**2. Clinical features**

### **2.1. Duchenne and Becker muscular dystrophy**

Neonate boys with DMD are rarely symptomatic, and the disease will not be recognized until the second or third year of life. The patient may show evidence of mild muscle weakness before the 12th month of life (i.e., poor head control after the 6th week, mild inability to sit unsup‐ ported at the 6th month). It is possible that he achieves the motor milestones of walking (12th month) and running (2nd year) during the toddler period, but he will eventually be brought to medical attention due to being less active than expected, as well as being prone to falling [6].

One of the earliest clinical signs of DMD is pseudohypertrophy of the gastrocnemii in the calves caused by hypertrophy of muscle fibers combined with fat infiltration and proliferation of collagen. The muscles have a firm and rubbery consistency, as well as being hypotonic compared with unaffected muscles. By the age of 3–5 years, the clinical picture of DMD gradually appears and "the patient straddles as he stands and waddles as he walks". In order to rise from the ground, the typical Gowers' sign (i.e., the child first extends the arms and legs assuming a four‐point position and then works each hand alternately up the corresponding thigh) is present and it is fully expressed by the age of 5 or 6 years. While standing and walking, the patient places the feet wide apart to increase the base of support, and as a result of gluteus medius weakness, there is waddling when walking [7].

The main clinical feature of patients with dystrophinopathy is an early loss of ambulation depending on the availability of DYSTROPHIN. Patients with DMD completely lack DYS‐ TROPHIN—the pathological mechanisms are discussed in Appendix 2—and are presented with the most severe disease progression. This is indicated by a loss of ambulation around 10 years of age and consequent ventilation assistance, followed by death during the second or third decade [4]. Conversely, patients with BMD still express a truncated form of DYSTRO‐ PHIN. Although only partially functional, this still has an effect on disease progression and life expectancy, which are drastically prolonged [5]. Patients with XLDCM show the absence of DYSTROPHIN in the heart, while expression in skeletal muscles is conserved. Several hypotheses have been proposed for this peculiar genotype [3]. In patients with dystrophin‐ opathy, the routine use of corticosteroids and nocturnal ventilation support have dramatically improved the life expectancy and its quality. Unfortunately, this brings up other complications, as the incidence of cardiomyopathy is raising and is nearly ubiquitous in older patients with DMD. In this perspective, monitoring and treatment of cardiac complications becomes more

This chapter contains an overview of the current monitoring and treatment guidelines and state‐of‐the‐art therapies for dystrophin‐deficient cardiomyopathies. The clinical features of dystrophinopathies with an emphasis on cardiac disease progression will be discussed briefly, followed by a description of the diagnostic process and current management strategies. Conclusions from recent clinical trials on current symptomatic treatments will be summarized and emerging therapies will be discussed in detail, from promising preclinical research to

Neonate boys with DMD are rarely symptomatic, and the disease will not be recognized until the second or third year of life. The patient may show evidence of mild muscle weakness before the 12th month of life (i.e., poor head control after the 6th week, mild inability to sit unsup‐ ported at the 6th month). It is possible that he achieves the motor milestones of walking (12th month) and running (2nd year) during the toddler period, but he will eventually be brought to medical attention due to being less active than expected, as well as being prone to falling [6].

One of the earliest clinical signs of DMD is pseudohypertrophy of the gastrocnemii in the calves caused by hypertrophy of muscle fibers combined with fat infiltration and proliferation of collagen. The muscles have a firm and rubbery consistency, as well as being hypotonic compared with unaffected muscles. By the age of 3–5 years, the clinical picture of DMD gradually appears and "the patient straddles as he stands and waddles as he walks". In order to rise from the ground, the typical Gowers' sign (i.e., the child first extends the arms and legs assuming a four‐point position and then works each hand alternately up the corresponding thigh) is present and it is fully expressed by the age of 5 or 6 years. While standing and walking,

and more important.

290 Cardiomyopathies - Types and Treatments

ongoing clinical trials.

**2. Clinical features**

**2.1. Duchenne and Becker muscular dystrophy**

The typical posture of a patient with DMD is lumbar lordosis and scoliosis (due to weakness of abdominal muscles and paravertebral muscles) with hip flexion and abduction, knee flexion and plantar flexion, as well as winging of the scapulae. Other common presentations in toddlers include falling, troubles in running or using the stairs and developmental delays [7, 8]. As the muscular wasting progresses, the weakness will spread to the muscles of the legs and forearms and patients may end up being confined to a wheelchair by 7 years of age, while other patients may continue walking with increasing difficulty until 10 years of age. Death usually occurs around the second decade of life, caused by pulmonary infections, respiratory failure, aspiration, airway obstruction or heart failure [6].

In BMD, the weakness and hypertrophy appear in the same muscles as DMD, but the onset is later (5–45 years; mean age: 12 years) with most patients losing ambulation in the third or fourth decade. However, some patients may have a milder phenotype with the onset of muscular weakness in late adulthood [6].

