INTRODUCTION — The muscular dystrophies are an inherited group of progressive myopathic disorders resulting from defects in a number of genes required for normal muscle function. Muscle weakness is the primary symptom.
The clinical characteristics and diagnosis of the Duchenne and Becker muscular dystrophies are reviewed here. Other aspects are discussed separately. (See "Duchenne and Becker muscular dystrophy: Genetics and pathogenesis" and "Duchenne and Becker muscular dystrophy: Management and prognosis".)
Other muscular dystrophies are reviewed elsewhere. (See "Emery-Dreifuss muscular dystrophy" and "Limb-girdle muscular dystrophy" and "Oculopharyngeal, distal, and congenital muscular dystrophies" and "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)
TERMINOLOGY — The Duchenne and Becker muscular dystrophies (as well as a third intermediate form) are caused by mutations of the DMD gene that encodes dystrophin and are therefore named dystrophinopathies. Progressive weakness is the principal symptom as muscle fiber degeneration is the primary pathologic process.
The dystrophinopathies are inherited as X-linked recessive traits and have varying clinical characteristics that present with a continuum of severity. However, for diagnostic and management purposes, the dystrophinopathies are usually split into the following categories:
●Duchenne muscular dystrophy (DMD) is associated with the most severe clinical symptoms (see 'Duchenne muscular dystrophy' below)
●Becker muscular dystrophy (BMD) has a similar presentation to DMD, but typically has a later onset and a milder clinical course (see 'Becker muscular dystrophy' below)
●Patients with an intermediate phenotype (outliers) may be classified clinically as having either mild DMD or severe BMD (see 'Intermediate phenotype' below)
●DMD-associated dilated cardiomyopathy (DCM) is the term used when the heart is primarily affected and skeletal muscle is spared (see 'DMD-associated dilated cardiomyopathy' below)
GENETICS AND EPIDEMIOLOGY — DMD and BMD are caused by a defective DMD gene located on the X chromosome that is responsible for the production of dystrophin. (See "Duchenne and Becker muscular dystrophy: Genetics and pathogenesis".)
In studies from Europe and North America, the incidence of DMD ranges from 1 in 3500 to 1 in 5050 live male births [1-3]. In 2010, the prevalence of DMD and BMD in the United States was 1.38 per 10,000 male individuals, ages 5 to 24 years [3].
CLINICAL PHENOTYPES — Dystrophinopathies encompass the phenotypes of DMD (severe), BMD (mild), an intermediate phenotype between DMD and BMD, and DMD-associated dilated cardiomyopathy with little or no clinical skeletal muscle disease.
Duchenne muscular dystrophy — DMD is associated with more severe clinical symptoms and an earlier age of onset compared with BMD [4].
Weakness — Although histologic and laboratory evidence of a myopathy may be observed from birth among male children with DMD, the clinical onset of weakness usually occurs between two and three years of age, although affected boys are usually late walkers [5]. A slow and ungainly run is common in the first two to three years. In some cases, the onset of symptoms occurs later.
Weakness selectively affects the proximal before the distal limb muscles, and the lower before the upper extremities. The affected child therefore has difficulty running, jumping, and walking up steps. When arising from the floor, affected boys may also use hand support to push themselves to an upright position, an action termed Gower's sign. An unusual waddling gait, lumbar lordosis, and calf enlargement are usually observed. Complaints of leg pain may also be found with early disease. Other motor signs and symptoms that may be present include toe walking, decreased endurance, decreased head control when pulled to sit, flat feet, frequent falls, clumsiness, gross motor delay, inability to keep up with peers, loss of motor skills, and muscle pain or cramping [6].
Physical examination reveals pseudohypertrophy of the calf and (occasionally) quadriceps muscles, lumbar lordosis, a waddling gait, shortening of the Achilles tendons, hypotonia, and hyporeflexia or areflexia.
Patients usually require a wheelchair by the age of 12 to 13 years. Children who are full-time wheelchair users in particular tend to have evidence of scoliosis with poor pulmonary function.
