Duchenne Muscular Dystrophy: Clinical and Therapeutic Approach

Abstract

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are dystrophinopathies, a group of muscular dystrophies caused by mutations in the dystrophin gene. Duchenne muscular dystrophy is the most common muscular dystrophy that occurs in children. A mutation in the DMD gene leads to a loss of expression of the dystrophin protein, a subsarcolemmal protein that provides strength, stability, and functionality to the myofibrils. Patients with dystrophinopathies with basic progressive weakness of the musculoskeletal system develop complications of many organ systems that significantly contribute to the deterioration of the clinical condition and shorter life expectancy. Multidisciplinary care has extended the patients’ life expectancy and the development of subspecialist branches has enabled the improvement of diagnostic methods and treatment. Recently, therapeutic options in the treatment of DMD have advanced significantly, and new genetic and molecular therapies are emerging. The advent of gene therapy as a causal therapy for DMD has placed additional emphasis on diagnosing and treating the disease as early as possible. This achieves an additional prolongation of life expectancy, increases the quality of life in patients with DMD, and provides hope for patients and their families.

1. Introduction

Muscular dystrophies are inherited, progressive muscle disorders resulting from defects in one or more genes needed for normal muscle structure and function. Muscular dystrophies are distinguished by the selective distribution of weakness and the specific nature of the genetic abnormality involved, which affect all races and ethnic groups. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are dystrophinopathies, a group of muscular dystrophies caused by mutations in the dystrophin gene. DMD is a severe X-linked recessive neuromuscular disorder caused by mutations in the dystrophin gene that result in absent or insufficient functional dystrophin, a cytoskeletal protein that enables the strength, stability, and functionality of myofibers. Dystrophin is bound to actin in the cytosol by a transmembrane complex and connects the cytoskeleton and extracellular matrix, allowing contractility of the muscle fiber. Gene that encodes dystrophin is one of the largest genes in the human body. It occupies about 1% of the whole x-chromosome. Duchenne muscular dystrophy is the most common muscular dystrophy that occurs in children, with a frequency of 1 in 3500 live-born male children. In contrast, Becker muscular dystrophy occurs much less frequently, approximately 1 in 30,000 live-born male children. According to epidemiological data, frequency occurrence is approximately the same in all countries of the world [1].

2. Pathophysiology

DMD is inherited in an X-linked pattern. The gene that can carry a DMD-causing mutation is on the X chromosome. Every boy inherits an X chromosome from his mother and a Y chromosome from his father. Girls get two X chromosomes, one from mother and one from father. Due to the X-linked inheritance, each son born to a woman with a dystrophin mutation on one of her two X chromosomes has a 50 percent chance of inheriting the flawed gene and having DMD. Each of her daughters has a 50 percent chance of inheriting the mutation and being a carrier who may pass the mutation onto their own children. Carriers may not have any disease symptoms but can have a child with the mutation or the disease [1]. However, the latest research shows that in some cases, female carriers may develop symptoms such as cardiomyopathy. It is important to note that one-third of boys with DMD are born to mothers without mutation in the X chromosome due to a new genetic mutation that arose in one of mother’s egg cells. Mutations in the DMD gene that cause phenotypic expression of the disease are numerous and highly variable. They include deletions of the whole gene, deletions or duplications of one or more exons, and insertions or alterations of a single nucleotide. Deletions of one or more exons of the DMD gene represent 60−70% of mutations in Duchenne muscular dystrophy, and 80−90% of mutations in Becker muscular dystrophies. Point mutations make up 25−35% of Duchenne mutations and 10−20% mutations in Becker muscular dystrophy. Duplications are the least represented, with a frequency of 5−10% in Duchenne and Becker muscular dystrophy. In more than 90% of patients, dystrophin deficiency is the result of “out of frame” mutations that cause the reading frame to shift. Such mutations cause transcription termination of informational RNA, resulting in complete dystrophin deficiency or the formation of very small amounts of abnormal dystrophin. If “in frame” mutations occur, which do not cause shift of the reading frame, there is a quantitative and qualitative change in dystrophin, and the clinical presentation is less severe. DMD mutations cause virtually no functional dystrophin to be made. On the other hand, patients with BMD make dystrophin that is partially functional, so the clinical presentation is less severe. They make a shortened form of the protein, which protects the muscles in BMD from degenerating as completely or as quickly as those of patients with DMD. Qualitative changes in dystrophin and its deficiency lead to membrane degradation. In the process of cell membrane breakdown, there is also a loss of certain muscle enzymes causing muscle weakness [2].

Previously said, DMD is inherited in an X-linked pattern, which means male children get affected. Female carriers may not have any disease symptoms but can have a child with the mutation or the disease [1]. However, the latest research shows that in some cases, female carriers may develop symptoms such as cardiomyopathy. It is important to note that one-third of boys with DMD are born to mothers without mutation in the X chromosome due to a new genetic mutation that arose in one of mother’s egg cells. Mutations in the DMD gene that cause phenotypic expression of the disease are numerous and highly variable. They include deletions of the whole gene, deletions or duplications of one or more exons, insertions, or alterations of a single nucleotide. Deletions of one or more exons of the DMD gene represent 60−70% of mutations in Duchenne muscular dystrophy, and 80−90% of mutations in Becker muscular dystrophies. Point mutations make up 25−35% of Duchenne mutations and 10−20% mutations in Becker muscular dystrophy. Duplications are the least represented, with a frequency of 5−10% in Duchenne and Becker muscular dystrophy. In more than 90% of patients, dystrophin deficiency is the result of “out of frame” mutations that cause the reading frame to shift. Such mutations cause transcription termination of informational RNA, resulting in complete dystrophin deficiency or the formation of very small amounts of abnormal dystrophin. If “in frame” mutations occur, which do not cause shift in the reading frame, there is a quantitative and qualitative change in dystrophin, and the clinical presentation is less severe. Patients with BMD make dystrophin that is partially functional. They make a shortened form of the protein, which protects the muscles in BMD from degenerating as completely or as quickly as those of patients with DMD. Qualitative changes in dystrophin and its deficiency lead to membrane degradation. In the process of cell membrane breakdown, there is also a loss of certain muscle enzymes causing muscle weakness [2].

