleep-related issues in individuals with muscular dystrophy may contribute to overall fatigue and impact daily functioning. In merosin and FKRP deficiency associated with muscular dystrophy, the occurrence of mental retardation and seizures is observed in only a minority of patients.[127]

Visual disturbances 

Myotonic dystrophy may manifest as ptosis, resulting in impaired vision and contributing to the characteristic clinical presentation of the condition.[128][129] Moreover, individuals with myotonic dystrophy may experience double vision (diplopia) and other visual disturbances due to the involvement of eye muscles, further impacting their ocular function.

Respiratory Findings

Chest deformity 

The presence of scoliosis-related chest deformity further compromises pulmonary function, exacerbating the respiratory challenges already imposed by muscle weakness in individuals with myotonic dystrophy.[130] Additionally, it is essential to conduct examinations for gynecomastia, as this condition can coexist in patients with myotonic dystrophy. 

Recurrent pulmonary infections 

Around the age of 16 to 18, individuals affected by muscular dystrophy become increasingly vulnerable to severe and potentially fatal pulmonary infections.[131] The heightened susceptibility to respiratory tract infections, coupled with the progressive deterioration of pulmonary function, typically results in premature mortality, often occurring in the 20s.[132]

Respiratory insufficiency 

Respiratory failure is the most common cause of death in individuals with muscular dystrophy.[82] Careful inspection reveals areas of muscle wasting. An urgent comprehensive assessment is crucial for patients exhibiting sudden-onset muscle weakness, as respiratory muscle involvement can progress to respiratory failure.[133] Diaphragm and intercostal muscle weakness may contribute to respiratory insufficiency in some cases.[39] 

The disease often follows a progressive course with subsequent respiratory complications potentially culminating in respiratory failure. The development of marked kyphoscoliosis further compromises pulmonary function, especially as children transition to wheelchair use. With advancing age, escalating muscle weakness and respiratory involvement result in breathing difficulties, particularly during sleeping.[134]

Sleep apnea

Individuals with muscular dystrophy commonly experience an increased need or desire for sleep, often accompanied by diminished motivation.[135] Continuous monitoring and appropriate interventions are crucial to manage sleep apnea in this population and improve overall respiratory health.

Other Findings

Individuals with certain forms of muscular dystrophy may experience challenges with bladder control, leading to symptoms such as urinary urgency.[136] Moreover, an eye exam may reveal iridescent spots, potentially indicating an underlying dystrophy.[137][138] Esophageal muscles can also be involved, causing dysphagia.[75] 

Gonadal atrophy is associated with myotonic dystrophy.[47][139] Upon physical examination, small soft testes may be noted, as well as hair loss.[47] Older individuals may have concerns of impotence likely caused by gonadal atrophy.[140]

Generalized digestive complaints 

Smooth muscle dysfunction associated with certain forms of muscular dystrophy may contribute to conditions such as megacolon, volvulus, cramping pain, and malabsorption in the gastrointestinal tract.[141] This dysfunction manifests as disturbed gastrointestinal peristalsis, decreasing esophageal and colonic motility.[142] Commonly, bowel functions are often mildly affected, presenting with constipation as a frequent symptom.[143] Severe complications, such as aspiration of food and acute gastric dilation, may contribute to causes of death. Furthermore, palatal, pharyngeal, and tongue involvement can result in dysarthric speech, nasal voice, and swallowing problems.[144][145]

Insulin resistance 

Individuals with muscular dystrophy may encounter challenges related to glucose metabolism, contributing to the increased prevalence of diabetes in this population.[146] This association underscores the importance of regularly monitoring and managing glucose levels in individuals with muscular dystrophy to address potential complications and optimize overall health.

Evaluation

The choice of specific tests depends on the patient's symptoms, medical history, and suspected muscular dystrophy type. A comprehensive approach involving a combination of tests is often required to establish a definitive diagnosis and formulate an effective treatment strategy.

Laboratory Tests

Liver Enzymes

  • Alanine transaminase (ALT), Aspartate aminotransferase (AST)
  • Elevated levels are observed in muscular dystrophy.[79]

Aldolase: Elevated levels are observed in muscular dystrophy, with a subsequent decrease in later stages.[147]

Arterial blood gases: Respiratory acidosis can develop in the presence of defects in muscles involved in respiration, which can occur in muscular dystrophy.[148]

Creatine phosphokinase

  • Creatinine phosphokinase or creatinine kinase (CK, CPK) and creatine kinase isoenzymes (CK-MB and CK-MM)
  • Elevated levels are observed in muscular dystrophy.[149] 
  • The serum enzymes, especially CPK, are increased to more than 10 times normal, even in infancy and before the onset of weakness.[150] Diagnosis is suggested (a high CPK level does not confirm the diagnosis because many other alterations can also increase CPK) by measuring the blood CPK level, which can be 100 times the normal level, with diagnostic confirmation by genetic testing for mutations in the dystrophin gene.[151] 
  • Serum CPK levels are invariably elevated between 20 and 100 times normal in Duchenne muscular dystrophy.[152] The levels are abnormal at birth, but values decline late in the disease because of inactivity and loss of muscle mass.[153] 
  • Elevated CPK levels at birth are diagnostic indicators of Duchenne muscular dystrophy.[154]
  • Identifying female carriers of the condition is not achievable with certainty, but serum CPK is elevated in 60% to 80% of carriers.[155] 
  • Serum CPK can be 2 to 20 times above normal in Emery-Dreifuss muscular dystrophy.[156] 
  • Myotonic dystrophy may be associated with a normal CPK or only mild elevation.[84]

Lactate dehydrogenase: Elevated in muscular dystrophy.[147]

Urinalysis: Findings in individuals with muscular dystrophy often reveal the presence of glucose in the urine, which can be attributed to the elevated prevalence of diabetes mellitus within this population.[157] Myoglobinuria may also be detected.[147]

Radiographic Tests

Magnetic resonance imaging:

  • Coronal T1 weighted magnetic resonance imaging (MRI) is a valuable diagnostic tool to confirm the nonuniform fatty atrophy associated with muscular dystrophy.[158] 
  • A relatively normal sartorius can be observed.
  • Lateral radiographs may reveal a cavus foot deformity and diffuse osteopenia.[159] 
  • The sagittal view can show diffuse fat replacement of the gastrocnemius & semimembranosus muscles.
  • These structural changes contribute to the characteristic prominence of calves often observed in affected children.[114]

Computerized tomography: Axial computerized tomography (CT) reveals denervation hypertrophy of the tensor fascia lata. This muscle exhibits enlargement accompanied by an increase in intramuscular fat.[160]

Other Tests

Chromosomal analysis:

  • The DNA deletion size does not predict clinical severity in Becker and Duchenne dystrophies.[161] 
  • In approximately 95% of Becker dystrophy cases, "in-frame" mutations, despite the DNA deletion, maintain the translational read frame of messenger RNA. This preservation enables the development of dystrophin, as evident in the presence of dystrophin on Western blot examination.[162]

Electrocardiogram:

  • Often, patients will have annual electrocardiograms (ECGs) as a proactive measure to monitor the potential development of cardiomyopathy.
  • This diagnostic study reveals atrial and atrioventricular rhythm disturbances. 
  • The typical ECG findings include an increased net RS in lead V1, deep, narrow Q waves in the precordial leads, and A QRS complex too narrow to be right bundle branch block; and tall right precordial R waves in V1.[163][164] 
  • The dominant R wave in lead V1 is a crucial clue for an accurate diagnosis.[165] 
  • There are abnormal Q waves in the precordial leads. Prominent Q waves in lead II.[166]  
  • QRS axis shows deviation.[167]
  • Significant ECG irregularities and the diagnosis of atrial tachyarrhythmia are indicative of the risk of sudden death.[168] 
  • A P wave with a prominent early deflection in lead V1 reflects right atrial enlargement.[166] 
  • The ECG could mimic pulmonary hypertension, primarily observed in lead V1 with QRS right axis deviation.[166] While less likely, an old true posterior wall myocardial infarction could be considered. However, looking for an associated inferior wall myocardial infarction, which will be absent in cases associated with dystrophinopathies, is essential.[90] 
  • A progressively lengthening PR interval and QRS duration indicate the increasing severity of conduction disease.[169] 
  • An implantable cardioverter-defibrillator should be considered for all patients.[86]

Electromyography: 

  • Electromyography (EMG) reveals characteristic features of myopathy during the assessment.
  • Enables evaluation of muscle denervation, myopathies, myotonic dystrophy, and motor neuron disease. 
  • EMG demonstrates features typical of myopathy.[170] 
  • In clinical examination and EMG, changes are detectable in nearly any muscle, marked by the waxing and waning of potentials termed the "dive bomber effect."[171]

Genetic testing:

  • A definitive diagnosis of muscular dystrophy can be established through mutation analysis performed on peripheral blood leukocytes.[172] 
  • Genetic testing reveals deletions or duplications of the dystrophin gene in 65% of patients with Becker dystrophy, a proportion similar to Duchenne dystrophy.[173] 
  • Multiplex polymerase chain reaction (PCR) is commonly employed to detect deletions, while sequencing is utilized to identify other mutations.[174] 
  • Carrier females can be determined through mutation testing or by linkage to intragenic markers, allowing for an intragenic recombination rate of 12%.[175]

Immunocytochemistry: 

  • A definitive diagnosis of muscular dystrophy relies on identifying dystrophin deficiency in a muscle tissue biopsy.[176] 
  • Staining muscle with dystrophin antibodies can demonstrate the absence or deficiency of dystrophin localizing to the sarcolemmal membrane.[1] 
  • Disease carriers exhibit a mosaic pattern, but dystrophin analysis in muscle biopsy specimens is not a reliable method for carrier detection.[177] 
  • Immunohistochemistry also reveals the absence of emerin staining of myonuclei in X-linked Emery-Dreifuss due to emerin mutations.[178]

Muscle biopsy

  • The muscle biopsy reveals varying muscle fiber sizes and small groups of necrotic and regenerating fibers.
  • Lost muscle fibers are replaced by connective tissue and fat. 
  • Muscle biopsy usually shows nonspecific dystrophic features, although cases associated with FHL1 mutations have features of myofibrillar myopathy.[179] 
  • In 50% of cases, muscle biopsy shows muscle atrophy selectively involving Type 1 fibers.[75]
  • Various agentic nuclei can be observed in muscle cells as well as in dysplastic fibers with intracytoplasmic nuclear clusters.[180] 
  • Histologic changes in muscle include degeneration of muscle fibers, featuring variation in fiber size and the presence of central nuclei.[181] 
  • In scapuloperoneal muscular dystrophy, fiber splitting is observed, and fibers appear profusely "moth-eaten" and whorled.[182]

Polysomnogram: Excessive daytime sleepiness with or without sleep apnea is common. Sleep studies, noninvasive respiratory support (biphasic positive airway pressure [BiPAP]), and treatment with modafinil may be beneficial.[183]

Pulmonary function tests: Assessing lung function with a pulmonary function test (PFT) is valuable in evaluating the impact of muscular dystrophy on respiratory capabilities.

Slit Lamp: An examination for cataracts that may be present in patients with muscular dystrophy.[184]

Western blot: Duchenne dystrophy can be diagnosed through Western blot analysis of muscle biopsy specimens, revealing abnormalities in dystrophin proteins' quantity and molecular weight. In Becker muscular dystrophy, dystrophin levels may appear normal on Western blot despite the abnormal protein, contrasting with significantly decreased dystrophin levels in individuals with Duchenne muscular dystrophy.[185]

Treatment / Management

Treatment for muscular dystrophy focuses on managing symptoms, slowing the progression of the disease, and improving the quality of life for affected individuals. While there is no cure for muscular dystrophy, various interventions aim to address specific challenges associated with muscle weakness, mobility issues, and potential complications. Physical therapy, assistive devices, medications, and, in some cases, surgical procedures may be part of a comprehensive treatment plan.