Elevated CK and transaminases — Serum creatine kinase (CK) concentrations are elevated in children with DMD prior to the appearance of any clinical signs of disease; increased levels are even observed among newborns [7]. Serum CK peaks by age 2 years; it is usually 10 to 20 times the upper limit of normal and may be higher [8]. These levels then progressively fall at a rate of about 25 percent per year, eventually reaching the normal range in many cases, as more and more muscle is replaced by fat and fibrosis. Aldolase levels and other muscle enzymes, such as aspartate transaminase (AST) and alanine transaminase (ALT), are also elevated.
Growth delay — Growth velocity with DMD is typically slower than normal in the first years of life, leading to short stature, even among boys naïve to treatment with glucocorticoids [9,10].
Cardiomyopathy — DMD causes a primary dilated cardiomyopathy (DCM) and conduction abnormalities, especially intraatrial and interatrial but also involving the atrioventricular (AV) node, and a variety of arrhythmias, primarily supraventricular [11,12]. The cardiomyopathy is characterized by extensive fibrosis of the posterobasal left ventricular wall, resulting in the characteristic electrocardiographic changes of tall right precordial R waves with an increased R/S ratio and deep Q waves in leads I, aVL, and V5-6 (waveform 1) [13]. As the disease progresses, fibrosis can spread to the lateral free wall of the left ventricle. Significant mitral regurgitation is often present due to involvement of the posterior papillary muscle [14].
The incidence of symptomatic cardiomyopathy in patients with DMD increases gradually in the teenage years; it is defined as left ventricular ejection fraction less than 55 percent. This was illustrated in a series of 328 boys with DMD in which clinically apparent cardiomyopathy was observed in about one-third of patients by age 14 years, one-half by 18 years, and all patients older than 18 [15]. Ultrasonography can detect structural changes in the myocardium and exercise cardiac magnetic resonance imaging can detect abnormalities in left ventricular systolic function that are aggravated by exercise stress well before the onset of overt cardiomyopathy [16,17].
Despite the high incidence of DCM, the majority of children with DMD are relatively asymptomatic until late in the disease course, probably because of their inability to exercise [18]. Heart failure and arrhythmias may develop in the late stages of the disease, especially during intercurrent infections or surgery. In rare cases, heart failure dominates the picture and can be the immediate cause of death without marked compromise of respiratory function [19].
The possible role of therapy in slowing progression of the cardiomyopathy is discussed separately. (See "Duchenne and Becker muscular dystrophy: Management and prognosis", section on 'Cardiac management'.)
Orthopedic complications — Fractures involving the arms and legs are frequent in DMD [20]. One series of 378 patients (ages 1 to 25 years) with DMD found that 79 (21 percent) had experienced fractures [21]. The most common mechanism was falling; about half of the fractures occurred among patients who were independent with ambulation. Vertebral fractures are also frequent with glucocorticoid therapy. In one report of 75 patients treated with glucocorticoids, vertebral compression fractures occurred in 32 percent [22].
A progressive scoliosis develops in nearly all children with DMD [23-26]. Scoliosis, in combination with progressive weakness, results in impaired pulmonary function. With progressive disease, patients may eventually suffer acute respiratory failure. In DMD, the median age at which the forced vital capacity declines to a value below 50 percent of predicted is 16 years [27,28]. (See "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation".)
Cognitive and behavioral disorders — Children with DMD frequently have varying degrees of mild cognitive impairment or global developmental delay [29-31]. However, an occasional child may have average or above-average intelligence. Compared with the general population, DMD is also associated with increased rates of autism spectrum disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and anxiety [30,32-35].
Clinical course — Patients with DMD often require a wheelchair by about age 12 to 13 years and die in their late teens or twenties from respiratory insufficiency or cardiomyopathy; only a few DMD patients survive beyond the third decade [36]. (See "Duchenne and Becker muscular dystrophy: Management and prognosis", section on 'Prognosis'.)
Becker muscular dystrophy — Compared with DMD, the age of onset of symptoms of those with BMD is usually later, though it varies widely from 5 to 60 years of age, and the degree of clinical involvement milder [37]. This retained strength permits the clinical distinction between BMD and DMD. Patients typically remain ambulatory at least until age 16 and commonly well into adult life. Some patients maintain ambulation into old age. Cognitive impairment, intellectual disability, behavioral disorders, and contractures are also not as common or severe as compared with DMD [38], and there is relative preservation of neck flexor muscle strength in BMD and intermediate types of muscular dystrophy.
