eMedicine Specialties > Neurology > Neuromuscular Diseases

Dystrophinopathies

Author: Michelle L Mellion, MD, Assistant Professor of Clinical Neurosciences, Warren Alpert Medical School of Brown University, Rhode Island Hospital
Coauthor(s): Brian S Tseng, MD, PhD, Assistant Professor, Department of Neurology, Division of Pediatric Neurology, Harvard Medical School, Massachusetts General Hospital
Contributor Information and Disclosures

Updated: Feb 26, 2009

Introduction

Background

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy affecting 1 in 3500 boys born worldwide. Although the name Duchenne is inextricably linked to the most common childhood muscular dystrophy, it was Gowers who recognized Sir Charles Bell for providing the first clinical description of Duchenne dystrophy in his 1830 publication, The Nervous System of the Human Body. Others, including Edward Meryon in 1852 and John Little in 1853, described families of boys with delayed motor milestones, calf enlargement, progressive inability to ambulate, heel cord contractures, and death at an early age.

In an 1868 publication, Duchenne established the diagnostic criteria that are still used. These criteria include (1) weakness with onset in the legs; (2) hyperlordosis with wide-based gait; (3) hypertrophy of weak muscles; (4) progressive course over time; (5) reduced muscle contractility on electrical stimulation in advanced stages of the disease; and (6) absence of bladder or bowel dysfunction, sensory disturbance, or febrile illness.

Gowers was the first to deduce the genetic basis for the disease and the first to describe patients with delayed onset of disease. In 1962, Becker proposed that the less symptomatic patients reflected milder mutations in the same gene. These patients are now classified as having Becker muscular dystrophy (BMD).

In 1986, exactly 100 years after Gowers' keen observations, Kunkel identified the Duchenne muscular dystrophy gene located at band Xp21 and provided molecular genetic confirmation of the X-linked inheritance pattern. The Duchenne muscular dystrophy gene was named dystrophin. It is the largest recorded human gene encoding a 427-kd protein, dystrophin. Dystrophin plays an integral role in sarcolemmal stability. Research by Ervasti as well as Yoshida and Ozawa in the 1990s shed further light on the complex association of the dystrophin protein with a number of transmembrane proteins and glycoproteins, referred to as sarcoglycans and dystroglycans.^1,2

Another similar 395-kd protein, known as utrophin, has also been identified. This protein has a similar structure to dystrophin and seems able to perform some of the same functions. Despite there being no cure for the dystrophinopathies, knowing the genetic cause and related functions of dystrophin has been invaluable in creating new molecular and pharmacologic techniques for diagnosis and treatment. 

Pathophysiology

Dystrophin protein is integral to the structural stability of the myofiber. Without dystrophin, muscles are susceptible to mechanical injury and undergo repeated cycles of necrosis and regeneration. Ultimately, regenerative capabilities are exhausted or inactivated. In the 1850s, Edward Meryon used a small harpoonlike device to perform muscle biopsies and described the tissue from an affected patient: "The striped elementary primitive fibers were completely destroyed. The sarcous element being diffused, and in many places, converted into oil globules and granular matter, whilst the sarcolemma or tunic of the elementary fibre was broken down and destroyed." In order to understand how a mutation in the gene can cause such devastation, accurate conceptualization of the structure of dystrophin is necessary.

Dystrophin protein is encoded by the largest gene described to date. It occupies almost 2% of the X chromosome and nearly 0.05% of the entire genome. The gene consists of 79 exons and 8 promoters spread over 2.2 million base pairs of genomic DNA. It is expressed mainly in smooth, cardiac, and skeletal muscle, with lower levels in the brain.

In muscle, dystrophin is expressed as a 427-kd protein that consists of 2 apposed globular heads with a flexible rod-shaped center that links the intracellular actin cytoskeleton to the extracellular matrix via the dystroglycan complex. The protein is organized into 4 structural domains including the amino-terminal actin-binding domain, a central rod domain, a cysteine-rich domain, and a carboxy-terminal domain. Its amino terminal end insinuates with the subsarcolemmal actin filaments of myofibrils, while cysteine-rich domains of the carboxy-terminal end associate with beta-dystroglycan as well as elements of the sarcoglycan complex, all of which are contained within the sarcolemmal membrane. Beta-dystroglycan in turn anchors the entire complex to the basal lamina via laminin.

Deletions or duplications of the dystrophin gene that do not disturb the reading frame may lead to minor alterations in the protein structure, and by extension, the function of dystrophin particularly, particularly if in-frame changes are located within the amino-terminal or central regions. In contrast, mutations that disturb the reading frame, including premature stop codons, produce a severely truncated, completely dysfunctional protein product or no protein at all.