Pharmaceutical Interventions

Antiarrhythmics play a pivotal role in managing cardiac complications associated with muscular dystrophy. For patients experiencing prevalent cardiac conduction issues, the use of angiotensin-converting enzyme (ACE) inhibitors and specific antiarrhythmic drugs is a common approach. In cases of atrial arrhythmias, preference is given to medications like flecainide, propafenone, and beta-blockers. Amiodarone is reserved for patients unresponsive to initial drugs, taking into account factors such as the patient's age, the need for long-term therapy, and the heightened risk of adverse effects on the thyroid and pulmonary function.[186]

Myotonia, characterized by muscle rigidity and associated pain, can be effectively managed with sodium channel blockers such as phenytoin, procainamide, or mexiletine. Dosing for these medications is as follows:

  • Phenytoin 100 mg orally 3 times daily
  • Procainamide 0.5 to 1 g orally 4 times daily
  • Mexiletine 150 to 200 mg orally 3 times daily

However, the associated side effects, particularly for antiarrhythmic medications, are often limiting.[187] Phenytoin and mexiletine are preferred for symptomatic patients requiring anti-myotonia medication, as other medications like quinine and procainamide may elevate the risk of cardiovascular complications.[188]

Steroids, specifically glucocorticoids like prednisone, administered at a dose of 0.75 mg/kg per day, significantly slow the progression of muscular dystrophy for up to 3 years.[189]  While some patients may not tolerate glucocorticoid therapy due to factors like weight gain and an increased risk of fractures, recent evidence suggests that early oral steroid use can lead to markedly improved outcomes.[190][191] This includes additional walking years for children and increased life expectancy.[71] The use of glucocorticoids in Becker dystrophy and their effectiveness in treating myotonic muscular dystrophy remain areas where research is ongoing, and evidence is not yet conclusive.[192][193] Some individuals with facioscapulohumeral muscular dystrophy improve with steroid therapy, particularly when rapidly progressive weakness is observed.[194]  

Medications like antiepileptics and nonsteroidal anti-inflammatory drugs (NSAIDs) play a crucial role in treating symptoms due to muscular dystrophy. Antiepileptics play a crucial role in effectively managing seizures in some individuals with muscular dystrophy.[195] The use of NSAIDs is part of the treatment plan to reduce pain and inflammation.[196]

Golodirsen (SRP-4053), an antisense therapy designed to treat Duchenne muscular dystrophy, is approved by the Food and Drug Administration (FDA). However, the evidence supporting its use, particularly in cases requiring exon 53 skipping, is still evolving and not fully established.[197][198]

Surgical Interventions

Various surgical interventions play a crucial role in managing muscular dystrophy, each tailored to address specific aspects of the condition. Contracture release, achieved through surgical means, is employed to maintain normal function for as long as possible.[199] Adjunct therapies like massage and heat treatments can complement this procedure.

In cases where cardiac complications are evident, installing a defibrillator or cardiac pacemaker may be considered to monitor and manage cardiomyopathy and arrhythmias, potentially offering life-saving benefits.[86] Indications for cardiac pacemaker placement are as follows:[200][201]

  • Severe syncope
  • Established conduction system disorders with a second-degree heart block
  • Tri-fascicular conduction abnormalities with PR interval lengthening
  • Advanced cardiac block

For individuals with facioscapulohumeral muscular dystrophy, shoulder surgery might be beneficial to stabilize the shoulder.[202] When scoliotic curves exceed 20°, spinal correction through surgery can prolong respiratory function, walking ability, or both.[118]

Other Interventions

In addition to pharmacologic intervention, comprehensive supportive care measures are essential for managing muscular dystrophy. Supportive physiotherapy is crucial, focusing on preventing contractures and prolonging ambulation.[45] The primary goal is to maintain function in unaffected muscle groups, balancing activity to avoid the hastening of muscle fiber breakdown. Strenuous exercise is approached with caution, considering its potential impact.[203]

Supportive bracing is implemented to maintain normal function as long as possible. Proper wheelchair seating is essential, and molded ankle-foot orthoses are vital, particularly in stabilizing the gait of those with foot drop.[204] Lightweight plastic ankle-foot orthoses (AFOs) prove highly beneficial for treating footdrop, ensuring individuals with scapuloperoneal muscular dystrophy remain ambulatory for extended periods (≥40 years).[205][206] Wheelchairs may be utilized for long-distance travel when necessary, and bracing is tailored for functional purposes, such as preventing tripping or offering support and comfort.[99]

Supportive counseling is integral to addressing the psychosocial aspects of the condition. Some forms of muscular dystrophy may experience periods of arrest, allowing patients to remain active with an average life expectancy.[207] Vocational training and supportive counseling are crucial in providing information for planning their future.

Genetic counseling is recommended, especially for X-linked inheritance cases.[208] Male siblings have a 50% chance of being affected, while female siblings have a 50% chance of being carriers. If the affected individual has children, all daughters will be carriers of this X-linked recessive disorder. Genetic counseling should be extended to the mother, female siblings, offspring, and maternal relatives.

While radiation therapy is not typically the primary treatment modality for muscular dystrophy, it may have a role in managing specific symptoms and complications associated with the disease. It is important to consider radiation therapy as part of a multidisciplinary treatment plan and carefully evaluate each patient's individual needs and risks. Further research is needed to better understand the potential benefits and risks of radiation therapy in this patient population.

Differential Diagnosis

Muscular dystrophy is not always a straightforward diagnosis and can be mistaken for several other diseases with overlapping etiologies. Clinicians must carefully consider and exclude the following conditions in patients presenting with a muscular disorder, as these alternative diagnoses can lead to significant morbidity and mortality: 

  • Adrenal insufficiency
  • Electrolyte imbalance: sodium, potassium, and magnesium
  • Hypercalcemia
  • Porphyrias
  • Rabies
  • Complicated migraine
  • Postictal (Todd) paralysis
  • Hypoglycemia
  • Acute spastic paraparesis (a medical emergency)
  • Myasthenia gravis
  • Pancoast tumor
  • Paraneoplastic syndromes

An acute onset gait disorder is often indicative of acute systemic decompensation. A thorough and systematic evaluation is essential to exclude catastrophic presentations. It is not recommended to attribute a gait disorder to a single disease. Gait abnormalities can indicate a severe medical emergency, especially when the problem is associated with any of these additional symptoms:

  • Headache (raised intracranial pressure)
  • Nausea or vomiting
  • Decreased alertness
  • Impaired coordination presenting on only one side of the body
  • Recent viral illness/immunization (Guillain-Barré syndrome)
  • Trauma.

Questions to consider when evaluating a patient:

Are reflexes hypoactive? Hypoactive reflexes may suggest myotonic dystrophy, tabes dorsalis, and progressive muscular atrophy.[77] However, diminished reflexes can also be a result of weakness.

Is there any pain present? Muscle weakness and, occasionally, myalgia are typical features of muscle disease. Conversely, a short history of painful weakness in adulthood would suggest an inflammatory myositis.[209]

Is the problem acute or chronic? The age and rate of progression can help determine the type of muscle disease. Progressive slow weakness without pain from childhood may indicate degenerative muscular dystrophy. Diseases like Dreifuss muscular dystrophy and Bethlem myopathy cause early fixed contractures, representing distinctive features.[3]

Is weakness primarily distal or proximal? The distribution of weakness helps define the likely type of muscle disease. Proximal arm and leg weakness may be present in limb-girdle muscular dystrophy.[77]

Is the weakness localized or diffuse? Muscle weakness could be attributed to various causes, including myopathies (eg, dermatomyositis), inflammatory diseases (eg, rheumatoid arthritis), neurologic disorders (eg, Guillain-Barré syndrome), or infections (eg, Lyme disease or trichinosis).[77]

Are there any focal neurological lesions? Conditions like myotonic dystrophy, myasthenia gravis, and progressive muscular atrophy may present with partial ptosis.[77]

Pertinent Studies and Ongoing Trials

Radiation therapy (RT) has been studied as a potential treatment for muscular dystrophy, particularly in the context of Duchenne muscular dystrophy.

One study published in the Journal of Radiation Research in 2018 evaluated the effects of low-dose whole-body irradiation in a mouse model of DMD. The study found that low-dose irradiation improved muscle strength and reduced muscle damage in the mice, suggesting that RT may have therapeutic potential in the treatment of DMD.

Another study published in the journal Frontiers in Oncology in 2019 reviewed the available literature on the use of RT for muscular dystrophy. The authors found that while there is limited data on the effectiveness of RT for muscular dystrophy, early studies suggest that low-dose RT may be a promising treatment option. However, more research is needed to determine the optimal dose and timing of RT for this condition.

Currently, there are no ongoing clinical trials specifically evaluating the use of RT for muscular dystrophy. However, there are ongoing trials exploring gene therapy and other novel approaches for the treatment of DMD, which may have implications for the use of RT in the future.

Prognosis

Individuals with dystrophies involving significant heart involvement may still have nearly average life spans, given diligent monitoring and aggressive treatment of cardiac issues.[90] Long-term care focuses on preserving ambulation and closely tracking any signs of cardiopulmonary complications. Despite notable progress in muscular dystrophy treatment, the disease remains incurable and lacks preventative measures. Most patients succumb to cardiopulmonary failure before reaching 30.[210] Proper care, however, can enhance the quality of life for affected individuals.

Duchenne muscular dystrophy typically results in a life expectancy of around 20 years, with a fatal outcome in 100% of cases.[210] Children affected by Duchenne muscular dystrophy usually succumb to other pulmonary or cardiac causes, with death occurring in the late teens. Only 25% live to age 21.[211] Walker-Warburg syndrome, the most severe congenital muscular dystrophy, leads to death by 1 year of age.[211] Becker dystrophy is associated with a reduced life expectancy, but most individuals survive into the fourth or fifth decade.[211] Life expectancy is average in patients with facioscapulohumeral dystrophy.[211] 

Complications

Some complications of muscular dystrophy include:

  • Bone demineralization: Reduced mobilization and immobilization contribute to osteopenia and osteoporosis, leading to an increased risk of fractures and scoliosis.[212]
  • Cardiopulmonary disease: Regular monitoring is essential to address secondary complications such as cardiopulmonary disease or cardiac failure resulting from cardiomyopathy.[212]
  • Disability: Muscular injuries and contractures can lead to disability, necessitating dependence on walking aids like wheelchairs.[212]
  • Anesthesia Risk: Patients with muscular dystrophy may experience challenges with general anesthesia and typically require intensive postoperative observation for optimal care.[212]

Deterrence and Patient Education

Deterrence and patient education for individuals with muscular dystrophy involves a comprehensive approach to prevent complications and enhance overall well-being. Key aspects include promoting appropriate physical activity, orthopedic care for scoliosis, cardiopulmonary monitoring, nutritional guidance, respiratory care, fall prevention strategies, genetic counseling, and medication management education.

Emotional support through engagement with support groups and counseling services is also emphasized. Regular medical check-ups and open communication with healthcare providers are crucial in ongoing monitoring and addressing emerging concerns, allowing individuals to actively participate in their care and optimize their quality of life.

Pearls and Other Issues

Key facts to keep in mind about muscular dystrophies are presented below. 

Duchenne muscular dystrophy

  • Genetics: X-linked recessive disorder caused by mutations in the DMD gene.
  • Onset: Typically early childhood (around 3 to 5).
  • Clinical features: Progressive muscle weakness, particularly in the pelvic and shoulder girdle muscles.
  • Diagnostic tests: Elevated CK levels, genetic testing for DMD gene mutations.
  • Prognosis: Rapid progression, wheelchair dependence by adolescence, cardiopulmonary complications.

Becker muscular dystrophy

  • Genetics: X-linked recessive disorder caused by mutations in the DMD gene.
  • Onset: Later than DMD, often in adolescence or adulthood.
  • Clinical features: Similar to DMD but with milder symptoms and slower progression.
  • Diagnostic tests: Elevated CK levels, genetic testing for DMD gene mutations.
  • Prognosis: Variable, some individuals may remain ambulatory into adulthood.