In patients with BMD, serum CK concentrations are usually elevated above the upper limit of normal by a factor of five or more [8].
Although muscle involvement is less severe than in DMD, cardiac involvement in BMD is often a predominant feature of the presentation [39]. In one report, for example, echocardiography revealed evidence of cardiac involvement in 60 to 70 percent of patients (mean age 18) with subclinical or benign BMD [40]. It was suggested that, because patients with mild BMD are still able to perform strenuous exercise, the associated mechanical stress on the heart may be harmful for myocardial cells with abnormal dystrophin.
Echocardiography reveals early right ventricular involvement with the later development of left ventricular dysfunction [40]. All four chambers are eventually involved with fibrosis, and a cardiomyopathy with heart failure can be rapidly progressive. In addition, abnormalities of the AV node and infranodal conduction system can result in fascicular and bundle branch block and can progress to complete heart block. Although not typically performed, endomyocardial biopsy shows a variable distribution of dystrophin in cardiomyocytes [41]. Discontinuous immunostaining of cardiac dystrophin is characteristic of BMD and the absence of immunostaining may be associated with more severe cardiac disease.
Patients with BMD usually survive beyond the age of 30 years. (See "Duchenne and Becker muscular dystrophy: Management and prognosis", section on 'Prognosis'.)
Intermediate phenotype — The intermediate group of patients, also known as outliers, has a clinical phenotype best characterized as mild DMD or severe BMD; these individuals usually require a wheelchair between the ages of 13 and 15 years inclusive [8].
DMD-associated dilated cardiomyopathy — DMD-associated dilated cardiomyopathy is the term applied to patients who have predominant cardiac involvement with little or no clinical evidence of skeletal muscle disease [8,42]; some patients have "subclinical" skeletal muscle involvement consistent with BMD [40].
Males typically present with DCM and congestive heart failure between ages 20 and 40 years and females present later in life [43,44]. There is rapid progression to death over several years in males and slower progression over a decade or more in females [43].
Symptomatic females — Clinically apparent symptoms occur in approximately 22 percent of female carriers of a mutated dystrophin gene [45]. Symptomatic female DMD carriers have a high variability in age of onset and degree of muscle weakness or cardiac involvement [46]. Weakness ranges from mild to, rarely, a classic DMD phenotype.
Serum CK is increased in approximately 70 and 50 percent of Duchenne and Becker female carriers, respectively, although the values decline with age [47]. Hence, many carriers have CK values in the normal range, so genetic testing (ideally with the mutation first identified in the affected boy) should be used to determine carrier status wherever possible. The elevations are usually mild (up to three times the upper limit of normal). In symptomatic carriers, however, the CK levels may be much higher.
EVALUATION AND DIAGNOSIS — The diagnosis of DMD and BMD is confirmed by the finding of a pathologic mutation in the dystrophin gene with genetic testing, or (less often) by muscle biopsy evidence of total absence of dystrophin in DMD or reduced dystrophin in BMD.
When to suspect the diagnosis — A dystrophinopathy should be suspected in the following situations [6]:
●Any evidence of delayed motor milestones in a young child with a positive family history of DMD
●When there is no family history of DMD, a child not walking by 16 to 18 months, or the presence of Gower's sign, toe walking, or calf hypertrophy (see 'Weakness' above)
●Unexplained increases in transaminases (eg, aspartate transaminase and alanine transaminase)
Additional symptoms and signs that may be associated with DMD include the following [48]:
●Poor head control
●Not running by age 3 years
●Struggling to hop, climb stairs, or get up from the floor in school-aged children
●Frequent trips or falls
●Abnormal gait
●Muscle pain or cramps
●Episodes of myoglobinuria
●Learning difficulties and behavioral issues
●Speech and language delay
●Autistic spectrum disorder
Approach to confirm the diagnosis — When dystrophinopathy is suspected, a creatine kinase (CK) level should be obtained and the child should be referred to a neuromuscular specialist [6]. An increased CK level is compatible with the diagnosis (table 1) and should lead to genetic analysis [6]. However, a normal CK level makes DMD and BMD unlikely and should prompt an evaluation for alternative diagnoses. (See 'Differential diagnosis' below.)