In both DMD and BMD groups, the median age of diagnosis of cardiac involvement is 14 years, with all patients having cardiac problems after 18 years of age [8]. While in BMD, the cardiac involvement can be the presenting symptom at diagnosis [9], and in patients with DMD, the presentation at diagnosis is usually subclinical and asymptomatic. Patients often have unspecific symptoms including fatigue, weight loss, nausea, sleep disturbance, cough, palpitations, sweating, chest and abdominal discomfort, decreased urinary output, irritability and concentration difficulties [8].

The physical examination may present some problems in patients with advanced muscular dystrophy (MD) due to scoliosis, immobility or glucocorticoid‐related obesity. Tachycardia will be present, unless treated with β‐blockers. Hypotension may be present—as a result of DYSTROPHIN loss in both vascular smooth muscles and low oral fluid intake—causing altered cardiac pacemaker activity, altered myocardial contractility and altered vasomotor tone. Edema is not commonly present, even in the presence of advanced right and left cardiac failure [9].

At auscultation the cardiac apex may be displaced as a result of scoliosis, with S3 gallop and S4 gallop commonly heard as a result of acute congestive heart failure and left ventricular (LV) dysfunction, respectively [9]. Moderate mitral regurgitation (due to posterior wall fibrosis and LV thinning) and moderate tricuspid regurgitation may be present [10]. Neck venous en‐ gorgement may be seen as a result of abdominal compression caused by scoliosis [8].

As dystrophy progresses, the LV function worsens, leading to the clinical picture of dilated cardiomyopathy (DCM), which can be complicated by arrhythmias. DCM is an enlargement of one or both of the ventricles combined with systolic dysfunction, usually preceding signs and symptoms of congestive heart failure. The hallmarks of DCM are decreased LV function (decreased ejection fraction), LV dilation and mitral regurgitation. The latter manifests as palpitations, vertigo, dizziness, syncope or sudden cardiac death. Moreover, in DMD, the arrhythmia occurs even in the absence of myocardial fibrosis [11]. **Table 1** provides a summary with the most important clinical characteristics for DMD, BMD and XLDCM.


**Table 1.** Characteristics of Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and X‐linked dilated cardiomyopathy (XLDCM).

### **2.2. X-linked dilated cardiomyopathy**

XLDCM is a cardio‐specific dystrophinopathy presenting with congestive heart failure (CHF) due to DCM in 10‐ to 20‐year‐old patients, without the dystrophinopathy‐related involvement of skeletal muscles (**Table 1**). Patients show a brisk and progressive heart failure and ventric‐ ular arrhythmias, with untreated patients that may die of congestive heart failure not long after diagnosis [3].

### **3. Diagnosis and monitoring**

Dystrophinopathy is generally underdiagnosed and definitive diagnosis can even take up to 2, 5 years from the onset of symptoms [12]. The first diagnostic test performed, when dystro‐ phinopathy is expected, is a serum creatine kinase (CK) measurement. In most cases, CK levels are elevated, around 50–100 times in DMD, while in BMD levels are lower but still higher compared to healthy patients [13]. A second level diagnostic test is a mutation analysis, which reveals the specific genetic alteration and is useful to discriminate between DMD and BMD [14]. Differences between DMD and BMD are clarified by the reading frame concept (Appendix 3) [15]. For 5% of the cases, mutation analysis is not able to diagnose for dystrophinopathy [16]. In this circumstance, a muscle biopsy is taken and the reduction or the absence of DYSTRO‐ PHIN is analyzed by tissue staining (immunohistochemistry and immunofluorescence) or immunoblot (Western blot).

Recognizing cardiac complications in patients with dystrophinopathy is challenging, espe‐ cially because of physical inactivity and respiratory complications [8]. Hence, cardiomyopa‐ thies are underdiagnosed in these patients [17]. Clinical guidelines were created in 2010, recommending an echocardiogram every 2 years from the moment of diagnosis of dystro‐ phinopathy or from the age of 6 years. From 10 years of age, a yearly screening to asses LV function is suggested [14]. Recently, it has been documented that cardiac MRI is more sensitive and can distinguish cardiac complications in an earlier stage for patients with dystrophinop‐ athy [18]. Therefore, it is recommended to perform a cardiac MRI instead of echocardiography, also because patients with dystrophinopathy can suffer from scoliosis, which makes diagnosis with echocardiography more complicated. However, cardiac MRI can also be challenging for pediatric patients because of the need for sedation, cost and lack of accessibility. Sinus tachycardia is also known to precede any cardiac complications in patients with DMD [19].

As mentioned before, early diagnosis of cardiomyopathy onset is essential in patients with dystrophinopathy. Hence, clinical trials are still undertaken to study whether electrocardio‐ gram (ECG), echocardiography, cardiac MRI and sera biomarkers can improve early detection of myocardial involvement and clinical outcome (NCT02020954).
