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] 

Details

Author

Andrew LaPelusa

Author

Ria Monica D. Asuncion

Editor:

Michael Kentris

Updated:

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Send Us Your Comments

References

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