In most cases, molecular genetic testing can confirm a definitive diagnosis of a dystrophinopathy without recourse to muscle biopsy [8]. However, a small percentage of patients with a dystrophinopathy do not have coding region pathogenic variants and, thus, a mutation may be hard to detect [49]. (See 'Genetic analysis' below.)
When no disease-causing mutation of the DMD gene is found and other conditions like spinal muscular atrophy (SMA), inflammatory myopathy, or myopathy of systemic disease have been excluded (see 'Differential diagnosis' below), genetic testing targeted at certain gene mutations that cause limb-girdle muscular dystrophy (LGMD) or a next-generation sequencing-based muscular dystrophy gene panel or general neuromuscular gene panel is the next step because of the phenotypic resemblance between DMD/BMD and certain LGMDs. (See 'Limb-girdle muscular dystrophy' below.)
When thorough molecular genetic testing fails to identify a disease-causing mutation, muscle biopsy should be obtained for dystrophin analysis. (See 'Muscle biopsy and dystrophin analysis' below.)
Genetic analysis — Molecular genetic testing is indicated for patients with an elevated serum CK level and clinical findings suggestive of a dystrophinopathy. The diagnosis is established if a disease-causing mutation of the DMD gene is identified (table 2). Given the high frequency of deletions and duplications, it is advisable to pursue "large" deletion/duplication genetic testing first and, if negative, proceed to next-generation exome or genome sequence analysis, which includes not only "small" mutation detection but also micro deletion/duplication analysis.
Techniques — A number of methods are available for molecular genetic analysis of the DMD gene, including:
●Analysis for deletions/duplications (the most common form of mutations seen in about 70 to 80 percent of DMD/BMD cases)
●Next-generation sequence analysis (exome or genome) to detect point mutations and small rearrangements (found in about 20 to 30 percent of DMD/BMD cases)
Multiplex ligation-dependent probe amplification (MLPA) has been one of the main techniques for the detection of deletions and duplications of the DMD gene. However, many laboratories now use next-generation sequencing, usually combined with deletion and duplication testing. MLPA can be performed in both probands and carrier females using either MLPA [50-52] or array-MLPA [53]. Approximately 98 percent of deletions can also be detected by multiplex polymerase chain reaction (PCR) [54]. Other methods include quantitative PCR, long-range PCR, and chromosomal microarray (CMA) that includes the DMD gene/chromosome segment and is designed to detect even single-exon deletions or duplications. However, since the sensitivity of CMA is not sufficient to detect all exon-level DMD deletions and duplications, CMA is not recommended as a primary assay for dystrophinopathies [8].
Approximately 11 to 13 percent of males with DMD or BMD have disease-causing mutations due to duplications that lead to in-frame or out-of-frame transcripts (figure 1) [55].
Approximately 20 to 30 percent of DMD/BMD mutations are small deletions or insertions, single-base changes, and splice site mutations. These can usually be detected by next-generation sequencing [56]. The mutation detection frequency was increased to nearly 100 percent through a muscle biopsy-based approach using protein- and RNA-based analyses combined with direct complementary DNA (cDNA) sequencing [57]. As a complementary technique, transcriptome sequencing (RNA sequencing) analysis of muscle RNA, with or without direct genomic sequencing, may improve the detection and interpretation of pathogenic coding and noncoding/intronic variants like pathogenic pseudoexon inclusion missed by standard diagnostic genetic techniques [58,59].
When the proband has an unknown DMD mutation, the carrier status of at-risk females may be determined through linkage analysis.