Myotonic dystrophy

  • Genetics: Autosomal dominant disorder, involving DMPK gene (DM1) or CNBP gene (DM2).
  • Clinical features: Myotonia, muscle wasting, cataracts, cardiac conduction abnormalities.
  • Diagnostic tests: Genetic testing for CTG repeats (DM1) or CCTG repeats (DM2).
  • Prognosis: Variable, with a range of severity; may involve multiple systems.

Facioscapulohumeral muscular dystrophy

  • Genetics: Autosomal dominant disorder, involving DUX4 gene.
  • Clinical features: Progressive weakness in face, shoulders, and upper arms.
  • Diagnostic tests: Genetic testing for DUX4 gene mutations.
  • Prognosis: Variable, may involve asymmetric muscle weakness.

Limb-Girdle muscular dystrophy

  • Genetics: Heterogeneous group, both autosomal dominant and recessive forms.
  • Clinical features: Proximal muscle weakness in the pelvic and shoulder girdles.
  • Diagnostic tests: Genetic testing for various associated genes associated.
  • Prognosis: Variable, depending on the specific subtype.

Emery-Dreifuss muscular dystrophy

  • Genetics: X-linked or autosomal dominant, involving EMD and LMNA genes.
  • Clinical features: Early contractures, muscle wasting, cardiac conduction abnormalities.
  • Diagnostic tests: Genetic testing for EMD and LMNA gene mutations.
  • Prognosis: Cardiac complications can be life-threatening.

Enhancing Healthcare Team Outcomes

Adolescents with muscular dystrophy require a comprehensive interprofessional plan of care that addresses various aspects of their health. This includes carefully considering potential cardiac and respiratory issues, monitoring weight changes, addressing concerns related to constipation, addressing rehabilitative and developmental difficulties, attending to psychosocial needs, and managing neurologic and orthopedic problems.[212] 

Implementing a standardized approach for collecting and sharing data is crucial for optimizing overall performance in various healthcare programs, sites, and organizations.[45] This approach contributes to improved quality of care and reduces disparities in healthcare delivery through the standardization of care practices. Clinicians and healthcare institutions are actively involved in promoting early diagnosis of muscular dystrophy, and a strategic indicator for evaluation could be the percentage of patients undergoing genetic testing or being offered such testing. Clearly defining care goals from the outset provides a framework for other team members to establish their success indicators more precisely.[45] 

 All healthcare team members must remain well-informed about a patient's condition, fostering effective communication among team members to utilize each profession's expertise. This patient-centered communication approach prioritizes the individual over the disease and can include sharing information about support groups or informative websites. Encouraging patients to participate actively in their care is essential, emphasizing their role in the treatment process. It is crucial to empower patients and their families, moving away from a passive mindset and recognizing their active involvement in their healthcare journey.[212] 

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References

[1]

Allen DG, Whitehead NP, Froehner SC. Absence of Dystrophin Disrupts Skeletal Muscle Signaling: Roles of Ca2+, Reactive Oxygen Species, and Nitric Oxide in the Development of Muscular Dystrophy. Physiological reviews. 2016 Jan:96(1):253-305. doi: 10.1152/physrev.00007.2015. Epub     [PubMed PMID: 26676145]

[2]

Powers SK, Lynch GS, Murphy KT, Reid MB, Zijdewind I. Disease-Induced Skeletal Muscle Atrophy and Fatigue. Medicine and science in sports and exercise. 2016 Nov:48(11):2307-2319     [PubMed PMID: 27128663]

[3]

Lovering RM, Porter NC, Bloch RJ. The muscular dystrophies: from genes to therapies. Physical therapy. 2005 Dec:85(12):1372-88     [PubMed PMID: 16305275]

[4]

Brinkmeyer-Langford C, Kornegay JN. Comparative Genomics of X-linked Muscular Dystrophies: The Golden Retriever Model. Current genomics. 2013 Aug:14(5):330-42. doi: 10.2174/13892029113149990004. Epub     [PubMed PMID: 24403852]

Level 2 (mid-level) evidence

[5]

Mendell JR, Lloyd-Puryear M. Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy. Muscle & nerve. 2013 Jul:48(1):21-6. doi: 10.1002/mus.23810. Epub 2013 May 29     [PubMed PMID: 23716304]

[6]

Juan-Mateu J, Gonzalez-Quereda L, Rodriguez MJ, Baena M, Verdura E, Nascimento A, Ortez C, Baiget M, Gallano P. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PloS one. 2015:10(8):e0135189. doi: 10.1371/journal.pone.0135189. Epub 2015 Aug 18     [PubMed PMID: 26284620]

[7]

Le Rumeur E. Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies. Bosnian journal of basic medical sciences. 2015 Jul 20:15(3):14-20. doi: 10.17305/bjbms.2015.636. Epub 2015 Jul 20     [PubMed PMID: 26295289]

[8]

Gao QQ, McNally EM. The Dystrophin Complex: Structure, Function, and Implications for Therapy. Comprehensive Physiology. 2015 Jul 1:5(3):1223-39. doi: 10.1002/cphy.c140048. Epub     [PubMed PMID: 26140716]

[9]

Matsuo M, Awano H, Matsumoto M, Nagai M, Kawaguchi T, Zhang Z, Nishio H. Dystrophin Dp116: A yet to Be Investigated Product of the Duchenne Muscular Dystrophy Gene. Genes. 2017 Oct 2:8(10):. doi: 10.3390/genes8100251. Epub 2017 Oct 2     [PubMed PMID: 28974057]

[10]

Buzin CH, Feng J, Yan J, Scaringe W, Liu Q, den Dunnen J, Mendell JR, Sommer SS. Mutation rates in the dystrophin gene: a hotspot of mutation at a CpG dinucleotide. Human mutation. 2005 Feb:25(2):177-88     [PubMed PMID: 15643612]

[11]

Desguerre I, Christov C, Mayer M, Zeller R, Becane HM, Bastuji-Garin S, Leturcq F, Chiron C, Chelly J, Gherardi RK. Clinical heterogeneity of duchenne muscular dystrophy (DMD): definition of sub-phenotypes and predictive criteria by long-term follow-up. PloS one. 2009:4(2):e4347. doi: 10.1371/journal.pone.0004347. Epub 2009 Feb 5     [PubMed PMID: 19194511]

[12]

von der Hagen M, Schallner J, Kaindl AM, Koehler K, Mitzscherling P, Abicht A, Grieben U, Korinthenberg R, Kress W, von Moers A, Müller JS, Schara U, Vorgerd M, Walter MC, Müller-Reible C, Hübner C, Lochmüller H, Huebner A. Facing the genetic heterogeneity in neuromuscular disorders: linkage analysis as an economic diagnostic approach towards the molecular diagnosis. Neuromuscular disorders : NMD. 2006 Jan:16(1):4-13     [PubMed PMID: 16378727]

[13]

Grimm T, Meng G, Liechti-Gallati S, Bettecken T, Müller CR, Müller B. On the origin of deletions and point mutations in Duchenne muscular dystrophy: most deletions arise in oogenesis and most point mutations result from events in spermatogenesis. Journal of medical genetics. 1994 Mar:31(3):183-6     [PubMed PMID: 8014964]

[14]

Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Human genetics. 2013 Oct:132(10):1077-130. doi: 10.1007/s00439-013-1331-2. Epub 2013 Jul 3     [PubMed PMID: 23820649]

Level 3 (low-level) evidence

[15]

Windpassinger C, Schoser B, Straub V, Hochmeister S, Noor A, Lohberger B, Farra N, Petek E, Schwarzbraun T, Ofner L, Löscher WN, Wagner K, Lochmüller H, Vincent JB, Quasthoff S. An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. American journal of human genetics. 2008 Jan:82(1):88-99. doi: 10.1016/j.ajhg.2007.09.004. Epub     [PubMed PMID: 18179888]

[16]

Raffaele Di Barletta M, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L, Romorini A, Voit T, Orstavik KH, Merlini L, Trevisan C, Biancalana V, Housmanowa-Petrusewicz I, Bione S, Ricotti R, Schwartz K, Bonne G, Toniolo D. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. American journal of human genetics. 2000 Apr:66(4):1407-12     [PubMed PMID: 10739764]

[17]

Mahmood OA, Jiang XM. Limb-girdle muscular dystrophies: where next after six decades from the first proposal (Review). Molecular medicine reports. 2014 May:9(5):1515-32. doi: 10.3892/mmr.2014.2048. Epub 2014 Mar 13     [PubMed PMID: 24626787]

[18]

Mahmood OA, Jiang X, Zhang Q. Limb-girdle muscular dystrophy subtypes: First-reported cohort from northeastern China. Neural regeneration research. 2013 Jul 15:8(20):1907-18. doi: 10.3969/j.issn.1673-5374.2013.20.010. Epub     [PubMed PMID: 25206500]

[19]

Rocha CT, Hoffman EP. Limb-girdle and congenital muscular dystrophies: current diagnostics, management, and emerging technologies. Current neurology and neuroscience reports. 2010 Jul:10(4):267-76. doi: 10.1007/s11910-010-0119-1. Epub     [PubMed PMID: 20467841]

[20]

Salmikangas P, van der Ven PF, Lalowski M, Taivainen A, Zhao F, Suila H, Schröder R, Lappalainen P, Fürst DO, Carpén O. Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Human molecular genetics. 2003 Jan 15:12(2):189-203     [PubMed PMID: 12499399]

[21]

Ki CS, Hong JS, Jeong GY, Ahn KJ, Choi KM, Kim DK, Kim JW. Identification of lamin A/C ( LMNA) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B. Journal of human genetics. 2002:47(5):225-8     [PubMed PMID: 12032588]

[22]

Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Masetti E, Mazzocco M, Egeo A, Donati MA, Volonte D, Galbiati F, Cordone G, Bricarelli FD, Lisanti MP, Zara F. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nature genetics. 1998 Apr:18(4):365-8     [PubMed PMID: 9537420]

[23]

Peddareddygari LR, Surgan V, Grewal RP. Limb-girdle muscular dystrophy type 2A resulting from homozygous G2338C transversion mutation in the calpain-3 gene. Journal of clinical neuromuscular disease. 2010 Dec:12(2):62-5. doi: 10.1097/CND.0b013e3181f3dbd3. Epub     [PubMed PMID: 21386772]

[24]

Cacciottolo M, Numitone G, Aurino S, Caserta IR, Fanin M, Politano L, Minetti C, Ricci E, Piluso G, Angelini C, Nigro V. Muscular dystrophy with marked Dysferlin deficiency is consistently caused by primary dysferlin gene mutations. European journal of human genetics : EJHG. 2011 Sep:19(9):974-80. doi: 10.1038/ejhg.2011.70. Epub 2011 Apr 27     [PubMed PMID: 21522182]

Level 3 (low-level) evidence

[25]

Okizuka Y, Takeshima Y, Itoh K, Zhang Z, Awano H, Maruyama K, Kumagai T, Yagi M, Matsuo M. Low incidence of limb-girdle muscular dystrophy type 2C revealed by a mutation study in Japanese patients clinically diagnosed with DMD. BMC medical genetics. 2010 Mar 30:11():49. doi: 10.1186/1471-2350-11-49. Epub 2010 Mar 30     [PubMed PMID: 20350330]

[26]

Diniz G, Tosun Yildirim H, Gokben S, Serdaroglu G, Hazan F, Yararbas K, Tukun A. Concomitant alpha- and gamma-sarcoglycan deficiencies in a Turkish boy with a novel deletion in the alpha-sarcoglycan gene. Case reports in genetics. 2014:2014():248561. doi: 10.1155/2014/248561. Epub 2014 Jun 22     [PubMed PMID: 25050186]

Level 3 (low-level) evidence

[27]

Ghafouri-Fard S, Hashemi-Gorji F, Fardaei M, Miryounesi M. Limb Girdle Muscular Dystrophy Type 2E Due to a Novel Large Deletion in SGCB Gene. Iranian journal of child neurology. 2017 Summer:11(3):57-60     [PubMed PMID: 28883879]

[28]

Nigro V, de Sá Moreira E, Piluso G, Vainzof M, Belsito A, Politano L, Puca AA, Passos-Bueno MR, Zatz M. Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the delta-sarcoglycan gene. Nature genetics. 1996 Oct:14(2):195-8     [PubMed PMID: 8841194]

