Duchenne Muscular Dystrophy Case File

Duchenne Muscular Dystrophy Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 47

A 3-year-old boy is brought to his pediatrician to be evaluated for difficulty walking and clumsiness. According to his parents, the patient began walking at the age of 18 months, but in the past year he has begun to fall more frequently and has difficulty getting up from the floor, often supporting himself with his hands along the length of his legs. Birth and developmental history until symptom onset are reportedly normal. There is no contributing family history. On physical examination, the young boy has significant muscle weakness of his hip flexors, knee extensors, deltoids, and biceps muscles. His calves are large, and he walks on his toes during ambulation. He has the presence of a Gowers sign. Laboratory studies reveal an elevated serum creatine kinase (CK) level of greater than 900 IU/L. Electromyography (EMG) of his muscles reveals a myopathy. Nerve conduction studies (NCSs) reveal relative normal nerve function.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 47:

Duchenne Muscular Dystrophy                                                      

Summary: A 3-year-old boy presents with regression of motor milestones with gait instability. His examination is significant for proximal muscle weakness, toe walking, and calf enlargement. Diagnostic studies are significant for a primary muscle disorder with myopathic changes on electrodiagnostic testing and significantly elevated levels of a muscle enzyme, CK.

• Most likely diagnosis: Muscular dystrophy (MD)/Duchenne muscular dystrophy (DMD)
• Next diagnostic step: Genetic testing for dystrophin mutation
• Next step in therapy: Supportive management of mobility and monitoring of cardiac and respiratory function

ANALYSIS

Objectives

1. Know the clinical presentation of the most common childhood-onset MD.
2. Be familiar with the diagnostic workup of MD.
3. Be familiar with the treatment and management of DMD.

Considerations

This previously healthy 3-year-old boy is noted to have regression of motor milestones, but other developmental milestones are normal; this is suggestive of a neuromuscular disorder. The diagnostic studies are supportive of a primary muscle disorder. An important consideration in this case is the clinical presentation. The toddler has proximal muscle weakness resulting in gait instability (toe walking) and inability to rise from a sitting position or from a fall, often requiring the child to push on his knees to upright himself. The EMG/nerve conduction velocity (NCV) studies reveal a muscle problem. The elevated muscle enzyme, CK, supports a muscle destructive process. Thus, the clinical consideration is of a primary myopathy, either acquired or inherited. In this case, the toddler presents with regression of motor milestones, enlarged calves, an elevated CK, and no family history. Although not completely specific, the presentation is highly suggestive of DMD, the most common form of MD. It is caused by the absence of dystrophin, a protein involved in maintaining the integrity of muscle. The most distinctive feature of DMD is a progressive proximal MD with characteristic enlargement (pseudohypertrophy) of the calves. The bulbar (extraocular) muscles are spared, but the myocardium is affected. There is massive elevation of CK levels in the blood, myopathic changes by EMG, and myofiber degeneration with fibrosis and fatty infiltration on muscle biopsy. DMD has an X-linked recessive inheritance pattern, affecting only males. In the absence of a family history, a patient younger than 2 or 3 is unlikely to be diagnosed. Most boys with DMD walk independently at a later age than average. Parents usually worry something is unusual in the way the child walks, due to frequent falling or difficulty rising from the ground or going up steps. The serum CK level is always at least five times the upper limit of normal and makes the diagnosis of DMD probable. However, the diagnosis is confirmed by genetic testing and/or muscle biopsy.

APPROACH TO:

Duchenne/Becker Muscular Dystrophy                                            

DEFINITIONS

MYOPATHY: Disorders in which the primary symptom is muscle weakness because of dysfunction of muscle fiber.

CREATINE KINASE: An enzyme found primarily in the heart and skeletal muscles and, to a lesser extent, in the brain. Significant injury to any of these structures will lead to a measurable increase in serum CK levels.

MUSCULAR DYSTROPHY (MD): Inherited disease characterized by progressive weakness and degeneration of the skeletal muscles that control movement.

X-LINKED INHERITANCE: Inherited disease passed from mother to son because of a genetic abnormality on the X chromosome.

DYSTROPHIN PROTEIN: Rod-shaped protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. Its gene is the longest known to date and accounts for 0.1% of the human genome.

GOWERS SIGN: Clinical assessment of strength in proximal lower extremities performed by having the patient rise from a seated or lying position on the floor. A positive sign is characterized by placing the hands on the knees to aid in rising (tripod sign). This may be seen in any disease process resulting in proximal lower extremity muscle weakness.