3. Clinical presentation

In Duchenne muscular dystrophy, no abnormality is noted in the patient at birth, and manifestations of the muscle weakness do not begin until the child begins to walk. Clinical symptoms of Duchenne muscular dystrophy are usually noticed around the age of 3, most often between the ages of 3 and 5. However, taking a more detailed history often reveals that motor development has been slower before. Children with Duchenne may be slower to sit, stand, or walk. Most are unable to run and jump properly due to weakness in the muscles of the body. Self-walking occurs later, approximately at 15 months of age. Signs and symptoms of DMD, which typically appear in early childhood, might include: later onset of independent sitting, frequent falls, clumsiness, difficulty rising from a lying or sitting position, trouble running and jumping, waddling gait, walking on the toes, muscle pain and stiffness, large calf muscles, learning disabilities, and delayed growth. In toddlers, parents may notice enlarged calf muscles. This enlargement is known as pseudohypertrophy, or “false enlargement,” because the abnormal muscle tissue is replaced by a fat tissue. A baby or a toddler with DMD may seem clumsy and fall often. Parents may also note that children have trouble climbing stairs, getting up from the floor, or running. When arising from the floor, patients may use hand support to push themselves to an upright position. It is called the Gowers sign. In 1879, a British neurologist, Sir William Richard Gowers, described the most significant Gowers sign as the characteristic pattern seen in patients with Duchenne muscular dystrophy wherein they “climb up” their thighs with the aid of their hands to overcome the weakness of their pelvic and proximal lower limb muscles [1, 2]. Weakness of the hip girdle and upper thigh muscles leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in the hip becomes flexed, and lumbar lordosis increases. Patients with DMD usually have difficulties standing up from a sitting position, so they need to use strength from the arm muscles. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step, so the waddling gait appears. On average, muscles lose approximately 2% of their strength each year. According to the time period and disease progression, the course of DMD is classified into five phases: diagnosis (infancy/childhood), early ambulatory (childhood), late ambulatory (late childhood/adolescent/young adult), early nonambulatory (adolescent/young adult), and late nonambulatory (adult). Ambulation is the ability to walk without the need for any kind of assistance. Classification is important for establishing diagnostic and treatment protocols that are carried out at a particular stage [2].

Loss of ambulation occurs in untreated patients at the end of the first decades of life, while in patients treated with corticosteroids it occurs two to three years later. Respiratory problems are the main cause of mortality and morbidity in patients with DMD. Respiratory function gradually deteriorates due to weakening of the respiratory muscles, intercostal, and diaphragm. All respiratory functions are affected–oxygen exchange, mucociliary activity, and respiratory control during wakefulness and sleep. Significant cause of mortality and morbidity is cardiac complications. Lack of dystrophin in the heart leads to the development of cardiomyopathy, progressive myocardial fibrosis leading to ventricular dysfunction and sometimes life-threatening cardiac arrhythmias. Body weight can vary from malnutrition to normal values or malnutrition. Glucocorticoid therapy increases appetite and sodium and water retention, and due to muscle weakness, patients have limited physical activity. During adolescence, the risk of malnutrition increases due to dysphagia, mandibular contracture, and constipation. Endocrinological complications that may occur due to glucocorticoid therapy include reduced growth, delayed puberty, and, rarely, adrenal insufficiency. Some patients with DMD may have certain cognitive difficulties, and it is believed that the expression of dystrophin in the brain is variable and that depends on the type of gene mutation. The life expectancy of patients with DMD was approximately 20 years [1, 2].

Advances in diagnostic and therapeutic options have occurred to increase life expectancy by 10 and several years, and it is believed that the gene therapy, which is already underway, will further extend the life expectancy of people with DMD [2].

4. Diagnosis

Achieving a timely and accurate diagnosis of DMD and BMD is a crucial aspect of care. It is extremely important to recognize the early signs of muscular dystrophy, which, unfortunately, are often interpreted as a child’s clumsiness or laziness, so they are often not recognized until the 3rd or 4th year of life. Nonmotor manifestations (especially slow speech development) may be failed to observe, neuromuscular diseases are rare, and the attending physician often has no experience with this disease, which contributes to the delay of diagnosis for up to 30 months and the later start of pharmacological therapy and rehabilitation. The diagnosis is most often set in early childhood by the appearance of specific signs, such as muscle weakness, clumsiness, toe walking, difficulty climbing stairs, and a positive Gowers sign. When these symptoms occur, the patient first is referred to a pediatric neurologist who sets suspicion on muscular dystrophy. The role of laboratory tests is extremely important. The most important screening test for dystrophy is determination of serum creatine kinase (CK) levels with determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Slightly elevated or normal CK values are a sufficient condition to rule out the disease. In patients with DMD, CK, ALT, and AST levels are elevated from the early stages of the disease. Unfortunately, there are cases of patients with minimal clinical symptoms at an early age who have missed CK testing, and routine laboratory tests showed elevated ALT and AST values. That situation led them to the wrong focus on liver disease treatment and contributed to delayed diagnosis. In order to diagnose DMD and BMD, it is mandatory to perform genetic testing to determine the exact type and location of the mutation, which also affects the possibility of treatment with specific drugs for certain types of mutations [2].

Almost 70% of patients with DMD have a single-exon or multi-exon deletion or duplication in the dystrophin gene, so that is the reason why the first confirmatory test is dystrophin gene deletion and duplication testing. It is done by multiplex ligation-dependent probe amplification (MLPA) or comparative genomic hybridization array (array CGH) since use of multiplex polymerase chain reaction (PCR) can only identify deletions. Identification of the boundaries of a deletion or duplication mutation by MLPA or comparative genomic hybridization array could indicate whether the mutation is predicted to preserve or disrupt the reading frame. If deletion or duplication testing is negative, genetic sequencing should be done to screen for the types of mutations that are attributed to DMD. These mutations include point mutations (nonsense or missense), small deletions, and small duplications or insertions, which can be identified using next-generation sequencing. Finally, if genetic testing does not confirm a clinical diagnosis of DMD, then a muscle biopsy sample should be tested for the presence of dystrophin protein by immunohistochemistry of tissue cryosections or by western blot of a muscle protein extract. In muscle biopsy, the presence of dystrophins is determined by immunohistochemical methods and the amount and size of dystrophin. However, a muscle biopsy can confirm the diagnosis but not the treatment options, as it does not provide information on the type and location of the mutation [1].

5. Treatment

Multidisciplinary approach to care is essential for optimal management of the primary manifestations and for preventing secondary complications of Duchenne muscular dystrophy. Contemporary care has been organized by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients’ duration and quality of life. The neuromuscular specialist (usually pediatric neurologist) is qualified to guide patients and their families through the increasingly complex and technological diagnostic and therapeutic landscape of contemporary DMD care. Centers for Disease Control and Prevention (CDC) in cooperation with relevant organizations (TREAT-NMD network for neuromuscular diseases, the Muscular Dystrophy Association, and Parent Project Muscular Dystrophy) updated and upgraded recommendations from 2010 in the monitoring and treatment of patients with DMD. Division is essential for establishing a protocol for diagnostics and treatments carried out in each phase [2].