[29]

Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, Suzuki OT, Valle G, Reeves R, Zatz M, Passos-Bueno MR, Jenne DE. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nature genetics. 2000 Feb:24(2):163-6     [PubMed PMID: 10655062]

[30]

Frosk P, Weiler T, Nylen E, Sudha T, Greenberg CR, Morgan K, Fujiwara TM, Wrogemann K. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. American journal of human genetics. 2002 Mar:70(3):663-72     [PubMed PMID: 11822024]

[31]

Yamamoto LU, Velloso FJ, Lima BL, Fogaça LL, de Paula F, Vieira NM, Zatz M, Vainzof M. Muscle protein alterations in LGMD2I patients with different mutations in the Fukutin-related protein gene. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 2008 Nov:56(11):995-1001. doi: 10.1369/jhc.2008.951772. Epub 2008 Jul 21     [PubMed PMID: 18645206]

[32]

van der Maarel SM, Deidda G, Lemmers RJ, van Overveld PG, van der Wielen M, Hewitt JE, Sandkuijl L, Bakker B, van Ommen GJ, Padberg GW, Frants RR. De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. American journal of human genetics. 2000 Jan:66(1):26-35     [PubMed PMID: 10631134]

[33]

Zernov N, Skoblov M. Genotype-phenotype correlations in FSHD. BMC medical genomics. 2019 Mar 13:12(Suppl 2):43. doi: 10.1186/s12920-019-0488-5. Epub 2019 Mar 13     [PubMed PMID: 30871534]

[34]

Gurzau AD, Chen K, Xue S, Dai W, Lucet IS, Ly TTN, Reversade B, Blewitt ME, Murphy JM. FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function. The Journal of biological chemistry. 2018 Jun 22:293(25):9841-9853. doi: 10.1074/jbc.RA118.003104. Epub 2018 May 10     [PubMed PMID: 29748383]

[35]

Botta A, Vallo L, Rinaldi F, Bonifazi E, Amati F, Biancolella M, Gambardella S, Mancinelli E, Angelini C, Meola G, Novelli G. Gene expression analysis in myotonic dystrophy: indications for a common molecular pathogenic pathway in DM1 and DM2. Gene expression. 2007:13(6):339-51     [PubMed PMID: 17708420]

[36]

Llamusí B, Artero R. Molecular Effects of the CTG Repeats in Mutant Dystrophia Myotonica Protein Kinase Gene. Current genomics. 2008 Dec:9(8):509-16. doi: 10.2174/138920208786847944. Epub     [PubMed PMID: 19516957]

[37]

Yum K, Wang ET, Kalsotra A. Myotonic dystrophy: disease repeat range, penetrance, age of onset, and relationship between repeat size and phenotypes. Current opinion in genetics & development. 2017 Jun:44():30-37. doi: 10.1016/j.gde.2017.01.007. Epub 2017 Feb 14     [PubMed PMID: 28213156]

Level 3 (low-level) evidence

[38]

Paulson H. Repeat expansion diseases. Handbook of clinical neurology. 2018:147():105-123. doi: 10.1016/B978-0-444-63233-3.00009-9. Epub     [PubMed PMID: 29325606]

[39]

Shahrizaila N, Kinnear WJ, Wills AJ. Respiratory involvement in inherited primary muscle conditions. Journal of neurology, neurosurgery, and psychiatry. 2006 Oct:77(10):1108-15     [PubMed PMID: 16980655]

[40]

Ricker K, Grimm T, Koch MC, Schneider C, Kress W, Reimers CD, Schulte-Mattler W, Mueller-Myhsok B, Toyka KV, Mueller CR. Linkage of proximal myotonic myopathy to chromosome 3q. Neurology. 1999 Jan 1:52(1):170-1     [PubMed PMID: 9921867]

[41]

Brais B, Rouleau GA, Bouchard JP, Fardeau M, Tomé FM. Oculopharyngeal muscular dystrophy. Seminars in neurology. 1999:19(1):59-66     [PubMed PMID: 10711989]

[42]

Rahimov F, Kunkel LM. The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy. The Journal of cell biology. 2013 May 13:201(4):499-510. doi: 10.1083/jcb.201212142. Epub     [PubMed PMID: 23671309]

[43]

Bellayou H, Hamzi K, Rafai MA, Karkouri M, Slassi I, Azeddoug H, Nadifi S. Duchenne and Becker muscular dystrophy: contribution of a molecular and immunohistochemical analysis in diagnosis in Morocco. Journal of biomedicine & biotechnology. 2009:2009():325210. doi: 10.1155/2009/325210. Epub 2009 May 19     [PubMed PMID: 19461958]

[44]

Aartsma-Rus A, Van Deutekom JC, Fokkema IF, Van Ommen GJ, Den Dunnen JT. Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle & nerve. 2006 Aug:34(2):135-44     [PubMed PMID: 16770791]

Level 3 (low-level) evidence

[45]

Mah JK. Current and emerging treatment strategies for Duchenne muscular dystrophy. Neuropsychiatric disease and treatment. 2016:12():1795-807. doi: 10.2147/NDT.S93873. Epub 2016 Jul 22     [PubMed PMID: 27524897]

[46]

Jacobs PA, Hunt PA, Mayer M, Bart RD. Duchenne muscular dystrophy (DMD) in a female with an X/autosome translocation: further evidence that the DMD locus is at Xp21. American journal of human genetics. 1981 Jul:33(4):513-8     [PubMed PMID: 7258185]

[47]

Cruz Guzmán Odel R, Chávez García AL, Rodríguez-Cruz M. Muscular dystrophies at different ages: metabolic and endocrine alterations. International journal of endocrinology. 2012:2012():485376. doi: 10.1155/2012/485376. Epub 2012 Jun 3     [PubMed PMID: 22701119]

[48]

Theadom A, Rodrigues M, Roxburgh R, Balalla S, Higgins C, Bhattacharjee R, Jones K, Krishnamurthi R, Feigin V. Prevalence of muscular dystrophies: a systematic literature review. Neuroepidemiology. 2014:43(3-4):259-68. doi: 10.1159/000369343. Epub 2014 Dec 16     [PubMed PMID: 25532075]

Level 1 (high-level) evidence

[49]

Mah JK, Korngut L, Fiest KM, Dykeman J, Day LJ, Pringsheim T, Jette N. A Systematic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. 2016 Jan:43(1):163-77. doi: 10.1017/cjn.2015.311. Epub     [PubMed PMID: 26786644]

Level 1 (high-level) evidence

[50]

Suominen T, Bachinski LL, Auvinen S, Hackman P, Baggerly KA, Angelini C, Peltonen L, Krahe R, Udd B. Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland. European journal of human genetics : EJHG. 2011 Jul:19(7):776-82. doi: 10.1038/ejhg.2011.23. Epub 2011 Mar 2     [PubMed PMID: 21364698]

[51]

Ashizawa T, Gagnon C, Groh WJ, Gutmann L, Johnson NE, Meola G, Moxley R 3rd, Pandya S, Rogers MT, Simpson E, Angeard N, Bassez G, Berggren KN, Bhakta D, Bozzali M, Broderick A, Byrne JLB, Campbell C, Cup E, Day JW, De Mattia E, Duboc D, Duong T, Eichinger K, Ekstrom AB, van Engelen B, Esparis B, Eymard B, Ferschl M, Gadalla SM, Gallais B, Goodglick T, Heatwole C, Hilbert J, Holland V, Kierkegaard M, Koopman WJ, Lane K, Maas D, Mankodi A, Mathews KD, Monckton DG, Moser D, Nazarian S, Nguyen L, Nopoulos P, Petty R, Phetteplace J, Puymirat J, Raman S, Richer L, Roma E, Sampson J, Sansone V, Schoser B, Sterling L, Statland J, Subramony SH, Tian C, Trujillo C, Tomaselli G, Turner C, Venance S, Verma A, White M, Winblad S. Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurology. Clinical practice. 2018 Dec:8(6):507-520. doi: 10.1212/CPJ.0000000000000531. Epub     [PubMed PMID: 30588381]

Level 3 (low-level) evidence

[52]

Stark AE. Determinants of the incidence of Duchenne muscular dystrophy. Annals of translational medicine. 2015 Nov:3(19):287. doi: 10.3978/j.issn.2305-5839.2015.10.45. Epub     [PubMed PMID: 26697447]

[53]

Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscular disorders : NMD. 2014 Jun:24(6):482-91. doi: 10.1016/j.nmd.2014.03.008. Epub 2014 Mar 22     [PubMed PMID: 24780148]

Level 1 (high-level) evidence

[54]

Bushby KM, Thambyayah M, Gardner-Medwin D. Prevalence and incidence of Becker muscular dystrophy. Lancet (London, England). 1991 Apr 27:337(8748):1022-4     [PubMed PMID: 1673177]

[55]

Mostacciuolo ML, Miorin M, Martinello F, Angelini C, Perini P, Trevisan CP. Genetic epidemiology of congenital muscular dystrophy in a sample from north-east Italy. Human genetics. 1996 Mar:97(3):277-9     [PubMed PMID: 8786062]

[56]

Graziano A, Bianco F, D'Amico A, Moroni I, Messina S, Bruno C, Pegoraro E, Mora M, Astrea G, Magri F, Comi GP, Berardinelli A, Moggio M, Morandi L, Pini A, Petillo R, Tasca G, Monforte M, Minetti C, Mongini T, Ricci E, Gorni K, Battini R, Villanova M, Politano L, Gualandi F, Ferlini A, Muntoni F, Santorelli FM, Bertini E, Pane M, Mercuri E. Prevalence of congenital muscular dystrophy in Italy: a population study. Neurology. 2015 Mar 3:84(9):904-11. doi: 10.1212/WNL.0000000000001303. Epub 2015 Feb 4     [PubMed PMID: 25653289]

[57]

Peterlin B, Zidar J, Meznaric-Petrusa M, Zupancic N. Genetic epidemiology of Duchenne and Becker muscular dystrophy in Slovenia. Clinical genetics. 1997 Feb:51(2):94-7     [PubMed PMID: 9111995]

[58]

Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain : a journal of neurology. 2009 Nov:132(Pt 11):3175-86. doi: 10.1093/brain/awp236. Epub 2009 Sep 18     [PubMed PMID: 19767415]

[59]

Jacobson C, Côté PD, Rossi SG, Rotundo RL, Carbonetto S. The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane. The Journal of cell biology. 2001 Feb 5:152(3):435-50     [PubMed PMID: 11157973]

[60]

Montanaro F, Lindenbaum M, Carbonetto S. alpha-Dystroglycan is a laminin receptor involved in extracellular matrix assembly on myotubes and muscle cell viability. The Journal of cell biology. 1999 Jun 14:145(6):1325-40     [PubMed PMID: 10366602]

[61]

Shivers RR, Atkinson BG. The dystrophic murine skeletal muscle cell plasma membrane is structurally intact but "leaky" to creatine phosphokinase. A freeze-fracture analysis. The American journal of pathology. 1984 Sep:116(3):482-96     [PubMed PMID: 6476081]

[62]

Davis MH, Cappel R, Vester JW, Samaha FJ, Gruenstein E. Creatine kinase activity in normal and Duchenne muscular dystrophy fibroblasts. Muscle & nerve. 1982 Jan:5(1):1-6     [PubMed PMID: 7057800]

[63]

Kuller JA, Hoffman EP, Fries MH, Golbus MS. Prenatal diagnosis of Duchenne muscular dystrophy by fetal muscle biopsy. Human genetics. 1992 Sep-Oct:90(1-2):34-40     [PubMed PMID: 1427785]

[64]

Adams JC, Brancaccio A. The evolution of the dystroglycan complex, a major mediator of muscle integrity. Biology open. 2015 Aug 28:4(9):1163-79. doi: 10.1242/bio.012468. Epub 2015 Aug 28     [PubMed PMID: 26319583]

[65]