Sporadic cases — For patients with a clinical phenotype that is suggestive of DMD/BMD or LGMD and no family history, genetic testing for mutations in the DMD gene can be performed first. If positive, it will confirm the diagnosis of DMD/BMD. If negative, the next step would be either genetic testing targeted at certain gene mutations that cause LGMD or a muscular dystrophy, or a general neuromuscular gene panel (next-generation sequencing-based) (see "Limb-girdle muscular dystrophy", section on 'Evaluation and diagnosis'). If that is also negative, a muscle biopsy for histology, immunohistochemistry with multiple antibodies, Western blot analysis of skeletal muscle for dystrophin, or muscle RNA-based sequencing could be performed. (See 'Muscle biopsy and dystrophin analysis' below.)
Familial cases — In cases of typical DMD or BMD with a family history of X-linked dystrophinopathy, molecular diagnosis is straightforward if the familial mutation has already been defined, as targeted genetic testing for the familial mutation can be offered to confirm the clinical diagnosis. In such cases, the clinical course in the older affected relative usually, but not always, predicts the severity of disease for other family members.
When the diagnosis of dystrophinopathy has not previously been confirmed by analysis of DNA or dystrophin in the proband, DNA-based deletion/duplication testing (and, if negative, DMD gene sequencing) should be attempted (see 'Techniques' above). If such analysis fails to detect a dystrophin gene abnormality, the next diagnostic step in most cases is a gene panel for LGMD (see 'Limb-girdle muscular dystrophy' below) or a more extensive next-generation sequencing-based gene panel for myopathies. If genetic testing for DMD, LGMD, and myopathy panel is negative, a muscle biopsy for histology, immunohistochemistry, and dystrophin analysis is the next step, including transcriptome analysis if available [58]. (See 'Muscle biopsy and dystrophin analysis' below.)
Symptomatic female carriers — Female carriers are usually asymptomatic but a minority have variable degrees of muscle weakness or cardiac involvement. Although rare, a DMD phenotype with an early onset, progressive muscular dystrophy can affect girls, particularly if one of the following genetic abnormalities is present:
●A normal karyotype but nonrandom (skewed) X chromosome inactivation [46], resulting in diminished expression of the normal dystrophin allele
●45,X, 46,XY, or Turner mosaic karyotypes [60]
●Apparently balanced X/autosome translocations with breakpoints in Xp21, within the dystrophin gene, and preferential inactivation of the normal X
●Uniparental disomy of the X chromosome [61]
After excluding other neuromuscular diseases (eg, inflammatory myopathy, spinal muscular atrophy) by electromyography, muscle imaging with magnetic resonance imaging (MRI), and/or muscle biopsy, chromosomal analysis is indicated in all symptomatic females, particularly those with markedly elevated serum CK levels. If negative, DNA testing as in males would be the next step.
Further genetic testing for DMD mutations may be diagnostic in those with 45X, 46XY, or Turner mosaic karyotypes. However, the relationship between X-inactivation status, dystrophin analysis and phenotype is complex [62]. Quantitative analysis of muscle dystrophin in female carriers is not useful in clinical practice because of the wide range of values and the significant overlap with normal values.
Immunohistochemistry of muscle biopsies for dystrophin expression from symptomatic carriers generally shows high proportions of dystrophin-negative fibers (mosaic pattern) but is now used only rarely in clinical practice.
At-risk females and prenatal diagnosis — Carrier detection of at-risk females and prenatal diagnosis becomes possible after the detection of a DNA deletion, duplication, or sequence variant in an affected family member [63]. If a mutation is not uncovered, linkage analysis may be attempted for detection of the abnormal allele. Genetic counseling for DMD/BMD can be complex and expert clinical genetic advice is essential. Even if the mother of an affected boy is not a carrier of his DMD mutation, she should be offered preimplantation or prenatal genetic diagnosis by noninvasive prenatal diagnosis or chorionic villus sampling because there is an appreciable chance of recurrence resulting from gonadal mosaicism. Similarly, sisters of an affected boy who has an apparent "de novo" mutation should be offered genetic testing as there is a small but appreciable risk of carrier status for them resulting from gonadal mosaicism.
Muscle biopsy and dystrophin analysis — Muscle biopsy and dystrophin analysis were once important for the diagnosis of DMD and related disorders. However, muscle biopsy is seldom needed in the modern era, since nearly all patients are diagnosed with genetic testing.