The mainstays of DMD remain physiotherapy and glucocorticoid treatment, which should be continued after the stage of loss of ambulation. The benefits of long-term glucocorticoid therapy have been shown to include loss of ambulation at a later age, preserved upper limb and respiratory function, and avoidance of scoliosis surgery. Recent studies confirm the benefits of starting glucocorticoids in younger children, before significant physical decline. Although the benefits of glucocorticoid therapy are well established, uncertainty remains fact about which glucocorticoids are best and at what doses. Glucocorticoids used in the treatment of DMD and BMD are prednisone and deflazacort (an oxazolone derivative of prednisone). As a starting dose, it is recommended to take prednisone at a dose of 0.75 mg/kg or deflazacort at a dose of 0.9 mg/kg [2]. The main side effects of glucocorticoids are decreased bone density, increased appetite and body weight, and growth retardation. In studies comparing prednisone and deflazacort, a smaller one was observed weight gain of patients on deflazacort therapy. It is important to note that the FDA approved deflazacort, making it the first glucocorticoid with a specific indication in the treatment of DMD. In cases of intolerance to side effects, recommendations are a reduction in the dose of glucocorticoids by 25−33%, with a revision of symptoms for a month [2, 3].

DMD is characterized by progressive muscle degeneration and weakness, risk of progressive contracture and deformity, decrease in pulmonary and heart function, and functional losses resulting from dystrophin deficiency. Improved DMD management has resulted in prolongation of ambulation, decreased prevalence of severe contracture and deformity, and prolonged function in all areas of life. Rehabilitation team includes physicians, physical therapists, occupational therapists, speech pathologists, and medical equipment providers. Rehabilitation management requires an understanding of DMD pathology, and disease progression [3, 4].

Rehabilitation assessment includes measures of passive ranges of motion, muscle extensibility, posture and alignment, strength, and function in all activities of everyday life. Specialized functional assessment includes analysis of patterns of movement and standardized assessments specific to DMD and other neuromuscular disorders. Foundational clinical assessments of function during the ambulatory period are the North Star Ambulatory Assessment (NSAA) and timed function tests and should be done every 6 months. The NSAA and timed function tests have high reliability and validity, as well as a correlation between tests across time and predictive capabilities regarding functional motor changes that are important in monitoring clinical progression and assessing new and emerging therapies. Identification of optimally responsive test ranges improves predictive capabilities. The North Star Ambulatory Assessment (NSAA) is a 17-item rating scale that is used to measure functional motor abilities in ambulant patients with DMD. It is usually used to monitor the progression of the disease and treatment effects. The NSAA scale consists of 17 components that are scored depending on the patient’s performance, with 2, 1, or 0 points. The maximum number of points is 34. The components that are assessed in patients are: standing, walking, getting up from a chair, standing on one leg—left and right, climbing stairs—left and right foot, descending the stairs—left and right foot, sitting from a lying position, raising from floor, lifting head, standing on heels, jumping, and hop on right and left leg and running 10 m. The examination must be performed without the use of those. The 6-min walk test is a sub-maximal exercise test used for evaluation of aerobic capacity and endurance. The distance covered over a time of 6 min is used as the outcome by which to compare changes in performance capacity. Tests that predict potential upcoming changes can be used to guide proactive care, such as impairment-level interventions and possible equipment needs. Specifically, before age of 7 years, gains might occur in the 6-min walk test and timed function tests. After 7 years, a 6-min walk test result of less than 325 m, time to stand more than 30 sec, time to climb four stairs more than 8 s, 10-min walk or run time more than 10–12 s, and mean linearized NSAA 34 or less (raw score of nine) have been associated with greater functional decline in ambulation over the subsequent 12 months. Functional assessment includes the assessment of activities of everyday living and the need for adaptive equipment or possible assistive technology. The NSAA, with revision, can be used to test children’s motor function from the age of 3. Hip kinematics during gait are clinically meaningful outcome measures at 4–8 years. Other measures assessing antigravity function include the Alberta Infant Motor Scale, Hammersmith Functional Motor Scale Expanded, and the Gross Motor Function Measure. In older individuals who are nonambulatory. The most popular is The Brooke Upper Extremity Scale, which assesses the function of the upper limb function. Consistent use of the same functional measurements is recommended. Assessment of motor skills by a specialist physiatrist should be monitored every 4-6 months, with more frequent checkups as needed [2, 3].

Direct physical, occupational, and speech therapy should be provided in outpatient and school settings and continue throughout adulthood. The goal of muscle extensibility and joint mobility management is prevention or minimization of the occurrence of contracture and deformities. The inability to move a joint through its full range of motion, muscle imbalance in a joint, chronic static positioning, and fibrotic changes in muscles can cause decreased muscle extensibility and joint contractures. Restricted patterns of breathing and fibrosis of intercostal muscles decrease chest wall mobility. The maintenance of passive ranges of movement, muscle extensibility, and chest wall mobility can optimize movement and functional positioning, maintain ambulation, prevent fixed contractures and deformities, and optimize respiratory function. A daily preventive home stretching program should begin before the loss of passive ranges of motion under the guidance of physical therapist. Regular stretching of ankle, knee, and hip should begin after diagnosis and continue into adulthood. Stretching of the upper extremities is especially important in the stage after loss of ambulation. Power stand-and-drive motorized wheelchairs are now frequently used instead of knee-ankle-foot orthoses to support standing mobility. Such orthoses might still be an appropriate choice in some situations but should be viewed as therapeutic rather than functional tools. Possible adaptive equipment and home renovations include patient lifts for safe transfers, stair lifts, bathing and bathroom equipment or renovations, special beds and mattresses, and vehicle modifications. Physical therapists prescribe, monitor, and guide exercise, which can prevent an unnecessarily sedentary lifestyle and the associated problems of social isolation and overweight. However, the effects of exercise on muscle degeneration in dystrophinopathies can include damage due to structural fragility of muscles, metabolic abnormalities, and reduced exercise capacity. Eccentric muscle activity or exercise and high-resistance exercise or strength training should be avoided. It is recommended to perform the submaximal aerobic exercise. Swimming is highly recommended from the early ambulatory stage and can be frequently continued into adulthood. Warm water allows children with DMD to perform targeted stretches, exercises, and function-based and play activities that are progressively lost to them on dry land. The Halliwick method is very popular. It is the concept for teaching people with any physical, mental, or sensory difficulties. One of the founders of the method, James McMillan, combined the principles of water, hydrostatics and hydrodynamics, with form and behavior bodies in water. The goal is to achieve: improving breathing control, rhythmic movement coordination, sensory integration, stability and mobility control, improving general fitness and health, and social interaction [5].