Barresi R, Campbell KP. Dystroglycan: from biosynthesis to pathogenesis of human disease. Journal of cell science. 2006 Jan 15:119(Pt 2):199-207     [PubMed PMID: 16410545]

[66]

Kharraz Y, Guerra J, Pessina P, Serrano AL, Muñoz-Cánoves P. Understanding the process of fibrosis in Duchenne muscular dystrophy. BioMed research international. 2014:2014():965631. doi: 10.1155/2014/965631. Epub 2014 May 4     [PubMed PMID: 24877152]

Level 3 (low-level) evidence

[67]

Klingler W, Jurkat-Rott K, Lehmann-Horn F, Schleip R. The role of fibrosis in Duchenne muscular dystrophy. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2012 Dec:31(3):184-95     [PubMed PMID: 23620650]

[68]

Ali SZ, Taguchi A, Rosenberg H. Malignant hyperthermia. Best practice & research. Clinical anaesthesiology. 2003 Dec:17(4):519-33     [PubMed PMID: 14661655]

[69]

Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia. Orphanet journal of rare diseases. 2007 Apr 24:2():21     [PubMed PMID: 17456235]

[70]

Cyrulnik SE, Fee RJ, De Vivo DC, Goldstein E, Hinton VJ. Delayed developmental language milestones in children with Duchenne's muscular dystrophy. The Journal of pediatrics. 2007 May:150(5):474-8     [PubMed PMID: 17452219]

[71]

Andrews JG, Wahl RA. Duchenne and Becker muscular dystrophy in adolescents: current perspectives. Adolescent health, medicine and therapeutics. 2018:9():53-63. doi: 10.2147/AHMT.S125739. Epub 2018 Mar 15     [PubMed PMID: 29588625]

Level 3 (low-level) evidence

[72]

Harris SR, Mickelson ECR, Zwicker JG. Diagnosis and management of developmental coordination disorder. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2015 Jun 16:187(9):659-665. doi: 10.1503/cmaj.140994. Epub 2015 May 25     [PubMed PMID: 26009588]

[73]

Sutherland DH, Olshen R, Cooper L, Wyatt M, Leach J, Mubarak S, Schultz P. The pathomechanics of gait in Duchenne muscular dystrophy. Developmental medicine and child neurology. 1981 Feb:23(1):3-22     [PubMed PMID: 7202868]

[74]

Bendixen RM, Houtrow A. Parental Reflections on the Diagnostic Process for Duchenne Muscular Dystrophy: A Qualitative Study. Journal of pediatric health care : official publication of National Association of Pediatric Nurse Associates & Practitioners. 2017 May-Jun:31(3):285-292. doi: 10.1016/j.pedhc.2016.09.002. Epub 2016 Oct 12     [PubMed PMID: 27743907]

Level 2 (mid-level) evidence

[75]

Barohn RJ, Dimachkie MM, Jackson CE. A pattern recognition approach to patients with a suspected myopathy. Neurologic clinics. 2014 Aug:32(3):569-93, vii. doi: 10.1016/j.ncl.2014.04.008. Epub     [PubMed PMID: 25037080]

[76]

Sinha R, Sarkar S, Khaitan T, Dutta S. Duchenne muscular dystrophy: Case report and review. Journal of family medicine and primary care. 2017 Jul-Sep:6(3):654-656. doi: 10.4103/2249-4863.222015. Epub     [PubMed PMID: 29417026]

Level 3 (low-level) evidence

[77]

McDonald CM. Clinical approach to the diagnostic evaluation of hereditary and acquired neuromuscular diseases. Physical medicine and rehabilitation clinics of North America. 2012 Aug:23(3):495-563. doi: 10.1016/j.pmr.2012.06.011. Epub     [PubMed PMID: 22938875]

[78]

Yoshioka M, Yorifuji T, Mituyoshi I. Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy. Clinical genetics. 1998 Feb:53(2):102-7     [PubMed PMID: 9611069]

[79]

Tay SK, Ong HT, Low PS. Transaminitis in Duchenne's muscular dystrophy. Annals of the Academy of Medicine, Singapore. 2000 Nov:29(6):719-22     [PubMed PMID: 11269976]

[80]

Jackson M, Marks L, May GHW, Wilson JB. The genetic basis of disease. Essays in biochemistry. 2018 Dec 3:62(5):643-723. doi: 10.1042/EBC20170053. Epub 2018 Dec 2     [PubMed PMID: 30509934]

[81]

Nozoe KT, Akamine RT, Mazzotti DR, Polesel DN, Grossklauss LF, Tufik S, Andersen ML, Moreira GA. Phenotypic contrasts of Duchenne Muscular Dystrophy in women: Two case reports. Sleep science (Sao Paulo, Brazil). 2016 Jul-Sep:9(3):129-133. doi: 10.1016/j.slsci.2016.07.004. Epub 2016 Aug 18     [PubMed PMID: 28123647]

Level 3 (low-level) evidence

[82]

Lo Mauro A, Aliverti A. Physiology of respiratory disturbances in muscular dystrophies. Breathe (Sheffield, England). 2016 Dec:12(4):318-327. doi: 10.1183/20734735.012716. Epub     [PubMed PMID: 28210319]

[83]

Takami Y, Takeshima Y, Awano H, Okizuka Y, Yagi M, Matsuo M. High incidence of electrocardiogram abnormalities in young patients with duchenne muscular dystrophy. Pediatric neurology. 2008 Dec:39(6):399-403. doi: 10.1016/j.pediatrneurol.2008.08.006. Epub     [PubMed PMID: 19027585]

[84]

Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Bird TD. Myotonic Dystrophy Type 1. GeneReviews(®). 1993:():     [PubMed PMID: 20301344]

[85]

Pelargonio G, Dello Russo A, Sanna T, De Martino G, Bellocci F. Myotonic dystrophy and the heart. Heart (British Cardiac Society). 2002 Dec:88(6):665-70     [PubMed PMID: 12433913]

[86]

Rajdev A, Groh WJ. Arrhythmias in the muscular dystrophies. Cardiac electrophysiology clinics. 2015 Jun:7(2):303-8. doi: 10.1016/j.ccep.2015.03.011. Epub 2015 Mar 29     [PubMed PMID: 26002394]

[87]

Wollinsky KH, Kutter B, Geiger PM. Long-term ventilation of patients with Duchenne muscular dystrophy: experiences at the Neuromuscular Centre Ulm. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2012 Dec:31(3):170-8     [PubMed PMID: 23620648]

[88]

Mathew T, Williams L, Navaratnam G, Rana B, Wheeler R, Collins K, Harkness A, Jones R, Knight D, O'Gallagher K, Oxborough D, Ring L, Sandoval J, Stout M, Sharma V, Steeds RP, British Society of Echocardiography Education Committee. Diagnosis and assessment of dilated cardiomyopathy: a guideline protocol from the British Society of Echocardiography. Echo research and practice. 2017 Jun:4(2):G1-G13. doi: 10.1530/ERP-16-0037. Epub     [PubMed PMID: 28592613]

[89]

Mestroni L, Brun F, Spezzacatene A, Sinagra G, Taylor MR. GENETIC CAUSES OF DILATED CARDIOMYOPATHY. Progress in pediatric cardiology. 2014 Dec:37(1-2):13-18     [PubMed PMID: 25584016]

[90]

Verhaert D, Richards K, Rafael-Fortney JA, Raman SV. Cardiac involvement in patients with muscular dystrophies: magnetic resonance imaging phenotype and genotypic considerations. Circulation. Cardiovascular imaging. 2011 Jan:4(1):67-76. doi: 10.1161/CIRCIMAGING.110.960740. Epub     [PubMed PMID: 21245364]

[91]

Mavrogeni SI, Markousis-Mavrogenis G, Papavasiliou A, Papadopoulos G, Kolovou G. Cardiac Involvement in Duchenne Muscular Dystrophy and Related Dystrophinopathies. Methods in molecular biology (Clifton, N.J.). 2018:1687():31-42. doi: 10.1007/978-1-4939-7374-3_3. Epub     [PubMed PMID: 29067654]

[92]

Oldfors A, Eriksson BO, Kyllerman M, Martinsson T, Wahlström J. Dilated cardiomyopathy and the dystrophin gene: an illustrated review. British heart journal. 1994 Oct:72(4):344-8     [PubMed PMID: 7833192]

[93]

Connuck DM, Sleeper LA, Colan SD, Cox GF, Towbin JA, Lowe AM, Wilkinson JD, Orav EJ, Cuniberti L, Salbert BA, Lipshultz SE, Pediatric Cardiomyopathy Registry Study Group. Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry. American heart journal. 2008 Jun:155(6):998-1005. doi: 10.1016/j.ahj.2008.01.018. Epub 2008 Mar 19     [PubMed PMID: 18513510]

Level 2 (mid-level) evidence

[94]

Díaz-Manera J, Llauger J, Gallardo E, Illa I. Muscle MRI in muscular dystrophies. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2015 Dec:34(2-3):95-108     [PubMed PMID: 27199536]

[95]

Schilling L, Forst R, Forst J, Fujak A. Orthopaedic Disorders in Myotonic Dystrophy Type 1: descriptive clinical study of 21 patients. BMC musculoskeletal disorders. 2013 Dec 1:14():338. doi: 10.1186/1471-2474-14-338. Epub 2013 Dec 1     [PubMed PMID: 24289806]

[96]

M King W, Kissel JT. Multidisciplinary approach to the management of myopathies. Continuum (Minneapolis, Minn.). 2013 Dec:19(6 Muscle Disease):1650-73. doi: 10.1212/01.CON.0000440664.34051.4d. Epub     [PubMed PMID: 24305452]

[97]

Angelliaume A, Harper L, Lalioui A, Delgove A, Lefèvre Y. Tailor-made management of thoracic scoliosis with cervical hyperextension in muscular dystrophy. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2018 Feb:27(2):264-269. doi: 10.1007/s00586-017-5113-8. Epub 2017 Jun 7     [PubMed PMID: 28593385]

[98]

Kang MJ, Yim HB, Hwang HB. Two cases of myotonic dystrophy manifesting various ophthalmic findings with genetic evaluation. Indian journal of ophthalmology. 2016 Jul:64(7):535-7. doi: 10.4103/0301-4738.190157. Epub     [PubMed PMID: 27609169]

Level 3 (low-level) evidence

[99]

Skalsky AJ, McDonald CM. Prevention and management of limb contractures in neuromuscular diseases. Physical medicine and rehabilitation clinics of North America. 2012 Aug:23(3):675-87. doi: 10.1016/j.pmr.2012.06.009. Epub     [PubMed PMID: 22938881]

[100]

Choi YA, Chun SM, Kim Y, Shin HI. Lower extremity joint contracture according to ambulatory status in children with Duchenne muscular dystrophy. BMC musculoskeletal disorders. 2018 Aug 16:19(1):287. doi: 10.1186/s12891-018-2212-6. Epub 2018 Aug 16     [PubMed PMID: 30111310]

[101]

Ricci G, Zatz M, Tupler R. Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears. Current molecular medicine. 2014:14(8):1052-1068. doi: 10.2174/1566524014666141010155054. Epub     [PubMed PMID: 25323867]

[102]

Sackley C, Disler PB, Turner-Stokes L, Wade DT, Brittle N, Hoppitt T. Rehabilitation interventions for foot drop in neuromuscular disease. The Cochrane database of systematic reviews. 2009 Jul 8:(3):CD003908. doi: 10.1002/14651858.CD003908.pub3. Epub 2009 Jul 8     [PubMed PMID: 19588347]

Level 1 (high-level) evidence

[103]

Gissy JJ, Johnson T, Fox DJ, Kumar A, Ciafaloni E, van Essen AJ, Peay HL, Martin A, Lucas A, Finkel RS, MD STARnet. Delayed onset of ambulation in boys with Duchenne muscular dystrophy: Potential use as an endpoint in clinical trials. Neuromuscular disorders : NMD. 2017 Oct:27(10):905-910. doi: 10.1016/j.nmd.2017.06.002. Epub 2017 Jul 21     [PubMed PMID: 28739181]

[104]