Microscopic evaluation in the early stages of the disease reveals widespread myonecrosis with fiber splitting (see image below). Interspersed between the dying myocytes are ghost cells, the shells of formerly healthy tissue. Inflammatory cell infiltration of the necrotic fibers may be observed in particularly aggressive areas of muscle biopsies. Fibers that survive exhibit considerable variability and often demonstrate internal nuclei. As the disease progresses, dead muscle fibers are cleared away by macrophages and replaced by fatty and connective tissue elements, conveying a deceptively healthy appearance to the muscle (pseudohypertrophy), especially calves and forearms.

Frequency

United States

Duchenne muscular dystrophy is by far the most common childhood-onset muscular dystrophy, afflicting 1 in 3300 boys with an overall prevalence of 63 cases per million. The prevalence of the Becker phenotype is 24 cases per million. One third of these cases are due to spontaneous mutations, while the rest are inherited in an X-linked dominant manner. Gonadal mosaicism accounts for approximately 20% of new Duchenne muscular dystrophy cases.

Mortality/Morbidity

Duchenne muscular dystrophy is much more than a disease of skeletal muscles. Dystrophin is also found in the heart, brain, and smooth muscle. Late-stage cardiac fibrosis can lead to output failure and pulmonary congestion, a common cause of death. Additionally, cardiac fibrosis can include cardiomyopathy and conduction abnormalities, which can induce fatal arrhythmias.

Weakness of skeletal muscle can contribute to cardiopulmonary complications. Scoliotic deformity from paraspinal muscle asymmetric atrophy impairs pulmonary and gastrointestinal function, predisposing individuals to pneumonia, respiratory failure, and poor nutrition. Smooth muscle dysfunction as a result of abnormal or absent dystrophin, plus inactivity, leads to gastrointestinal dysmotility, causing constipation and diarrhea.

In general, patients with Becker muscular dystrophy have much greater phenotypic variability; patients may become wheelchair bound as early as age 20 years or as late as age 70 years. Motor dysfunction usually is at least a decade later than in Duchenne muscular dystrophy. Once wheelchair bound, patients with dystrophy become much more susceptible to the scourges of the sedentary, which include scoliosis, contractures, decubitus ulcers, and impaired pulmonary function. Cardiomyopathy also occurs in patients with Becker muscular dystrophy, and conduction abnormalities may dominate the clinical picture, necessitating medications, implantation of a defibrillator, or even evaluation for heart transplant.

Although significant advances have been made in understanding the molecular underpinnings of the disorder, Duchenne muscular dystrophy remains an incurable illness with a mortality rate of 100%. Like its clinical presentation, the prognosis of patients with Becker muscular dystrophy is variable, with patients who are less affected ultimately dying of other diseases after a near-normal life span.

Sex

• Duchenne and Becker muscular dystrophy almost exclusively affect males because of the X-linked inheritance pattern.
• Rarely, skewed random inactivation of healthy copies of the X chromosome leads to the Becker/Duchenne phenotype in females who carry the dystrophin mutation.
• Females with Turner syndrome (XO) or uniparental disomy or those who have translocations between the X and autosomal chromosomes may similarly manifest the Duchenne phenotype. Elevations of creatine phosphokinase (CPK) level are found in two thirds of female carriers, the vast majority of whom are clinically asymptomatic.

Age

• Duchenne muscular dystrophy clinically manifests in patients aged 3-7 years, with development of lordosis, a waddling gait, and the Gowers sign. Calf pseudohypertrophy follows 1-2 years later. Most patients are wheelchair bound by age 12 years.
• Becker muscular dystrophy follows a much more variable course, manifesting any time from age 3 years to late adulthood.

Clinical

History

• Waddling gait, manifesting in children aged 2-6 years, is often the first symptom in patients with Duchenne muscular dystrophy and is secondary to hip girdle muscle weakness.
• Sometimes a young boy may come to medical attention because of elevated liver function enzymes (AST, ALT), and in such cases serum creatine kinases CK and GGT levels should be checked prior to considering liver biopsies. Occasionally a young boy may be referred for speech delay or learning issues, but he may turn out to harbor a dystrophin mutation. Most children with dystrophinopathy have IQs about one standard deviation lower than the general population. 
  
  More children with Duchenne muscular dystrophy have low intellectual skills than children in the general population, but certainly plenty of exceptions exist. The low intellectual skills, such as cognitive issues (learning differences, attention deficit hyperactivity disorder, obsessive-compulsive disorder, pervasive developmental disorder, mental retardation), are seen in up to 30% of patients with dystrophinopathy. Children with Duchenne or Becker muscular dystrophy perform particularly poorly on tests of verbal skills and have challenges in processing complex verbal information.³  
• In some older boys or young men, dilated cardiomyopathy findings may lead to provincial diagnoses such as viral or idiopathic cardiomyopathy when in fact a dystrophin mutation may be the underlying reason.
• Because of proximal lower back and extremity weakness, parents often note that the boy pushes on his knees in order to stand; this is known as Gowers sign.
  