Patients and their families are at increased risk of depression and anxiety, particularly at major care transition points in the progression of the disease. The neuromuscular care team should include a mental health clinician (psychologist, psychiatrist) who has specialized training and experience in assisting families and patients with chronic medical or neurodevelopmental conditions. DMD may affect a patient’s ability to consistently access his educational environment. Accommodations should be provided to maximize a patient’s ability to function normally with his peers [5].

The aim of musculoskeletal care is to maintain motor function for as long as possible, minimize joint contractures, promote bone health, and maintain a straight spine. Assessment for scoliosis should be done at least annually. In ambulatory stage, visual assessment is appropriate, with radiographic assessment only if a curve is observed on examination or if visual inspection alone is inadequate, for example, in children with obesity. Inspection of the spine should be done at every clinical examination in an early nonambulatory stage. Experienced clinicians should be able to monitor the spine in nonambulatory boys by inspection, while less experienced clinicians should obtain a spine radiograph when a child first becomes nonambulatory. Once a curve has been detected with radiography, further surveillance depends on the skeletal maturity of the individual. Skeletally immature individuals should undergo radiographs once every 6 months, while skeletally mature individuals should undergo radiographs at least once a year. A curve of 20° or more should warrant involvement of an orthopedic surgeon. It is not recommended to use the spinal orthoses. Patients treated with corticosteroids have milder spinal curvatures and less frequent need for spinal surgeries. In late nonambulatory stage, clinicians should examine the spine at every clinical visit. Individuals with known scoliosis should have yearly anteroposterior upright spinal radiographs when there is any concern about progression [3].

Patients on glucocorticoid therapy as part of DMD treatment often develop osteoporosis. It is often manifested as trauma to the lower spine or fracture of the long bones [4]. This outcome is not surprising because of known toxicity of glucocorticoid therapy on bone density and, in combination with progressive myopathy, the risk for reduction in bone strength. Approximately 20−60% of children with DMD develop long bone fractures (most commonly the distal femur, tibia, and fibula), and about 30% of them have vertebral fractures. Vertebral fractures are often asymptomatic and are mostly found during control radiological images of the spine, so the prevalence is probably higher than available in the literature. If left untreated, vertebral fractures lead to chronic back pain and spinal deformities [4].

Despite the high incidence of fractures, no studies have yet been published on DMD or diseases associated with osteoporosis in which the benefit and safety of the therapy being assessed used in first-line fracture prevention. According to the latest guidelines, it is considered how bone mineral density (BMD) obtained by densitometry is no longer a major factor in assessing bone fragility. Bone mineral density is now supplementing the approach used to identify the earliest signs of impending bone fractures. Due to a large number of vertebral fractures that are asymptomatic, it is important to emphasize how spinal radiographs should be done regularly, regardless of the absence of symptoms [6].

Fractures are more likely to occur in children whose BDM Z value is higher than −2 SD (standard deviation), thus emphasizing the inadequacy of densitometry as the only method for assessing fracture risk. Regarding bone health, the approach of a patient with DMD at diagnosis includes paying attention to the existence of back pain, before starting glucocorticoid therapy, patient should test levels of serum calcium, phosphate, magnesium, alkaline phosphatase, and parathyroid hormone levels. Also, when making a diagnosis once a year, calcium and vitamin D intake should be determined, serum 25-hydroxyvitamin D3 and perform densitometry [7].

Intravenous bisphosphonates are used for treatment of osteoporosis caused by glucocorticoids. Treatment also includes calcium and vitamin D supplementation. Bisphosphonates are synthetic analogs of pyrophosphate that bind to hydroxyapatite in bone and strongly inhibit bone resorption by slowing down maturation and osteoclast activity. Indications for initiating intravenous treatment with bisphosphonates have not changed from before and include the presence of vertebral or long vertebral fracture bones. Renal function should be measured before initiating intravenous bisphosphonate therapy. It is important to emphasize that intravenous bisphosphonates are used in treatment, not oral ones. It is essential to measure the dose over long periods of time, as well as monitor safety and efficacy of treatment [6, 7].

The most common cause of morbidity and mortality in people with DMD is respiratory complications. The most common complications are respiratory muscle fatigue, atelectasis, mucus plugging, pneumonia, and respiratory failure. Untreated complications can put patients at risk of severe dyspnoea, lengthy hospital admissions due to pneumonia, and death due to respiratory arrest or respiratory-induced cardiac arrhythmias [3]. Respiratory management includes monitoring of respiratory muscle function and the timely use of lung volume recruitment, methods of assisted coughing, and nocturnally assisted ventilation and subsequent daytime ventilation. These therapies can decrease respiratory complications, improve quality of life, and prolong patients’ survival. Patients should typically be using most of these therapies by the age of 18–21 years [8]. Serial monitoring of pulmonary function is critical for respiratory care. Forced vital capacity (FVC) rises with growth until an individual becomes nonambulatory. FVC reaches a peak, followed by a plateau, and then deteriorates over the time. Deteriorating FVC may occur in the absence of dyspnoea and remain unrecognized unless pulmonary function is measured regularly. Because the rate of change in FVC over time can vary greatly among individuals, serial measurement of FVC is necessary to characterize each individual’s respiratory phenotype. During the ambulatory stage, sleep studies with capnography might be necessary, especially for individuals with weight gain due to glucocorticoid therapy and for individuals with symptoms of sleep-disordered breathing. According to guidelines from the US Centers for Disease Control and Prevention, it is important for patients with DMD to receive yearly immunization with the inactivated influenza vaccine (the injectable vaccine, not the live, attenuated nasal vaccine) and pneumococcal vaccines (including PCV13 and PPSV23) Patients and their caregivers should be educated about respiratory complications during the ambulatory stage of DMD to prepare them for possible future medical complications and therapies. The need for respiratory interventions occurs usually after the loss of ambulation. It is recommended to measure FVC, maximum inspiratory and expiratory pressures (MIP and MEP), peak cough flow, and blood oxygen saturation by pulse oximetry (SpO2) at least every 6 months in all nonambulatory individuals. End-tidal or transcutaneous partial pressure of carbon dioxide in the blood should be measured every 6 months or any time SpO2 is 95% or lower in room air. As their vital capacity decreases, patients with DMD develop noncompliant chest walls and lung volume restriction. To preserve lung compliance, lung volume recruitment is indicated when FVC is 60% predicted or less, achieved with a self-inflating manual ventilation bag or mechanical insufflation-exsufflation device to provide deep lung inflation once or twice daily [3, 8].