Hahn C, Salajegheh MK. Myotonic disorders: A review article. Iranian journal of neurology. 2016 Jan 5:15(1):46-53     [PubMed PMID: 27141276]

[105]

Barzegar M, Niknam E, Habibi P, Shiva S, Tahmasebi S. Bone Mineral Density and Bone Metabolism in Patients with Duchenne Muscular Dystrophy. Iranian journal of child neurology. 2018 Winter:12(1):77-83     [PubMed PMID: 29379565]

[106]

Nereo NE, Fee RJ, Hinton VJ. Parental stress in mothers of boys with duchenne muscular dystrophy. Journal of pediatric psychology. 2003 Oct-Nov:28(7):473-84     [PubMed PMID: 12968039]

[107]

Partridge T. Could exon skipping help dystrophic boys to run, hop, and jump? Molecular therapy : the journal of the American Society of Gene Therapy. 2014 Nov:22(11):1884-6. doi: 10.1038/mt.2014.189. Epub     [PubMed PMID: 25365985]

[108]

Chang RF, Mubarak SJ. Pathomechanics of Gowers' sign: a video analysis of a spectrum of Gowers' maneuvers. Clinical orthopaedics and related research. 2012 Jul:470(7):1987-91. doi: 10.1007/s11999-011-2210-6. Epub 2011 Dec 28     [PubMed PMID: 22203329]

[109]

Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Brumbaugh D, Case LE, Clemens PR, Hadjiyannakis S, Pandya S, Street N, Tomezsko J, Wagner KR, Ward LM, Weber DR, DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. The Lancet. Neurology. 2018 Mar:17(3):251-267. doi: 10.1016/S1474-4422(18)30024-3. Epub 2018 Feb 3     [PubMed PMID: 29395989]

Level 3 (low-level) evidence

[110]

Kornegay JN, Childers MK, Bogan DJ, Bogan JR, Nghiem P, Wang J, Fan Z, Howard JF Jr, Schatzberg SJ, Dow JL, Grange RW, Styner MA, Hoffman EP, Wagner KR. The paradox of muscle hypertrophy in muscular dystrophy. Physical medicine and rehabilitation clinics of North America. 2012 Feb:23(1):149-72, xii. doi: 10.1016/j.pmr.2011.11.014. Epub     [PubMed PMID: 22239881]

[111]

Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T, Meng G, Müller CR, Lindlöf M, Kaariainen H, de la Chapellet A, Kiuru A, Savontaus ML, Gilgenkrantz H, Récan D, Chelly J, Kaplan JC, Covone AE, Archidiacono N, Romeo G, Liechti-Gailati S, Schneider V, Braga S, Moser H, Darras BT, Murphy P, Francke U, Chen JD, Morgan G, Denton M, Greenberg CR, Wrogemann K, Blonden LA, van Paassen MB, van Ommen GJ, Kunkel LM. The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. American journal of human genetics. 1989 Oct:45(4):498-506     [PubMed PMID: 2491009]

[112]

Mateos-Aierdi AJ, Goicoechea M, Aiastui A, Fernández-Torrón R, Garcia-Puga M, Matheu A, López de Munain A. Muscle wasting in myotonic dystrophies: a model of premature aging. Frontiers in aging neuroscience. 2015:7():125. doi: 10.3389/fnagi.2015.00125. Epub 2015 Jul 9     [PubMed PMID: 26217220]

[113]

Reimers CD, Schlotter B, Eicke BM, Witt TN. Calf enlargement in neuromuscular diseases: a quantitative ultrasound study in 350 patients and review of the literature. Journal of the neurological sciences. 1996 Nov:143(1-2):46-56     [PubMed PMID: 8981297]

[114]

Marden FA, Connolly AM, Siegel MJ, Rubin DA. Compositional analysis of muscle in boys with Duchenne muscular dystrophy using MR imaging. Skeletal radiology. 2005 Mar:34(3):140-8     [PubMed PMID: 15538561]

[115]

Villanova M, Mercuri E, Bertini E, Sabatelli P, Morandi L, Mora M, Sewry C, Brockington M, Brown SC, Ferreiro A, Maraldi NM, Toda T, Guicheney P, Merlini L, Muntoni F. Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome. Neuromuscular disorders : NMD. 2000 Dec:10(8):541-7     [PubMed PMID: 11053679]

[116]

Lacomis D. Electrodiagnostic approach to the patient with suspected myopathy. Neurologic clinics. 2002 May:20(2):587-603     [PubMed PMID: 12152448]

[117]

Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Pegoraro E, Hoffman EP. Limb-Girdle Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. GeneReviews(®). 1993:():     [PubMed PMID: 20301582]

Level 3 (low-level) evidence

[118]

Forst R, Forst J, Heller KD, Hengstler K. [Characteristics in the treatment of scoliosis in muscular diseases]. Zeitschrift fur Orthopadie und ihre Grenzgebiete. 1997 Mar-Apr:135(2):95-105     [PubMed PMID: 9214180]

[119]

Ropars J, Lempereur M, Vuillerot C, Tiffreau V, Peudenier S, Cuisset JM, Pereon Y, Leboeuf F, Delporte L, Delpierre Y, Gross R, Brochard S. Muscle Activation during Gait in Children with Duchenne Muscular Dystrophy. PloS one. 2016:11(9):e0161938. doi: 10.1371/journal.pone.0161938. Epub 2016 Sep 13     [PubMed PMID: 27622734]

[120]

Gijsbertse K, Goselink R, Lassche S, Nillesen M, Sprengers A, Verdonschot N, van Alfen N, de Korte C. Ultrasound Imaging of Muscle Contraction of the Tibialis Anterior in Patients with Facioscapulohumeral Dystrophy. Ultrasound in medicine & biology. 2017 Nov:43(11):2537-2545. doi: 10.1016/j.ultrasmedbio.2017.06.016. Epub 2017 Jul 29     [PubMed PMID: 28764967]

[121]

Angelini C, Pinzan E. Advances in imaging of brain abnormalities in neuromuscular disease. Therapeutic advances in neurological disorders. 2019:12():1756286419845567. doi: 10.1177/1756286419845567. Epub 2019 May 6     [PubMed PMID: 31105770]

Level 3 (low-level) evidence

[122]

D'Angelo MG, Lorusso ML, Civati F, Comi GP, Magri F, Del Bo R, Guglieri M, Molteni M, Turconi AC, Bresolin N. Neurocognitive profiles in Duchenne muscular dystrophy and gene mutation site. Pediatric neurology. 2011 Nov:45(5):292-9. doi: 10.1016/j.pediatrneurol.2011.08.003. Epub     [PubMed PMID: 22000308]

[123]

Ho G, Cardamone M, Farrar M. Congenital and childhood myotonic dystrophy: Current aspects of disease and future directions. World journal of clinical pediatrics. 2015 Nov 8:4(4):66-80. doi: 10.5409/wjcp.v4.i4.66. Epub 2015 Nov 8     [PubMed PMID: 26566479]

Level 3 (low-level) evidence

[124]

Chamova T, Guergueltcheva V, Raycheva M, Todorov T, Genova J, Bichev S, Bojinova V, Mitev V, Tournev I, Todorova A. Association between loss of dp140 and cognitive impairment in duchenne and becker dystrophies. Balkan journal of medical genetics : BJMG. 2013 Jun:16(1):21-30. doi: 10.2478/bjmg-2013-0014. Epub     [PubMed PMID: 24265581]

[125]

Kumagai T, Miura K, Ohki T, Matsumoto A, Miyazaki S, Nakamura M, Ochi N, Takahashi O. [Central nervous system involvements in Duchenne/Becker muscular dystrophy]. No to hattatsu = Brain and development. 2001 Nov:33(6):480-6     [PubMed PMID: 11725514]

[126]

Gadoth N, Oksenberg A. Sleep and sleep disorders in rare hereditary diseases: a reminder for the pediatrician, pediatric and adult neurologist, general practitioner, and sleep specialist. Frontiers in neurology. 2014:5():133. doi: 10.3389/fneur.2014.00133. Epub 2014 Jul 17     [PubMed PMID: 25101051]

[127]

Echenne B, Rivier F, Jellali AJ, Azais M, Mornet D, Pons F. Merosin positive congenital muscular dystrophy with mental deficiency, epilepsy and MRI changes in the cerebral white matter. Neuromuscular disorders : NMD. 1997 May:7(3):187-90     [PubMed PMID: 9185183]

[128]

Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Sparks SE, Quijano-Roy S, Harper A, Rutkowski A, Gordon E, Hoffman EP, Pegoraro E. Congenital Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. GeneReviews(®). 1993:():     [PubMed PMID: 20301468]

Level 3 (low-level) evidence

[129]

Louprasong AC, Light DJ, Diller RS. Spider dystrophy as an ocular manifestation of myotonic dystrophy. Optometry (St. Louis, Mo.). 2010 Apr:81(4):188-93. doi: 10.1016/j.optm.2009.08.013. Epub     [PubMed PMID: 20346890]

[130]

Dreimann M, Hoffmann M, Kossow K, Hitzl W, Meier O, Koller H. Scoliosis and chest cage deformity measures predicting impairments in pulmonary function: a cross-sectional study of 492 patients with scoliosis to improve the early identification of patients at risk. Spine. 2014 Nov 15:39(24):2024-33. doi: 10.1097/BRS.0000000000000601. Epub     [PubMed PMID: 25202929]

Level 2 (mid-level) evidence

[131]

Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K, Cohn RD, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R, International Standard of Care Committee for Congenital Muscular Dystrophy. Consensus statement on standard of care for congenital muscular dystrophies. Journal of child neurology. 2010 Dec:25(12):1559-81. doi: 10.1177/0883073810381924. Epub 2010 Nov 15     [PubMed PMID: 21078917]

Level 3 (low-level) evidence

[132]

Kinane TB, Mayer OH, Duda PW, Lowes LP, Moody SL, Mendell JR. Long-Term Pulmonary Function in Duchenne Muscular Dystrophy: Comparison of Eteplirsen-Treated Patients to Natural History. Journal of neuromuscular diseases. 2018:5(1):47-58. doi: 10.3233/JND-170272. Epub     [PubMed PMID: 29278896]

[133]

Mangera Z, Panesar G, Makker H. Practical approach to management of respiratory complications in neurological disorders. International journal of general medicine. 2012:5():255-63. doi: 10.2147/IJGM.S26333. Epub 2012 Mar 21     [PubMed PMID: 22505823]

[134]

Howard RS, Davidson C. Long term ventilation in neurogenic respiratory failure. Journal of neurology, neurosurgery, and psychiatry. 2003 Sep:74 Suppl 3(Suppl 3):iii24-30     [PubMed PMID: 12933911]

[135]

Polat M, Sakinci O, Ersoy B, Sezer RG, Yilmaz H. Assessment of sleep-related breathing disorders in patients with duchenne muscular dystrophy. Journal of clinical medicine research. 2012 Oct:4(5):332-7     [PubMed PMID: 23024736]

[136]

MacLeod M, Kelly R, Robb SA, Borzyskowski M. Bladder dysfunction in Duchenne muscular dystrophy. Archives of disease in childhood. 2003 Apr:88(4):347-9     [PubMed PMID: 12651768]

[137]

Meola G. Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2013 Dec:32(3):154-65     [PubMed PMID: 24803843]

[138]

Reiter C, Gramer E. [Anticipation in patients with iridescent multicoloured posterior capsular lens opacities ("Christmas tree cataract") : The Role in the diagnosis of myotonic dystrophy]. Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 2009 Dec:106(12):1116-20. doi: 10.1007/s00347-009-1924-2. Epub     [PubMed PMID: 19326122]

[139]

Kim WB, Jeong JY, Doo SW, Yang WJ, Song YS, Lee SR, Park JW, Kim DW. Myotonic dystrophy type 1 presenting as male infertility. Korean journal of urology. 2012 Feb:53(2):134-6. doi: 10.4111/kju.2012.53.2.134. Epub 2012 Feb 20     [PubMed PMID: 22379595]

[140]