However, muscle biopsy with dystrophin analysis is still useful to confirm the clinical diagnosis of DMD/BMD in rare mutation-negative cases, particularly in the following circumstances:
●Genetic testing for DMD, LGMD, and a next-generation sequencing-based gene panel for myopathies is negative
●Genetic testing detects a likely pathogenic variant of unknown significance (VUS) which can be confirmed or excluded as a causative mutation with muscle biopsy testing
In such cases, a muscle biopsy for histology, immunohistochemistry, and dystrophin analysis is indicated, including transcriptome analysis if available [58].
A Western blot assay of dystrophin derived from a muscle biopsy specimen can also be used to predict the severity of the disease.
DMD and BMD may be distinguished by marked differences in dystrophin expression in skeletal muscle as detected by Western blotting. In normal individuals, dystrophin may easily be detected on Western blots of 100 mcg of total muscle protein, and evaluated either visually or by using densitometry. The quantity and quality of the dystrophin varies with the different disorders:
●Since the reading frame has been disrupted, nearly all patients with DMD display complete or almost complete absence of dystrophin [64].
●Most patients with BMD (approximately 85 percent) have dystrophin of abnormal molecular weight; it is smaller (80 percent) or larger (5 percent) among those with genetic deletion or duplication, respectively. Dystrophin is also frequently reduced in quantity among these individuals. The remaining 15 percent have a normal sized protein of reduced quantity.
●In mutation-negative patients, the diagnosis of DMD or BMD may be excluded in practically all cases if the dystrophin is normal in size and amount. In this setting, another myopathic process should be suspected, such as LGMD or other neuromuscular diseases (eg, acid maltase deficiency). (See 'Differential diagnosis' below.)
Dystrophin analysis by Western blotting may be useful to predict the severity of the evolving muscular dystrophy phenotype. The quantity (relative cellular abundance) of the dystrophin molecule determines disease severity in DMD, while the qualitative changes (normal or abnormal molecular weight) of dystrophin play a role in the clinical expression of BMD (table 3). The dystrophin level ranges below reflect approximate data from the literature [64,65]. However, the correlations are not always accurate in clinical practice:
●Less than 5 percent of the normal quantity of dystrophin is associated with DMD.
●Dystrophin levels between 5 to 20 percent of normal, regardless of protein size, correlate with the intermediate phenotype (mild DMD or severe BMD)
●Levels between 20 to 50 percent (dystrophin of normal molecular weight) or 20 to 100 percent (dystrophin of abnormal molecular weight) are associated with mild to moderate BMD
Muscle histology is not specific for diagnosis but demonstrates degeneration, regeneration, isolated "opaque" hypertrophic fibers, and significant replacement of muscle by fat and connective tissue [66-68].
Electromyography — With both DMD and BMD, electromyography reveals myopathic changes, usually consisting of small polyphasic potentials. However, electromyography is almost never used in the diagnosis of DMD and BMD.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of DMD includes several conditions that cause progressive neuromuscular weakness. In addition, the differential diagnosis of isolated DMD-associated dilated cardiomyopathy (DCM), which presents mainly in adults, includes multiple other causes of DCM.
Limb-girdle muscular dystrophy — The distinction between BMD and limb-girdle muscular dystrophy (LGMD) is often hard to make in patients with a negative family history for BMD. However, the calf muscle pseudohypertrophy is usually not as striking in LGMD.
Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by a mutation in the FKRP gene and phenotypically resembles DMD/BMD. In a study that screened 102 patients with a suspected diagnosis of sporadic DMD or BMD who were negative for dystrophin gene deletions or duplications, the FKRP gene L276I point mutation that causes LGMD2I was found in 13 of 102 patients (12.7 percent) [69]. This result suggests that a substantial number of patients with a phenotype of DMD/BMD who are negative for dystrophin gene mutations may have a form of LGMD and should be tested for the FKRP gene mutation. (See "Limb-girdle muscular dystrophy".)