During the nonambulatory stage, individuals with DMD often develop weak cough efforts, leading them to risk of atelectasis, pneumonia, ventilation-perfusion mismatch, and progression to respiratory failure, especially during respiratory infections. Treatment includes manual and mechanically assisted coughing, which are indicated when FVC is less than 50% predicted, when peak cough flow is less than 270 L/min, or when maximum expiratory pressure is less than 60 cm H2O. When SpO2 is less than 95% in room air, the frequency of assisted coughing should be increased to prevent and treat mucus plugging, atelectasis, and pneumonia. Antibiotic therapy is recommended during acute respiratory infection when individuals have three of the following five signs of pneumonia: elevated white blood count or C-reactive protein concentration, fever, sputum production, a pulmonary infiltrate on chest radiograph, or hypoxemia or respiratory distress [2, 3, 5].

In the late nonambulatory stage, patients with DMD need assisted ventilation to prolong survival. Signs or symptoms of hypoventilation or sleep-disordered breathing are indications for nocturnally assisted ventilation. Symptoms include fatigue, dyspnoea, morning or continuous headaches, frequent nocturnal awakenings, hypersomnolence, difficulty concentrating, awakenings with dyspnoea, and tachycardia. However, some individuals remain asymptomatic despite the presence of hypoventilation. Nocturnally assisted ventilation should be initiated if a patient’s FVC is less than 50% predicted, or when the absolute value of maximum inspiratory pressure is less than 60 cm H2O. Nocturnal ventilation is indicated for patients with abnormal sleep studies, such as overnight oximetry, combination oximetry–capnography, and polysomnography with capnography. Nonambulatory patients with symptoms of sleep-disordered breathing should have sleep studies annually. Because patients with DMD need assisted ventilation to treat hypoventilation, nocturnal noninvasively assisted ventilation (rather than continuous positive airway pressure at a constant level) is first-line therapy for individuals with DMD with obstructive sleep apnea [3, 5].

Continuous noninvasive ventilation methods include mouthpiece or sip ventilation with a portable volume ventilator during the day, changing to nasal ventilation with a bi-level pressure device overnight. Ventilation via tracheostomy or noninvasive ventilation is a controversial question. Some centers use time using the ventilator (16 h/day or more) as an indication for tracheostomy. Clinical experience supports the use of noninvasively assisted ventilation for up to 24 h/day. The decision depends on each individual’s preference and clinical course, the skills and usual practices of the individual’s clinicians, the standard of care, and the availability of home resources, such as overnight nursing. The use of noninvasive respiratory aids is challenging when individuals with very advanced DMD have acute respiratory illnesses and when they have chronic difficulty swallowing their saliva. Continuous ventilation provides life support, so a backup ventilator and a manual resuscitator should be available in case the primary ventilator malfunctions. The ventilation device and battery should attach to the individual’s wheelchair for mobility and quality of life [3, 8].

A major cause of disease-related morbidity and mortality among individuals with DMD is cardiovascular complications. Dystrophin deficiency in the heart muscle causes cardiomyopathy. As the disease progresses, the myocardium fails to meet physiological demands, which leads to heart failure. The failing myocardium can also cause life-threatening arrhythmias. Cardiac management has been challenging because the New York Heart Association (NYHA) classification of heart failure relies on reduced exercise tolerance and patients with DMD have skeletal muscle and cardiac disease combined. The symptoms of heart failure in the nonambulatory individual are frequently overlooked. Early diagnosis and treatment are essential to maximize duration and quality of life. The cardiologist should have clinical expertise in diagnosing and treating heart failure and the cardiomyopathy associated with neuromuscular disease [3]. The baseline cardiac assessment includes cardiac medical history, family history, and a physical examination. Electrocardiogram and noninvasive imaging are advised to establish baseline cardiac function and to screen for underlying anatomical. Echocardiography is recommended until at least age 6–7 years when cardiovascular MRI CMR can usually be done without anesthesia. Patients should have an annual cardiac assessment, until the age of 10 years, including electrocardiogram and noninvasive imaging. After the age of 10 years, asymptomatic patients should have a cardiac examination at least annually because of the increased risk of left ventricular dysfunction. First-line therapy for the treatment of heart disease associated with DMD is angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Dosing and ACE inhibitor selection are left to the decision of the cardiologist. Pharmacological therapy should be initiated with the appearance of heart failure symptoms or with the abnormalities such as depressed left ventricular ejection fraction, abnormal chamber dimensions, or the presence of myocardial fibrosis noted on imaging studies. Given the absence of dystrophin-specific targeted cardiac therapies, traditional treatment strategies for heart failure should be used. Progressive myocardial fibrosis may lead to ventricular dysfunction. More frequent cardiac monitoring is advised in the late, nonambulatory stage to reduce disease-related morbidity and mortality. Symptomatic heart failure can be particularly difficult to diagnose in nonambulatory patients with DMD. Clinical manifestations of heart failure: fatigue, sleep disturbance, and inability to tolerate daily activities are often unrecognized until late in the disease because of musculoskeletal limitations. The cardiologist should maximize medical therapy for heart failure. Consideration should also be given to thromboembolism prevention in patients with severe left ventricular dysfunction. Patients with DMD are at risk of rhythm abnormalities including atrial flutter or fibrillation, ventricular tachycardia, and ventricular fibrillation that can be treated with standard antiarrhythmic medications or device management. It is recommended to start annual Holter monitor screening with the onset of abnormal left ventricular function or development of myocardial fibrosis [3, 5].