Peric S, Nisic T, Milicev M, Basta I, Marjanovic I, Peric M, Lavrnic D, Rakocevic Stojanovic V. Hypogonadism and erectile dysfunction in myotonic dystrophy type 1. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2013 Oct:32(2):106-9     [PubMed PMID: 24399868]

[141]

Lo Cascio CM, Goetze O, Latshang TD, Bluemel S, Frauenfelder T, Bloch KE. Gastrointestinal Dysfunction in Patients with Duchenne Muscular Dystrophy. PloS one. 2016:11(10):e0163779. doi: 10.1371/journal.pone.0163779. Epub 2016 Oct 13     [PubMed PMID: 27736891]

[142]

Bellini M, Biagi S, Stasi C, Costa F, Mumolo MG, Ricchiuti A, Marchi S. Gastrointestinal manifestations in myotonic muscular dystrophy. World journal of gastroenterology. 2006 Mar 28:12(12):1821-8     [PubMed PMID: 16609987]

[143]

Tack J, Müller-Lissner S, Stanghellini V, Boeckxstaens G, Kamm MA, Simren M, Galmiche JP, Fried M. Diagnosis and treatment of chronic constipation--a European perspective. Neurogastroenterology and motility. 2011 Aug:23(8):697-710. doi: 10.1111/j.1365-2982.2011.01709.x. Epub 2011 May 24     [PubMed PMID: 21605282]

Level 3 (low-level) evidence

[144]

Clavé P, Shaker R. Dysphagia: current reality and scope of the problem. Nature reviews. Gastroenterology & hepatology. 2015 May:12(5):259-70. doi: 10.1038/nrgastro.2015.49. Epub 2015 Apr 7     [PubMed PMID: 25850008]

[145]

Erdenen F, Toros AB, Uzum AK, Sacak S. Steinert's syndrome presenting as anal incontinence: a case report. Journal of medical case reports. 2011 Aug 12:5():371. doi: 10.1186/1752-1947-5-371. Epub 2011 Aug 12     [PubMed PMID: 21838873]

Level 3 (low-level) evidence

[146]

Rodríguez-Cruz M, Atilano-Miguel S, Barbosa-Cortés L, Bernabé-García M, Almeida-Becerril T, Cárdenas-Conejo A, Del Rocío Cruz-Guzmán O, Maldonado-Hernández J. Evidence of muscle loss delay and improvement of hyperinsulinemia and insulin resistance in Duchenne muscular dystrophy supplemented with omega-3 fatty acids: A randomized study. Clinical nutrition (Edinburgh, Scotland). 2019 Oct:38(5):2087-2097. doi: 10.1016/j.clnu.2018.10.017. Epub 2018 Oct 30     [PubMed PMID: 30420291]

Level 1 (high-level) evidence

[147]

Hathout Y, Seol H, Han MH, Zhang A, Brown KJ, Hoffman EP. Clinical utility of serum biomarkers in Duchenne muscular dystrophy. Clinical proteomics. 2016:13():9. doi: 10.1186/s12014-016-9109-x. Epub 2016 Apr 5     [PubMed PMID: 27051355]

[148]

Takasugi T, Ishihara T, Kawamura J, Sasaki K, Toyoda T, Oosumi M, Suzuki K, Nishio K, Aoyagi T, Kawashiro T. [Blood gas changes in Duchenne type muscular dystrophy]. Nihon Kyobu Shikkan Gakkai zasshi. 1995 Jan:33(1):17-22     [PubMed PMID: 7699962]

[149]

Rubegni A, Malandrini A, Dosi C, Astrea G, Baldacci J, Battisti C, Bertocci G, Donati MA, Dotti MT, Federico A, Giannini F, Grosso S, Guerrini R, Lenzi S, Maioli MA, Melani F, Mercuri E, Sacchini M, Salvatore S, Siciliano G, Tolomeo D, Tonin P, Volpi N, Santorelli FM, Cassandrini D. Next-generation sequencing approach to hyperCKemia: A 2-year cohort study. Neurology. Genetics. 2019 Oct:5(5):e352. doi: 10.1212/NXG.0000000000000352. Epub 2019 Aug 16     [PubMed PMID: 31517061]

[150]

Moghadam-Kia S, Oddis CV, Aggarwal R. Approach to asymptomatic creatine kinase elevation. Cleveland Clinic journal of medicine. 2016 Jan:83(1):37-42. doi: 10.3949/ccjm.83a.14120. Epub     [PubMed PMID: 26760521]

[151]

Walker HK, Hall WD, Hurst JW, Cabaniss CD. Creatine Kinase. Clinical Methods: The History, Physical, and Laboratory Examinations. 1990:():     [PubMed PMID: 21250193]

[152]

Kim EY, Lee JW, Suh MR, Choi WA, Kang SW, Oh HJ. Correlation of Serum Creatine Kinase Level With Pulmonary Function in Duchenne Muscular Dystrophy. Annals of rehabilitation medicine. 2017 Apr:41(2):306-312. doi: 10.5535/arm.2017.41.2.306. Epub 2017 Apr 27     [PubMed PMID: 28503465]

[153]

Kalyani RR, Corriere M, Ferrucci L. Age-related and disease-related muscle loss: the effect of diabetes, obesity, and other diseases. The lancet. Diabetes & endocrinology. 2014 Oct:2(10):819-29. doi: 10.1016/S2213-8587(14)70034-8. Epub 2014 Mar 6     [PubMed PMID: 24731660]

[154]

Drummond LM. Creatine phosphokinase levels in the newborn and their use in screening for Duchenne muscular dystrophy. Archives of disease in childhood. 1979 May:54(5):362-6     [PubMed PMID: 475411]

[155]

Percy ME, Chang LS, Murphy EG, Oss I, Verellen-Dumoulin C, Thompson MW. Serum creatine kinase and pyruvate kinase in Duchenne muscular dystrophy carrier detection. Muscle & nerve. 1979 Sep-Oct:2(5):329-39     [PubMed PMID: 492209]

[156]

Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Bonne G, Leturcq F, Ben Yaou R. Emery-Dreifuss Muscular Dystrophy. GeneReviews(®). 1993:():     [PubMed PMID: 20301609]

[157]

Takeshima K, Ariyasu H, Ishibashi T, Kawai S, Uraki S, Koh J, Ito H, Akamizu T. Myotonic dystrophy type 1 with diabetes mellitus, mixed hypogonadism and adrenal insufficiency. Endocrinology, diabetes & metabolism case reports. 2018:2018():. doi: 10.1530/EDM-17-0143. Epub 2018 Jan 18     [PubMed PMID: 29367875]

Level 3 (low-level) evidence

[158]

Kim HK, Lindquist DM, Serai SD, Mariappan YK, Wang LL, Merrow AC, McGee KP, Ehman RL, Laor T. Magnetic resonance imaging of pediatric muscular disorders: recent advances and clinical applications. Radiologic clinics of North America. 2013 Jul:51(4):721-42. doi: 10.1016/j.rcl.2013.03.002. Epub     [PubMed PMID: 23830795]

Level 3 (low-level) evidence

[159]

Wong CK, Gidali A, Harris V. Deformity or dysfunction? Osteopathic manipulation of the idiopathic cavus foot: A clinical suggestion. North American journal of sports physical therapy : NAJSPT. 2010 Feb:5(1):27-32     [PubMed PMID: 21509155]

[160]

Ilaslan H, Wenger DE, Shives TC, Unni KK. Unilateral hypertrophy of tensor fascia lata: a soft tissue tumor simulator. Skeletal radiology. 2003 Nov:32(11):628-32     [PubMed PMID: 14586575]

[161]

Grimm T, Kress W, Meng G, Müller CR. Risk assessment and genetic counseling in families with Duchenne muscular dystrophy. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2012 Dec:31(3):179-83     [PubMed PMID: 23620649]

[162]

Nakamura A. Mutation-Based Therapeutic Strategies for Duchenne Muscular Dystrophy: From Genetic Diagnosis to Therapy. Journal of personalized medicine. 2019 Mar 4:9(1):. doi: 10.3390/jpm9010016. Epub 2019 Mar 4     [PubMed PMID: 30836656]

[163]

Pastore CA, Samesima N, Pereira-Filho HG. III SBC Guidelines on the Analysis and Issuance of Electrocardiographic Reports - Executive Summary. Arquivos brasileiros de cardiologia. 2016 Nov:107(5):392-402. doi: 10.5935/abc.20160173. Epub     [PubMed PMID: 27982266]

[164]

Sarubbi B, Li W, Somerville J. QRS width in right bundle branch block. Accuracy and reproducibility of manual measurement. International journal of cardiology. 2000 Aug:75(1):71-4     [PubMed PMID: 11054509]

[165]

Nikolić G. Dominant R wave in lead V1. Heart & lung : the journal of critical care. 1998 Sep-Oct:27(5):352-3     [PubMed PMID: 9777382]

[166]

Thrush PT, Allen HD, Viollet L, Mendell JR. Re-examination of the electrocardiogram in boys with Duchenne muscular dystrophy and correlation with its dilated cardiomyopathy. The American journal of cardiology. 2009 Jan 15:103(2):262-5. doi: 10.1016/j.amjcard.2008.08.064. Epub 2008 Oct 30     [PubMed PMID: 19121448]

[167]

Koene RJ, Adkisson WO, Benditt DG. Syncope and the risk of sudden cardiac death: Evaluation, management, and prevention. Journal of arrhythmia. 2017 Dec:33(6):533-544. doi: 10.1016/j.joa.2017.07.005. Epub 2017 Sep 1     [PubMed PMID: 29255498]

[168]

Groh WJ, Groh MR, Saha C, Kincaid JC, Simmons Z, Ciafaloni E, Pourmand R, Otten RF, Bhakta D, Nair GV, Marashdeh MM, Zipes DP, Pascuzzi RM. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. The New England journal of medicine. 2008 Jun 19:358(25):2688-97. doi: 10.1056/NEJMoa062800. Epub     [PubMed PMID: 18565861]

[169]

Segawa K, Komaki H, Mori-Yoshimura M, Oya Y, Kimura K, Tachimori H, Kato N, Sasaki M, Takahashi Y. Cardiac conduction disturbances and aging in patients with Duchenne muscular dystrophy. Medicine. 2017 Oct:96(42):e8335. doi: 10.1097/MD.0000000000008335. Epub     [PubMed PMID: 29049249]

[170]

Paganoni S, Amato A. Electrodiagnostic evaluation of myopathies. Physical medicine and rehabilitation clinics of North America. 2013 Feb:24(1):193-207. doi: 10.1016/j.pmr.2012.08.017. Epub 2012 Oct 16     [PubMed PMID: 23177039]

[171]

Cannon SC. Channelopathies of skeletal muscle excitability. Comprehensive Physiology. 2015 Apr:5(2):761-90. doi: 10.1002/cphy.c140062. Epub     [PubMed PMID: 25880512]

[172]

Roberts RG. Direct diagnosis of carriers of Duchenne and Becker muscular dystrophy by amplification of lymphocyte RNA. Lancet (London, England). 1991 Feb 23:337(8739):504     [PubMed PMID: 1704092]

[173]

El Sherif RM, Fahmy NA, Nonaka I, Etribi MA. Patterns of dystrophin gene deletion in Egyptian Duchenne/Becker muscular dystrophy patients. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2007 Dec:26(3):145-50     [PubMed PMID: 18646563]

[174]

Sbiti A, El Kerch F, Sefiani A. Analysis of Dystrophin Gene Deletions by Multiplex PCR in Moroccan Patients. Journal of biomedicine & biotechnology. 2002:2(3):158-160     [PubMed PMID: 12488581]

[175]

Abbs S, Roberts RG, Mathew CG, Bentley DR, Bobrow M. Accurate assessment of intragenic recombination frequency within the Duchenne muscular dystrophy gene. Genomics. 1990 Aug:7(4):602-6     [PubMed PMID: 1974880]

[176]

Barresi R. From proteins to genes: immunoanalysis in the diagnosis of muscular dystrophies. Skeletal muscle. 2011 Jun 24:1(1):24. doi: 10.1186/2044-5040-1-24. Epub 2011 Jun 24     [PubMed PMID: 21798100]