  

  

  Gowers sign.

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  Gowers sign.

• The calf enlargement imparts the illusory appearance of strength, but, in fact, the enlarged calf muscles are caused by fatty and fibrotic infiltration of degenerated muscles. This is seen in conjunction with more prominent toe-walking. Sometimes an apparent pseudohypertrophy is also seen in the forearms and tongue. However, another explanation may relate to compensatory hypertrophy of the calves secondary to weak tibialis anterior muscles, which tend to be affected earlier and more prominently.
• Contractures
• Inexorable progressive weakness is seen in the proximal musculature, initially in the lower extremities, but later involving the neck flexors, shoulders, and arms.
• Cardiac surveillance should be implemented at time of diagnosis and should incorporate echocardiography plus ECG and pediatric cardiology expertise.
• Around the age of 8 years, most patients notice difficulty with ascending stairs and respiratory muscle strength begins a slow but steady decline.
• Approximately the time that independent ambulation is most challenged, the forced vital capacity begins to gradually wane, leading to symptoms of nocturnal hypoxemia such as lethargy and early morning headaches.
• Scoliosis may progress especially when more wheelchair dependent.
• If wheelchair bound and profoundly weak, patients develop terminal respiratory or cardiac failure, usually by the early 20s, if not sooner. Poor nutritional intake can also be a serious complication in individuals with severe end-stage Duchenne muscular dystrophy.
• Some families and individuals become socially withdrawn and may impact further on overall psychosocial health. Family, financial, school, community, and sibling issues can be significant.

Physical

• Generally, neck flexors, wrist extensors, quadriceps, tibialis anterior, biceps, and triceps muscles are affected more than the neck extensors, wrist flexors, deltoids, hamstrings, gastrocnemii, and solei.
• Deep tendon reflexes, which tend to parallel muscle fiber loss, slowly diminish and ultimately disappear.
• By age 10 years, 70% of children are hobbled by contractures of the iliotibial bands, hip flexors, and heel cords. Most are wheelchair bound by this time, creating a vicious cycle of immobility and further formation of contractures.
• Asymmetric weakening of the paraspinal muscles leads to kyphoscoliosis, which in turn further compromises pulmonary and gastrointestinal function.
• Inability to generate a forceful cough underlies the development of atelectasis with attendant episodes of pneumonia.
• Compared with Duchenne muscular dystrophy, the Becker phenotype manifests slower (ie, in those aged 10-20 y) and evolves over a longer period of time. Muscle weakness is milder than in Duchenne muscular dystrophy, and calf pseudohypertrophy and contractures are not invariant features.
• In contrast to patients with Duchenne muscular dystrophy who are wheelchair bound by age 10 years, some patients with Becker muscular dystrophy are able to ambulate independently past the fourth decade of life; some are able to ambulate into the seventh decade of life.
• While average life expectancy of patients with mild Becker muscular dystrophy (ie, ~40s) is diminished compared to that of the general population, survival of these individuals into the seventh or eighth decade of their lives is not unusual.

Causes

Duchenne and Becker muscular dystrophy are caused by mutations in the same gene encoding dystrophin.

• Mutations that result in the absence or severe reduction of the dystrophin protein generally result in Duchenne muscular dystrophy, while those that lead to a less severe reduction and/or expression of an internally truncated, semifunctional protein generally result in Becker muscular dystrophy.
• The size of the mutation is not always a determining factor of severity. For example, premature stop codons may be a single DNA base change. There are correlations with the type of mutation, location, and severity. Deletions, duplications, and frame-shift mutations resulting in the absence or truncation of the protein are associated with the most severe phenotypes seen in Duchenne muscular dystrophy, while in-frame mutations generally lead to a less severe phenotype seen in Becker muscular dystrophy. Exceptions or clinical outliers defy these generalizations and researchers believe modifier genes may contribute.
• Analysis of the location of deletions has shown that the amino-terminal, cysteine-rich, and carboxy-terminal domains are essential for dystrophin function, while the central rod domain can accommodate large in-frame deletions.
• Larger deletions of one or more exons cause approximately 59% of Duchenne muscular dystrophy and 65% of Becker muscular dystrophy cases. Premature stop codon mutations are found in 15%, duplications in 5%, and the rest are caused by frameshift, insertions/deletions, splice site, or missense mutations.
• Despite the fact that most of the cases of Duchenne and Becker muscular dystrophy are transmitted in a known X-linked manner (mother may be a known carrier), one third are the result of a spontaneous mutation with no family history.

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