Patients with DMD often have gastrointestinal or nutritional complications, including weight gain or loss, dietary or nutrient imbalance, fluid imbalance, swallowing dysfunction, and mandibular contracture. The purpose of nutritional care is to prevent overweight or obesity and undernutrition or malnutrition through regular assessment of growth and weight. It also helps to promote a healthy, balanced diet, with optimum intake of calories, protein, fluid, and micronutrients. It is recommended for the care team to include a registered nutritionist who should see an individual with DMD at every visit, beginning at diagnosis. More frequent monitoring by the nutritionist will be necessary during periods when weight gain or loss is anticipated. A physical therapist should be consulted to design exercise programs for patients who are at risk of becoming overweight. A speech-language pathologist should be consulted for patients with suspected dysphagia. A gastroenterologist needs to be consulted for problems with constipation, gastroesophageal reflux, and gastrointestinal motility concerns, and when gastrostomy tube placement is needed. Good nutritional status is defined as weight for length, or body-mass index (BMI) for age, that falls between the 10th and 85th percentiles on standard growth charts. If BMI cannot be calculated in patients with DMD, because height cannot be measured, weight-for-age percentiles should be used. Patients with DMD have altered body composition, so the use of standard growth charts is not optimal. Patients with DMD are at risk of overweight or obesity in childhood, with an increased risk of undernutrition or malnutrition as they approach adulthood. In early childhood, glucocorticoid therapy increases the risk of being overweight due to increased appetite and caloric intake and sodium and fluid retention. Loss of ambulation leads to decreased activity, which reduces caloric needs and puts patients at risk of becoming overweight. The clinician should create a nutritional plan that includes recommendations for calorie, protein, micronutrient, and fluid intake. If weight gain is excessive, an obesity management plan should be created, which addresses both diet and physical activity. Dysphagia is common and frequently progressive in patients with DMD. Screening questions should focus on perceived difficulty with swallowing, time necessary to eat an average meal, and interference of eating with quality of life. If a patient responds to screening questions in the affirmative, the speech-language pathologist should be consulted for an assessment, including a videofluoroscopic swallowing study. Patients often lose weight unintentionally before and during the onset of clinical symptoms of dysphagia. Their BMI or weight percentiles might decrease from the overweight category into the normal range or into the underweight range as a result of dysphagia and disease progression. Family and specialists should consider gastrostomy tube placement to be a necessary and positive intervention when progressive weakness interferes with self-feeding and swallowing. Malnutrition that is unresponsive to interventions to improve oral caloric intake, presence of moderate or severe dysphagia, and inability to maintain adequate hydration are indications for gastrostomy tube placement. Constipation is frequent complication of DMD. Risk factors include decreased colonic transit time, abdominal muscle weakness, and dehydration. Daily treatment with osmotic laxatives such as polyethylene glycol, milk, or lactulose might be necessary. Risk factors for gastro-esophageal reflux include esophageal dysmotility, delayed gastric emptying time, glucocorticoid therapy, and scoliosis. Treatment of gastroesophageal reflux consists of gastric acid suppression proton-pump inhibitors such as lansoprazole or omeprazole. Dietary access includes eating smaller and more frequent meals and decreasing dietary fat intake. As skeletal muscle weakness progresses in individuals with DMD, a delay in gastric emptying can occur, which can lead to postprandial abdominal pain, nausea, vomiting, and loss of appetite. Treatment options include dietary modification, pharmacological therapy, and postpyloric feeding with a gastrojejunal feeding tube [2].

The endocrine complications of DMD and its treatment include impaired growth, delayed puberty, and rarely, adrenal insufficiency. The goals of endocrine care are to monitor growth and development, identify and diagnose hormone deficiencies, and provide endocrine hormone replacement therapy when indicated. Impaired linear growth is common in patients with DMD and exacerbated by glucocorticoid treatment. Linear growth should be assessed every 6 months until completion of puberty. Standing height is the most appropriate measure in ambulatory patients. Height should be followed on a standardized growth curve. Growth monitoring with use of non-standing height measure should begin during the ambulatory stage to allow more accurate assessment after individuals lose ambulation. In nonambulatory patients, arm span, ulnar length, tibia length, knee height, and segmentally measured recumbent length have all been used to assess growth. A decline in growth trajectory, as evidenced by downward crossing of height percentile or an annualized height velocity of less than 4 cm per year, is consistent with impaired linear growth and indicates the need endocrinologist. Patients with a height of less than the third percentile should be referred. Assessment of impaired linear growth should include standard screening tests to assess for endocrine hormone or other abnormalities associated with growth failure. It is not recommended the routine use of recombinant human growth hormone to treat DMD-related growth failure. The decision to treat with recombinant human growth hormone should be based on a discussion of the potential risks and benefits of the therapy and reserved for patients with abnormal growth hormone stimulation test results. Delayed puberty due to hypogonadism is a potential complication of glucocorticoid therapy and can lead to be psychological distress. The absence of pubertal development by the age of 14 requires prompt referral to an endocrinologist. Biochemical testing using pediatric or ultrasensitive assays should be done to confirm the diagnosis of hypogonadism in patients with evidence of delayed puberty. A radiograph of the left hand for establishing bone age should also be considered. Testosterone replacement therapy is recommended in patients older than 14 years with confirmed hypogonadism. The potential benefits of testosterone on emotional and physical health usually outweigh the potential side effects, such as behavioral changes, acne, rapid growth spurt, and epiphyseal closure. Testosterone replacement, in order to mimic normal puberty, should be initiated at a low dose and slowly increased to adult replacement doses over several years. Intramuscular or topical preparations can be used. Testosterone concentrations should be monitored in all patients [2, 5].

6. Gene therapy

Gene therapy is the special treatment of genetic diseases through the delivery of corrective “therapeutic DNA” into the genetic material of a patient’s cells. The corrective DNA is packaged within a vector that is used to effectively deliver the therapeutic DNA into targeted cells. The cell machinery uses the therapeutic DNA to produce functional proteins that the defective DNA could not, resulting in the correction of the underlying cause of disease pathology directly by restoring the lost function. Traditional drug-based approaches address disease symptoms but not the underlying genetic cause. Gene therapy directly targets the specific genetic defects that are the cause of the genetic disease. A major milestone in the treatment of DMD occurred in August 2014 with the registration of ataluren which was designed by PTC Therapeutics and registrated under the brand name Translarna™. Ataluren is an orally available, small molecule compound that targets nonsense mutations, and is the first drug in its class. It is indicated for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older. The presence of a nonsense mutation in the dystrophin gene should be determined by genetic testing [9]. Up to 15% of DMD cases are caused by this type of mutation. A nonsense mutation in DNA causes a premature stop codon within an mRNA. This premature stop codon in the mRNA causes disease by terminating translation before a full-length protein is generated. Ataluren enables ribosomal read through of mRNA containing such a premature stop codon, resulting in production of a full-length protein [10].

Before starting therapy with ataluren, the patient must be on glucocorticoid therapy for at least 6 months. Translarna was tested in a randomized, double-blind Phase 2b study (NCT00592553) conducted in 11 countries to assess the treatment’s safety, dosage, and efficacy in males (5 years or older) with DMD caused by nonsense mutations. Results at 48 weeks showed that the treatment was generally well-tolerated and led to increases in the distance walked in six minutes, a standard test of functional capacity, compared to a placebo. Statistically significant benefits were found in timed function tests, such as the 10-meter run/walk test, the 4-stair climbing test, and the ability to stand when lying on the back or with the face upward. STRIDE (strategic targeting of registries and international database of excellence) is an ongoing observational global study (NCT02369731) — is following patients treated with Translarna, plus standard care (including corticosteroids), for at least five years. It is being conducted in partnership with the neuromuscular network TREAT-NMD and is currently recruiting participants [9].

