Dystrophinopathies

Updated: Oct 05, 2016
  • Author: Dinesh G Nair, MD, PhD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
  • Print
Overview

Practice Essentials

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. Duchenne and Becker muscular dystrophies are caused by mutations in the same gene encoding dystrophin. These disorders almost exclusively affect males because of the X-linked inheritance pattern. See the image below.

(A) Normal dystrophin staining.(B) Intermediate dy (A) Normal dystrophin staining.(B) Intermediate dystrophin staining in a patient with Becker muscular dystrophy.(C) Absent dystrophin staining in a patient with Duchenne muscular dystrophy.

Signs and symptoms

Diagnostic criteria include the following:

  • Weakness with onset in the legs
  • Hyperlordosis with wide-based gait
  • Hypertrophy of weak muscles
  • Progressive course over time
  • Reduced muscle contractility on electrical stimulation in advanced stages of the disease
  • Absence of bladder or bowel dysfunction, sensory disturbance, or febrile illness

Stage 1 – Presymptomatic

Progression of muscular dystrophy occurs in 5 stages. In stage 1, creatine kinase levels are usually elevated. Patients have a positive family history.

Stage 2 – Early ambulatory

  • Waddling gait, manifesting in children aged 2-6 years; often the first clinical symptom in patients with Duchenne muscular dystrophy and is secondary to hip girdle muscle weakness
  • Inexorable progressive weakness in the proximal musculature, initially in the lower extremities, but later involving the neck flexors, shoulders, and arms
  • 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 the Gowers sign
  • Possible toe-walking
  • Can climb stairs

Stage 3 – Late ambulatory

  • More difficulty walking
  • Around age 8 years, most patients notice difficulty with ascending stairs, and respiratory muscle strength begins a slow but steady decline
  • Cannot arise from the floor
  • At approximately the same time as 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

Stage 4 – Early nonambulatory

  • Can self-propel for some time
  • Able to maintain posture
  • Possible development of scoliosis

Stage 5 – Late nonambulatory

  • 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
  • Contractures may develop [1]

See Clinical Presentation for more detail.

Diagnosis

Serum creatine phosphokinase (CPK) level

  • Always increased in patients with Duchenne muscular dystrophy or Becker muscular dystrophy, probably from birth
  • Often increased to 50-100 times the reference range (ie, as high as 20,000 mU/mL)
  • Decreases over time; in late-stage DMD, very little muscle mass remains to give rise to an elevated serum CPK level
  • Strongly suspect Duchenne muscular dystrophy in a child with proximal weakness and very elevated levels of CPK

Imaging studies

  • Radiographs of the spine are important for screening and evaluating the degree of scoliotic deformity
  • Chest radiography is often part of the evaluation as the disease progresses and dyspnea develops
  • Beyond imaging for scoliosis and dyspnea, imaging studies are of little help in making the diagnosis
  • Dual energy x-ray absorptiometry estimates bone mineral density, as individuals with dystrophinopathies can have accelerated osteopenia/osteoporosis/fracture risk

Electromyography

  • Electromyography (EMG), even though not diagnostic, narrows the differential diagnosis by effectively excluding primarily neurogenic processes such as spinal muscular atrophy
  • In general, the proximal muscles of the lower extremities may exhibit the more prominent EMG findings
  • A sufficient number of muscles must be sampled to establish the presence of a diffuse process such as a dystrophy

Molecular diagnosis

  • Duchenne or Becker muscular dystrophy can be reliably and accurately detected from peripheral blood samples in nearly all cases
  • If deletion/duplication genetic tests are uninformative, direct sequencing of the dystrophin gene is a viable option

Muscle biopsy

  • Required for diagnosis in patients without detectable mutations of the dystrophin gene
  • For some families of a young boy found to have a dystrophin mutation, the muscle biopsy can provide critically important dystrophin protein information such as molecular weight size and abundance
  • Immunolabeling of frozen muscle sections can enable epitope identification
  • Depending on the purpose of the biopsy, proper site selection is crucial

Cardiac assessment

  • ECG can uncover sinus arrhythmias and may show deep Q waves and elevated right precordial R waves
  • Transthoracic echocardiography often reveals small ventricles with prolonged diastolic relaxation
  • A Holter monitor is valuable for paroxysmal arrhythmias
  • Cardiac MRI and gadolinium enhancement can better characterize cardiac tissue changes

See Workup for more detail.

Management

Therapeutic strategies for the dystrophinopathies can be categorized into the following 3 groups:

  • Supportive pharmacologic therapy
  • Research gene therapy
  • Research cellular therapy

No cure yet exists for Duchenne or Becker muscular dystrophy, but medical and supportive treatments can reduce morbidity, improve quality of life, and prolong lifespan.

Supportive therapy

  • Corticosteroids are the only proven medical treatment for Duchenne muscular dystrophy [2]
  • Benefits include prolongation of ambulation, maintenance of strength and function, and delay in the development of scoliosis
  • Clinical improvement is seen as early as 1 month after starting treatment and can last as long as 3 years
  • Controversies exist with respect to the age at which to start corticosteroids, clinical criteria for starting corticosteroids, which corticosteroid to use, which dose and which regimen (continuous daily or intermittent) to use, and when to discontinue corticosteroid
  • ACE inhibitors may provide benefit in patients with and without ventricular dysfunction
  • With the supervision of an experienced physical therapist, daily joint-stretching exercises is important for parents to incorporate into the home regimen
  • Night splints can have a favorable influence
  • Judicious use of tendon release surgeries may prolong ambulation by as long as 2 years
  • Braces can be therapeutic adjuncts, but currently are less often used
  • Gentle sports or activities (eg, swimming, tricycle/bicycles) may be encouraged

See Treatment and Medication for more detail.

Next:

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. [3, 4]

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.

Previous
Next:

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 harpoon-like 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.

Structure of the dystroglycan complex (adapted fro Structure of the dystroglycan complex (adapted from Ozawa et al).
The molecular organization of integral and periphe The molecular organization of integral and peripheral components of the dystrophin-glycoprotein complex and novel proteins involved in muscular dystrophy in skeletal muscle.

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 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.

Point vs frameshift mutations. In contrast to most Point vs frameshift mutations. In contrast to most point mutations, which generally preserve the reading frame, frameshift mutations often lead to truncated protein products.

The functional loss of dystrophin protein initiates a cascade of events, including loss of other components of the dystrophin-associated glycoprotein complex, sarcolemmal breakdown with attendant calcium ion influx, phospholipase activation, oxidative cellular injury, and, ultimately, myonecrosis.

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.

Dystrophic muscle (A = Gomori trichrome; B = hemat Dystrophic muscle (A = Gomori trichrome; B = hematoxylin and eosin [H&E] stain).
Previous
Next:

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.

Previous
Next:

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

See the list below:

  • 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

See the list below:

  • 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.
Previous