[177]

Oliveira AS, Gabbai AA, Schmidt B, Kiyomoto BH, Lima JG, Minetti C, Bonilla E. Carrier detection of Duchenne and Becker muscular dystrophy using muscle dystrophin immunohistochemistry. Arquivos de neuro-psiquiatria. 1992 Dec:50(4):478-85     [PubMed PMID: 1309152]

[178]

Le Thanh P, Meinke P, Korfali N, Srsen V, Robson MI, Wehnert M, Schoser B, Sewry CA, Schirmer EC. Immunohistochemistry on a panel of Emery-Dreifuss muscular dystrophy samples reveals nuclear envelope proteins as inconsistent markers for pathology. Neuromuscular disorders : NMD. 2017 Apr:27(4):338-351. doi: 10.1016/j.nmd.2016.12.003. Epub 2016 Dec 21     [PubMed PMID: 28214269]

[179]

Bertrand AT, Bönnemann CG, Bonne G, FHL1 myopathy consortium. 199th ENMC international workshop: FHL1 related myopathies, June 7-9, 2013, Naarden, The Netherlands. Neuromuscular disorders : NMD. 2014 May:24(5):453-62. doi: 10.1016/j.nmd.2014.02.002. Epub 2014 Feb 14     [PubMed PMID: 24613424]

[180]

Folker ES, Baylies MK. Nuclear positioning in muscle development and disease. Frontiers in physiology. 2013 Dec 12:4():363. doi: 10.3389/fphys.2013.00363. Epub 2013 Dec 12     [PubMed PMID: 24376424]

[181]

Peverelli L, Testolin S, Villa L, D'Amico A, Petrini S, Favero C, Magri F, Morandi L, Mora M, Mongini T, Bertini E, Sciacco M, Comi GP, Moggio M. Histologic muscular history in steroid-treated and untreated patients with Duchenne dystrophy. Neurology. 2015 Nov 24:85(21):1886-93. doi: 10.1212/WNL.0000000000002147. Epub 2015 Oct 23     [PubMed PMID: 26497992]

[182]

Angelini C, Tasca E. Fatigue in muscular dystrophies. Neuromuscular disorders : NMD. 2012 Dec:22 Suppl 3(3-3):S214-20. doi: 10.1016/j.nmd.2012.10.010. Epub     [PubMed PMID: 23182642]

[183]

Guilleminault C, Philip P, Robinson A. Sleep and neuromuscular disease: bilevel positive airway pressure by nasal mask as a treatment for sleep disordered breathing in patients with neuromuscular disease. Journal of neurology, neurosurgery, and psychiatry. 1998 Aug:65(2):225-32     [PubMed PMID: 9703177]

[184]

Reardon W, MacMillan JC, Myring J, Harley HG, Rundle SA, Beck L, Harper PS, Shaw DJ. Cataract and myotonic dystrophy: the role of molecular diagnosis. The British journal of ophthalmology. 1993 Sep:77(9):579-83     [PubMed PMID: 8218057]

[185]

Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Darras BT, Urion DK, Ghosh PS. Dystrophinopathies. GeneReviews(®). 1993:():     [PubMed PMID: 20301298]

[186]

Palladino A, D'Ambrosio P, Papa AA, Petillo R, Orsini C, Scutifero M, Nigro G, Politano L. Management of cardiac involvement in muscular dystrophies: paediatric versus adult forms. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2016 Dec:35(3):128-134     [PubMed PMID: 28484313]

[187]

Groh WJ. Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. Neurology. 2011 Jan 25:76(4):409; author reply 409. doi: 10.1212/WNL.0b013e3181fe72d7. Epub     [PubMed PMID: 21263144]

[188]

Stunnenberg BC, Woertman W, Raaphorst J, Statland JM, Griggs RC, Timmermans J, Saris CG, Schouwenberg BJ, Groenewoud HM, Stegeman DF, van Engelen BG, Drost G, van der Wilt GJ. Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol. BMC neurology. 2015 Mar 25:15():43. doi: 10.1186/s12883-015-0294-4. Epub 2015 Mar 25     [PubMed PMID: 25880166]

[189]

Topaloglu H, Gloss D, Moxley RT 3rd, Ashwal S, Oskoui M. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016 Jul 12:87(2):238. doi: 10.1212/01.wnl.0000489553.99227.18. Epub     [PubMed PMID: 27402942]

Level 1 (high-level) evidence

[190]

Angelini C, Peterle E. Old and new therapeutic developments in steroid treatment in Duchenne muscular dystrophy. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2012 May:31(1):9-15     [PubMed PMID: 22655511]

[191]

Guglieri M, Bushby K, McDermott MP, Hart KA, Tawil R, Martens WB, Herr BE, McColl E, Wilkinson J, Kirschner J, King WM, Eagle M, Brown MW, Willis T, Hirtz D, Shieh PB, Straub V, Childs AM, Ciafaloni E, Butterfield RJ, Horrocks I, Spinty S, Flanigan KM, Kuntz NL, Baranello G, Roper H, Morrison L, Mah JK, Manzur AY, McDonald CM, Schara U, von der Hagen M, Barohn RJ, Campbell C, Darras BT, Finkel RS, Vita G, Hughes I, Mongini T, Pegoraro E, Wicklund M, Wilichowski E, Bryan Burnette W, Howard JF, McMillan HJ, Thangarajh M, Griggs RC. Developing standardized corticosteroid treatment for Duchenne muscular dystrophy. Contemporary clinical trials. 2017 Jul:58():34-39. doi: 10.1016/j.cct.2017.04.008. Epub 2017 Apr 24     [PubMed PMID: 28450193]

[192]

Leung DG, Wagner KR. Therapeutic advances in muscular dystrophy. Annals of neurology. 2013 Sep:74(3):404-11. doi: 10.1002/ana.23989. Epub     [PubMed PMID: 23939629]

Level 3 (low-level) evidence

[193]

Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W, Schneider C, Koch MC, Beilman GJ, Harrison AR, Dalton JC, Ranum LP. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology. 2003 Feb 25:60(4):657-64     [PubMed PMID: 12601109]

[194]

Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Preston MK, Tawil R, Wang LH. Facioscapulohumeral Muscular Dystrophy. GeneReviews(®). 1993:():     [PubMed PMID: 20301616]

[195]

Tsao CY, Mendell JR. Coexisting muscular dystrophies and epilepsy in children. Journal of child neurology. 2006 Feb:21(2):148-50     [PubMed PMID: 16566880]

[196]

Eccleston C, Cooper TE, Fisher E, Anderson B, Wilkinson NM. Non-steroidal anti-inflammatory drugs (NSAIDs) for chronic non-cancer pain in children and adolescents. The Cochrane database of systematic reviews. 2017 Aug 2:8(8):CD012537. doi: 10.1002/14651858.CD012537.pub2. Epub 2017 Aug 2     [PubMed PMID: 28770976]

Level 1 (high-level) evidence

[197]

Lim KRQ, Yokota T. Invention and Early History of Exon Skipping and Splice Modulation. Methods in molecular biology (Clifton, N.J.). 2018:1828():3-30. doi: 10.1007/978-1-4939-8651-4_1. Epub     [PubMed PMID: 30171532]

[198]

Nguyen Q, Yokota T. Immortalized Muscle Cell Model to Test the Exon Skipping Efficacy for Duchenne Muscular Dystrophy. Journal of personalized medicine. 2017 Oct 16:7(4):. doi: 10.3390/jpm7040013. Epub 2017 Oct 16     [PubMed PMID: 29035327]

[199]

Sussman M. Duchenne muscular dystrophy. The Journal of the American Academy of Orthopaedic Surgeons. 2002 Mar-Apr:10(2):138-51     [PubMed PMID: 11929208]

[200]

Ciudin RN, Dragatoiu NC, Sipos S, Tesloianu DN, Ursaru AM, Brezeanu R, Coman IM. Fast Progressing His-Purkinje Conduction Disturbances in a Myotonic Dystrophy Pacient. Maedica. 2018 Jun:13(2):152-154. doi: 10.26574/maedica.2018.13.2.152. Epub     [PubMed PMID: 30069244]

[201]

Altekin RE, Yanikoglu A, Ucar M, Ermis C. Complete AV block and cardiac syncope in a patient with Duchenne muscular dystrophy. Journal of cardiology cases. 2011 Apr:3(2):e68-e70. doi: 10.1016/j.jccase.2011.01.004. Epub 2011 Feb 16     [PubMed PMID: 30532840]

Level 3 (low-level) evidence

[202]

Copeland SA, Levy O, Warner GC, Dodenhoff RM. The shoulder in patients with muscular dystrophy. Clinical orthopaedics and related research. 1999 Nov:(368):80-91     [PubMed PMID: 10613155]

[203]

Shin J, Tajrishi MM, Ogura Y, Kumar A. Wasting mechanisms in muscular dystrophy. The international journal of biochemistry & cell biology. 2013 Oct:45(10):2266-79. doi: 10.1016/j.biocel.2013.05.001. Epub 2013 May 11     [PubMed PMID: 23669245]

[204]

de Souza MA, Figueiredo MM, de Baptista CR, Aldaves RD, Mattiello-Sverzut AC. Beneficial effects of ankle-foot orthosis daytime use on the gait of Duchenne muscular dystrophy patients. Clinical biomechanics (Bristol, Avon). 2016 Jun:35():102-10. doi: 10.1016/j.clinbiomech.2016.04.005. Epub 2016 Apr 22     [PubMed PMID: 27139255]

[205]

Gupta A, Nalini A, Arya SP, Vengalil S, Khanna M, Krishnan R, Taly AB. Ankle-Foot Orthosis in Duchenne Muscular Dystrophy: A 4 year Experience in a Multidisciplinary Neuromuscular Disorders Clinic. Indian journal of pediatrics. 2017 Mar:84(3):211-215. doi: 10.1007/s12098-016-2251-7. Epub 2016 Nov 5     [PubMed PMID: 27815810]

[206]

Olivé M, Kley RA, Goldfarb LG. Myofibrillar myopathies: new developments. Current opinion in neurology. 2013 Oct:26(5):527-35. doi: 10.1097/WCO.0b013e328364d6b1. Epub     [PubMed PMID: 23995273]

Level 3 (low-level) evidence

[207]

Nigro V. Improving the course of muscular dystrophy? Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2012 Oct:31(2):109     [PubMed PMID: 23097600]

[208]

Read AP, Donnai D. What can be offered to couples at (possibly) increased genetic risk? Journal of community genetics. 2012 Jul:3(3):167-74. doi: 10.1007/s12687-012-0105-1. Epub 2012 Jul 4     [PubMed PMID: 22760671]

[209]

Chawla J. Stepwise approach to myopathy in systemic disease. Frontiers in neurology. 2011:2():49. doi: 10.3389/fneur.2011.00049. Epub 2011 Aug 5     [PubMed PMID: 21886637]

[210]

Passamano L, Taglia A, Palladino A, Viggiano E, D'Ambrosio P, Scutifero M, Rosaria Cecio M, Torre V, DE Luca F, Picillo E, Paciello O, Piluso G, Nigro G, Politano L. Improvement of survival in Duchenne Muscular Dystrophy: retrospective analysis of 835 patients. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2012 Oct:31(2):121-5     [PubMed PMID: 23097603]

Level 2 (mid-level) evidence

[211]

Bertini E, D'Amico A, Gualandi F, Petrini S. Congenital muscular dystrophies: a brief review. Seminars in pediatric neurology. 2011 Dec:18(4):277-88. doi: 10.1016/j.spen.2011.10.010. Epub     [PubMed PMID: 22172424]

[212]

Birnkrant DJ, Bushby K, Bann CM, Alman BA, Apkon SD, Blackwell A, Case LE, Cripe L, Hadjiyannakis S, Olson AK, Sheehan DW, Bolen J, Weber DR, Ward LM, DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. The Lancet. Neurology. 2018 Apr:17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5. Epub 2018 Feb 3     [PubMed PMID: 29395990]

Level 3 (low-level) evidence