The schedule of taking therapy is three times a day. The recommended dose is 10 mg (per kg of body weight) in the morning and at midday, and 20 mg/kg in the evening. The total recommended daily dose is 40 mg/kg. Recommended dosing intervals are six hours between morning and midday doses, six hours between midday and evening doses, and 12 h between the evening dose and the dose the following morning. Ataluren (Translarna™) has been given “conditional approval”. This means that there is more evidence to come about this medicine [9, 10]. The European Medicines Agency will review new information on this medicine at least every year. Ataluren (Translarna™) has been approved in the European Union and Brazil. In 2020, the Committee for Medicinal Products for Human Use, part of the European Medicines Agency, recommended expanding the use of Translarna to DMD patients who lost their ability to walk.

In the U.S. however, the Food and Drug Administration rejected Translarna’s approval, stating that it is unable to approve the therapy due to the lack of substantial evidence of its effectiveness [9, 11].

US Food and Drug Administration (FDA) has approved the use of eteplirsen, trade name Exondys 51®. Eteplirsen is a gene therapy, indicated for the treatment of persons with DMD as due to mutation in exon 51, which affects about 13% of individuals with DMD. It is used with patients whose mutations result in a shift in the reading frame and synthesis of dysfunctional dystrophins. Sarepta Therapeutics, a global US biotechnology company that specializes in genetics research and medications for rare diseases, is responsible for placing eteplirsen on the market. Eteplirsen is based on morpholine phosphorodiamidate oligomer (phosphorodiamidate morpholin oligomer PMO), an oligomer used to modify gene expression. PMOs are short, single-stranded analogs of the DNA molecule, constructed upon morpholine rings connected by phosphorodiamidate bonds, and bind to complementary target mRNA sequences. PMO allows skipping exon 51, and in that way, correct the reading frame. The result is a synthesis of shorter, but functional dystrophin. Eteplirsen is administered intravenously. On the same principle is based golodirsen, a medicine approved by the FDA in December 2019, a trade name Vyondys 53®, and the difference is that it is used in patients with a mutation in exon 53. Although there has been an increase in functional synthesis in several randomized clinical trials of dystrophin, the safety of eteplirsen is still being investigated. The European Medicines Agency has refused conditionally approve the placing of eteplirsen on the European market [12, 13].

Sarepta Therapeutics made three approved antisense oligonucleotide products that are used in patients with DMD: Exondys 51® (eteplirsen), Vyondys 53® (golodirsen), and Amondys 45® (casimersen). These medicines target patients with DMD who have a confirmed mutation to exon 51, exon 53, and exon 45. On 25 February 2021, casimersen received its first approval in the USA. The approval of casimersen is granted under the US FDA accelerated approval program. Now it is continuing in the phase 3 development for the treatment of DMD. The approval was based on increase in dystrophin production in skeletal muscle in patients with DMD treated with casimersen. Another clinical benefit must be examined and confirmed for continued approval [14].

Great hopes are put in recent studies, which have shown highly promising improvements in animal models with intravascular delivery of the engineered micro-dystrophin gene by adeno-associated virus (AAV). Several human trials are now started to advance AAV micro-dystrophin therapy to DMD patients. In April 2022, Sarepta Therapeutics presented interim findings from its Phase 2 clinical trial (Study 102) in DMD for its new gene transfer therapy, using the AAV method. SRP-9001 (delandistrogene moxeparvovec) is an adeno-associated virus (AAV) mediated gene therapy that delivers a micro-dystrophin-encoding gene to the muscles and is considered to be a curative treatment. The specific vector deployed in the gene transfer, AAVrh74, has been shown to achieve the efficient delivery of micro-dystrophin to skeletal muscle with tolerable immunogenicity. Sarepta Therapeutics is responsible for global development and manufacturing of SRP-9001. In December 2019, Roche partnered with Sarepta to combine Roche’s global reach, commercial presence, and regulatory expertise with Sarepta’s gene therapy candidate for Duchenne to accelerate access to SRP-9001 for patients outside the United States. Sarepta owns exclusive rights to the micro-dystrophin gene therapy program initially developed at the Abigail Wexner Research Institute at Nationwide Children’s Hospital [15].

Sarepta’s Study SRP-9001-102 (Study 102) is a double-blind, 1:1 randomized, placebo-controlled clinical trial of SRP-9001 patients with Duchenne muscular dystrophy between the ages of 4 to 7. Study 102 uses SRP-9001 material and has two primary endpoints: micro-dystrophin expression at 12 weeks and change in NSAA total score at 48 weeks compared to placebo. Secondary endpoints include timed functional tests; micro-dystrophin expression measured by immuno-fluorescence fiber intensity; and micro-dystrophin expression measured by immuno-fluorescence percent dystrophin positive fibers. In Part 1, results from the treatment and placebo groups were compared 48 weeks following treatment. In Part 2, the study remained blinded to the participants and investigators, while all participants in the placebo group crossed over to active treatment and all participants were followed for another 48 weeks while safety and efficacy were evaluated. Participants will be evaluated for five years total after treatment. SRP-9001-treated participants from the placebo crossover group scored a statistically significant 2.0 points higher on the mean North Star Ambulatory Assessment at 48 weeks compared to propensity-score weighted external controls. Mean NSAA scores from these Part 2 participants improved 1.3 points from baseline for the SRP-9001 treated group and the NSAA scores in the external control group declined 0.7 points from baseline. Study is now undergoing and additional results will be shared at a future medical congress. CAP-1002 is an investigational cell therapy developed by Capricor Therapeutics. It is believed to be used in treatment of heart conditions, including cardiomyopathy, or disease of the heart muscle, linked to Duchenne muscular dystrophy (DMD). The lack of dystrophin in the heart muscle in patients with DMD causes cardiomyopathy, one of the leading causes of death in DMD patients. CAP-1002 consists of cardiosphere-derived cells (CDCs). They are progenitor cells capable of developing into mature heart cells. By releasing sacks of cellular material called exosomes, CDCs modulate immune cell activity to promote heart repair. The CDCs in CAP-1002 come from the heart tissue of a healthy donor. Preclinical studies with CAP-1002 in mouse models of DMD showed that CDCs were able to improve exercise capacity, heart function, and function of skeletal muscles. CAP-1002 also inhibited scarring, inflammation, and oxidative stress in the preclinical models. A Phase 1/2 clinical trial (NCT02485938) called HOPE (Heart Outcomes Prevention Evaluation)-Duchenne tested CAP-1002 in 25 male patients, ages 12 and up, with DMD-related cardiomyopathy. Most participants relied on a wheelchair and had substantial shoulder function impairment. All the participants in the open-label trial were given standard care, including corticosteroids, and 13 received one dose of CAP-1002 (75 million cells) administered directly into the heart [16].