CLINICAL APPROACH

Clinical Features and Epidemiology

Dystrophin-associated MDs are the most common types of inherited muscular dystrophies and are characterized by rapid progression of muscle degeneration that occurs early in life. The severe form occurs earlier and is called Duchenne, and the milder form, which can occur later, is called Becker MD (BMD). Both are caused by the same genetic mutation and follow an X-linked inheritance pattern, affecting mainly males—an estimated 1 in 3500 boys worldwide. Symptoms usually appear younger than age 6 but can appear as early as infancy. Patients present with progressive muscle weakness of the legs and pelvis, which is associated with a loss of muscle mass or muscle atrophy. Muscle weakness occurs in the arms, neck, and other areas, but it is usually not as severe or with as early an onset as the muscles of the lower extremities. Calf muscles initially grow larger because of replacement of muscle tissue with fat and connective tissue, a condition called pseudohypertrophy. With progressive weakness, muscle contractures occur in the hips, knees, and ankles. Thus, the muscles are unusable because the muscle fibers shorten and fibrosis (scarring) occurs in connective tissue. By age 10, braces might be required for walking, and by age 12, most patients are confined to a wheelchair. Bones develop abnormally, causing skeletal deformities of the spine (scoliosis) and other areas.

Muscular weakness and skeletal deformities contribute to respiratory or breathing problems, leading to frequent infections and often requiring assisted ventilation. Cardiac muscle is also commonly affected, leading to cardiomyopathy and in almost all cases leading to congestive heart failure and arrhythmias. Intellectual impairment can occur, but it is not inevitable and does not worsen as the disorder progresses. Death usually occurs by age 25, typically from respiratory (lung) disorders.

BMD is very similar to DMD and is caused by a mutation of the dystrophin gene on the X chromosome; however, BMD progresses at a much slower rate. This is because while DMD has a frameshift deletion that results in complete absence of dystrophin, BMD has an in-frame deletion that leads to a truncated protein with some function. BMD occurs in approximately 3 to 6 in 100,000 male births. Symptoms usually appear in males at approximately age 12 but can sometimes begin later. The average age of becoming unable to walk is 25 to 30. Women rarely develop symptoms. Muscle weakness is slowly progressive, causing difficulty with running, hopping, jumping, and eventually, walking. Patients may be able to walk well into adulthood, but it is associated with instability and frequent falls. Similar to DMD, patients with BMD experience respiratory weakness, skeletal deformities, muscle contractures, and calf pseudohypertrophy. Heart disease, including dilated cardiomyopathy, is also commonly associated, but heart failure is rare.

Etiology and Pathogenesis

The particular gene mutation that causes Duchenne and Becker muscular dystrophies (DBMD) is found on the X chromosome and results in loss or reduction of a functional muscle protein, dystrophin. A functional copy of the gene is needed for normal muscle function. In females, one functional copy is usually enough to compensate, and a female with a DBMD mutation usually has few or no symptoms. Most boys with DBMD inherited the mutation from their mother. However, in about 30% of the patients with DBMD, it is a result of a new mutation. In these cases, it is unlikely that future children will also have DBMD.

Dystrophin is considered a key structural element in the muscle fiber and the stabilization of the muscle plasma membrane, and it possibly has a role of signaling (Figure 47–1). Mechanically induced damage through muscle contractions puts a high stress on fragile membranes that could eventually lead to loss of regulatory processes leading to cell death. Altered regeneration, inflammation, impaired vessel response, and fibrosis are probably later events that take part in the MD.

DIAGNOSIS

The diagnosis of DMD and BMD depends on obtaining a complete medical and family history, documentation of muscle weakness, and pseudohypertrophy on physical examination. Diagnostic tests include measurement of a muscle enzyme, CK, in the blood. Because of the release of CK from damaged muscles, high blood levels of CK in DMD is often at least five times as high as the maximum for unaffected people. It is sometimes 50 to 100 times as high. In addition, electrodiagnostic studies of nerve and muscle function (EMG and NCSs) will confirm abnormal muscle function (myopathy) and the pattern or distribution of muscle dysfunction, in the absence of a peripheral nerve disorder.

Figure 47–1. Dystrophin and other sarcolemmal proteins in the cell membrane.

Genetic testing can establish the diagnosis of DMD or BMD and is often pursued prior to muscle biopsy. The dystrophin gene is the longest gene and therefore susceptible to genetic mutations. Approximately 60% of DMD cases are due to deletions of at least one exon in DMD, ~6% to duplications, and the rest to small mutations which results in absence of functional dystrophin

protein. Other are due to in-frame mutations, generating variants able to produce functional yet truncated versions of dystrophin. This kind of deletion occurs in patients with Becker MD (BMD). Most affected males have identifiable DMD pathogenic genetic variants. If genetic testing is positive, testing for the mutation can be offered to other family members. It is also used to determine probabilities of carrier status, prenatal diagnosis, and family planning.