Results from HOPE-Duchenne indicated that treatment with CAP-1002 reduced heart muscle scarring, and helped thicken the heart’s left ventricle, which is crucial for pumping oxygenated blood through the body. Benefits were still evident after six months and at one year. Capricor launched a double-blind Phase 2 trial (NCT03406780) called HOPE-2 in 2018. The study enrolled 20 boys and young men with relatively advanced DMD, 80% of whom were unable to walk. Participants were randomly assigned to receive a placebo or CAP-1002 (150 million cells per infusion), given via infusion into the bloodstream every three months for a year. All were given standard steroid treatment. Results from HOPE-2 showed that, compared with a placebo, CAP-1002 significantly improved upper limb function, as assessed via a validated test called performance of the upper limb (PUL) 1.2. It also improved several measures of lung and heart health. For example, left ventricle ejection fraction, which is an assessment of how much blood the heart pushes out to the body with each pump, was significantly higher, by 4% on average, among CAP-1002-treated patients. Capricor is planning a potentially pivotal Phase 3 clinical trial called HOPE-3 (NCT05126758) to test the safety and effectiveness of CAP-1002 in DMD. The study, which is not yet recruiting, plans to l about 68 boys and young men with DMD, ages 10 and older, who have some difficulty walking. Participants will be given infusions of CAP-1002 (150 million cells per infusion) or a placebo every three months for a year. The study’s main goal is to assess the effect of treatment on upper limb function [17].

During the period between May and July of 2020, the author and co-author conducted a research on topic ,clinical characteristics, diagnostic approach, and treatment of Duchenne muscular dystrophy in Dalmatia, which is also a part of master’s thesis. The aim of the study was to assess timely recognition of clinical characteristics and implementation of a multidisciplinary approach according to the latest guidelines and to analyze clinical courses in patients on gene therapy. The research is a cross-sectional and retrospective study. Patients with dystrophinopathies (DMD and BMD) and their contacts were singled out by retrospective analysis of medical documentation. The patient’s parents provided information on the patient’s medical history and more recent medical documentation by phone call and electronic mail because it was a period of the coronavirus pandemic. Data on current age, age at diagnosis, types of mutations, methods of confirming the diagnosis, clinical picture, and therapy they are receiving have been extracted. Numerical parameters included: ejection fraction, spirometry findings, bone mineral density obtained by densitometry (all parameters were extracted by recent medical documentation), and body mass index (it was measured by patients’ parents). Data on two patients with a missense mutation in the dystrophin gene are receiving ataluren gene therapy.

A total of 9 patients were included in the study, 8 with a diagnosis of Duchenne (DMD) and 1 with a diagnosis of Becker muscular dystrophy (BDM). The age at diagnosis of DMD ranged between 2 and 6.5 years, while in patients with BMD it was set at 11 years of age. In some patients, there is a delay in establishing an accurate diagnosis for several years (Table 1). According to the parents of the patients, a lot of time for establishing the diagnosis was lost due to the wrong focus on the liver diseases (elevated AST and ALT), as well as the attitudes that their children are just clumsy or lazy. Of the mutation types, 4 patients have deletions, 3 duplications, and 2 point mutations. Most diagnoses, in addition to MLPA analysis, included muscle biopsy. six patients are ambulatory, while 3 patients are dependent on wheelchair use. In all patients, there was normal ejection fraction, while the oldest subject in the study was the only one to have a pathological ultrasound of the heart with signs of cardiomyopathy. 7 patients have normal pulmonary function (it was measured by spirometry), while 2 developed chronic pulmonary insufficiency and used noninvasive ventilation methods. 6 patients are on glucocorticoid therapy and all of them are using deflazacort. An increased risk of pathological fractures due to decreased bone density is found in 3 patients due to densitometry results. 2 patients receive gene therapy with ataluren. 1 of them receives therapy for 8 months and is in ambulatory stage, while the other receive therapy for 6 years, no longer has the ability to move independently, but his hand function is preserved. It is important to stress the preserved hand function for patient in study and generally in patients with DMD who are nonambulatory. Hand function is more complex than the leg function and allows patients greater independence that reflects both the physical and mental condition of patients. Patients with DMD, with basic progressive muscle weakness, also develop complications of other organ systems, especially respiratory and cardiac complications. The importance of multidisciplinary care in patients with DMD is manifested in the prevention of complications, prolongation of life expectancy, and raising the quality of life. Gene therapies are taking place in the treatment of DMD, and the results of studies of these causal therapies show encouraging results. The advent of gene therapy as a causal therapy for DMD has placed additional emphasis on diagnosing DMD as early as possible, due to earlier initiation of the treatment, an additional prolongation of life expectancy, and increased quality of life in patients with DMD [18].

Patient number	Diagnosis	Age at first symptoms (years)	Age at diagnosis (years)
1	DMD	1	2
2	DMD	5	5
3	DMD	3	3
4	DMD	3	6
5	DMD	3	6,5
6	BMD	10	11
7	DMD	1,5	3,5
8	DMD	5	5
9	DMD	4,5	4,5

Table 1.

Presentation of patients with their diagnosis, age at first symptoms, and age at confirmed diagnosis.

DMD, Duchenne muscular dystrophy; BMD, Becker muscular dystrophy.

7. Conclusion

Improvements in the function, longevity, and quality of life of patients with Duchenne muscular dystrophy (DMD) have been achieved through a multidisciplinary approach to management across a range of healthcare specialties.

Patients with Duchenne and Becker muscular dystrophy with basic progressive muscle weakness of the skeletal system, develop complications of numerous organ systems that significantly contribute to the deterioration of the clinical condition and shorter life expectancy. Timely diagnosis and multidisciplinary care prolonged the life expectancy of patients with DMD, and the development of subspecialist branches has enabled the improvement of diagnostic methods and treatments.

It is important to notice subtle signs of the disease (slowed motor development and speech development, etc.) in order to be as early as possible suspected DMD and confirmed the diagnosis as soon as possible.

It is certainly necessary to emphasize again the timely diagnosis, because every day the patient receives pharmacological and physical therapy contributes to longer life expectancy and better quality of life. Primary pediatric care or family medicine doctors are usually the first ones who meet patients with undiagnosed DMD. Thus, it is very important to emphasize their role in timely and accurate diagnosis of DMD and BMD. At any sign of muscle weakness, doctors should refer patients to laboratory test because the most important screening test for dystrophinopathies is determination of serum creatine kinase (CK). Gene therapy as a causal therapy for DMD is a major milestone in treatment and is considered a therapy that will become the mainstay in the treatment of dystrophies in the future. For now, gene therapy is available to treat certain types of mutations, such as nonsense mutations. Great hopes are placed in microdystrophin studies, which are currently underway.

In the last few years, therapeutic options in the treatment of DMD have advanced significantly, and new ones are emerging. The very fact that there is a causal therapy puts emphasis on early diagnosis and the earliest possible start with a therapy that provides much hope for success in a treatment of patients with DMD and BMD [5].