Muscle biopsy is often diagnostic of the disease, with confirmation of muscle pathology and a loss or decrease of the dystrophin protein.

TREATMENT AND MANAGEMENT

Treatment is aimed at control of symptoms to maximize the quality of life. Modalities can include physical therapy, respiratory therapy, speech therapy, orthopedic appliances used for support, and corrective orthopedic surgery. Drug therapy includes corticosteroids to increase dystrophin expression and slow muscle degeneration, calcium and vitamin D to minimize bone loss, and vaccinations and antibiotics to fight respiratory infections. Some individuals can benefit from occupational therapy and assistive technology. Some patients might need assisted ventilation to treat respiratory muscle weakness and a pacemaker for cardiac abnormalities. Close surveillance is important to assess for development of complications. Therefore, patients require multispecialty care from pediatricians, neurologists, rehabilitative services, pulmonologists, and cardiologists. Recent advances have pointed toward gene therapy as the next step. Experimental treatments include exon-skipping, which uses oligonucleotides to skip entire exons to avoid frameshift mutations such that a truncated but still functional dystrophin protein can be expressed and insertion of the wild-type dystrophin gene using viruses, stem cell therapies, treatments targeted at membrane stabilization, and upregulation of cytoskeletal proteins.

COMPREHENSION QUESTIONS

47.1 A 3-year-old boy is brought into the pediatric neurologist’s office because of progressive weakness. The neurologist is contemplating a diagnosis between BMD and DMD. Which of the following statements is most accurate regarding these two conditions?

A. BMD differs from DMD because of later onset and different inheritance pattern.

B. BMD is similar to DMD because of a shared genetic mutation and inheritance pattern.

C. Mothers of BMD and DMD patients are often symptomatic in late adulthood.

D. BMD is a more rapidly progressive form of DMD.

47.2 A 32-year-old woman is 32 weeks pregnant and is a known carrier for DMD. She asks what the ramifications are for her unborn child. Which of the following statements is most accurate?

A. Almost 25% of her daughters will be affected with the disease.

B. About 50% of her daughters will be carriers.

C. About 75% of her sons will be affected with the disease.

D. One hundred percent of sons will either be carriers or inherit the disease.

47.3 A 5-year-old child presents to neurology clinic for evaluation of gait difficulty and weakness. Which of the following diagnostic tests is supportive in diagnosing DMD/BMD?

A. Serum CK

B. Echocardiogram

C. Pulmonary lung function tests

D. Magnetic resonance imaging (MRI) of the brain and spine

ANSWERS

47.1 B. BMD is very similar to DMD and is due to a mutation of the dystrophin gene on the X chromosome with a male-specific inheritance pattern; however, BMD progresses at a much slower rate.

47.2 B. Because males have only one X chromosome, a male carrying a copy with a dystrophin gene mutation will have the condition. Because females have two copies of the X chromosome, a female can have one copy with a DBMD mutation and one functional copy. Thus, a mother who is a carrier has a 50% chance passing the mutation to her sons or daughters. Of those children, 50% of the boys will have the disease and 50% of the girls will be carriers.

47.3 A. CK in DMD is often at least five times as high as the maximum for unaffected people. Because it is a primary skeletal muscle disorder, the other mentioned tests are of limited value.

    CLINICAL PEARLS    

▶ Both DMD and BMD are X-linked. When the woman is a carrier for the dystrophin mutation, half of her sons will have the disease, and half of her daughters will be carriers. ▶ Behavioral studies have shown that DMD boys have a cognitive impairment and a lower IQ (average 85) because of mutant dystrophin in neurons. ▶ Corticosteroids can be beneficial in the treatment of DMD and can be offered as a treatment option. ▶ Elevated CK levels are typical for DMD.

REFERENCES

Darras BT, Miller DT, Urion DK. Dystrophinopathies. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews® (Internet). Seattle, WA: University of Washington; 1993-2017. 

Deconinck N, Dan B. Pathophysiology of Duchenne muscular dystrophy: current hypotheses. Pediatr Neurol. 2007:36(1):1-7. 

Kalra V. Muscular dystrophies. Indian J Pediatr. 2000;67(12):923-928. 

Lim KR, Maruyama R, and Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017:11:533-545. 

Mah JK. Current and emerging treatment strategies for Duchenne muscular dystrophy. Neuropsychiatr Dis Treat. 2016;12:1795-1807. 

Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74:637-647. 

Wu B, Xiao B, Cloer C, et al. One-year treatment of morpholino antisense oligomer improves skeletal and cardiac muscle functions in dystrophic mdx mice. Mol Ther. 2011;19:576-583.

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