Emery-Dreifuss muscular dystrophy — Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogenous disorder with X-linked recessive, autosomal dominant, and autosomal recessive forms, whereas DMD and BMD are X-linked disorders The onset of symptoms from EDMD usually occurs in the first or second decade of life. The cardinal features are early contractures, childhood onset of slowly progressive humeroperoneal muscle weakness/wasting, and cardiac disease with conduction defects, arrhythmias, and cardiomyopathy. Typical features of EDMD (ie, contractures, humeroperoneal pattern of weakness, cardiac conduction defects, and modest elevation of creatine kinase [CK]) help to distinguish it from DMD and BMD.
In cases with typical clinical features of EDMD and a supportive family history, genetic testing may confirm the diagnosis. In cases with early contractures that otherwise lack typical features of EDMD, the presence of myopathic changes on EMG and muscle biopsy is supportive of EDMD. (See "Emery-Dreifuss muscular dystrophy".)
Spinal muscular atrophy — Spinal muscular atrophy (SMA) is characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, which results in progressive muscle weakness and atrophy. Unlike DMD, the inheritance pattern of the common forms of SMA is autosomal recessive. Both SMA type 2, which most often presents between 3 and 15 months of age, and SMA type 3, which usually presents between age 18 months and adulthood, may be confused with DMD.
With SMA, the ability to sit unassisted is attained but may be delayed. However, independent standing and walking is never achieved, in contrast to DMD. Weakness is predominately proximal and affects the legs more than the arms. Additional manifestations include sparing of face and eye muscles, tongue atrophy with fasciculations, areflexia, a fine tremor-like form of myoclonus (minipolymyoclonus) affecting distal limbs, dysphagia, and respiratory insufficiency. Muscular weakness usually leads to progressive scoliosis; the combination of respiratory muscle weakness and scoliosis may result in restrictive lung disease. Some develop joint contractures and ankylosis of the mandible. The ability to sit independently is usually lost in the teenage years. (See "Spinal muscular atrophy".)
Other features of SMA that help distinguish it from DMD include diffuse areflexia or hyporeflexia, modest CPK elevation, tongue fasciculations, and a neurogenic electromyography pattern. However, in SMA type 3, CK elevations may be as high as 1500 to 2000, which may suggest BMD or a symptomatic DMD carrier female.
Molecular genetic testing can confirm the diagnosis in infants and children with suspected SMA by detection of homozygous deletions of exons 7 of the SMN1 gene in the majority (95 percent) of patients. (See "Spinal muscular atrophy".)
Dilated cardiomopathy — DMD-associated dilated cardiomyopathy presents in adults with little or no skeletal muscle disease (see 'DMD-associated dilated cardiomyopathy' above). It must be distinguished from other causes of DCM (table 4 and table 5), as reviewed elsewhere. (See "Causes of dilated cardiomyopathy" and "Familial dilated cardiomyopathy: Prevalence, diagnosis and treatment" and "Genetics of dilated cardiomyopathy".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Muscular dystrophy".)
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●Basics topics (See "Patient education: Muscular dystrophy (The Basics)".)
●Beyond the Basics topics (See "Patient education: Overview of muscular dystrophies (Beyond the Basics)".)
SUMMARY AND RECOMMENDATIONS
●Terminology – Duchenne and Becker muscular dystrophies are caused by mutations of the dystrophin gene and are therefore named dystrophinopathies. Duchenne muscular dystrophy (DMD) is associated with the most severe clinical symptoms. Becker muscular dystrophy (BMD) has a similar presentation to DMD, but typically has a later onset and a milder clinical course. Patients with an intermediate phenotype (outliers) may be classified clinically as having either mild DMD or severe BMD. There are also patients with isolated cardiomyopathy without any skeletal muscle weakness. (See 'Terminology' above.)
●Clinical features of DMD – With DMD, the clinical onset of weakness usually occurs between two and three years of age (table 3). Muscle weakness affects the proximal before the distal limb muscles. Additional features include cardiomyopathy and conduction abnormalities, bone fractures, and scoliosis. Serum creatine kinase (CK) concentrations are markedly elevated. Affected children frequently have varying degrees of mild cognitive impairment. Physical examination reveals pseudohypertrophy of the calf and (occasionally) quadriceps muscles, lumbar lordosis, a waddling gait, shortening of the Achilles tendons, and hyporeflexia or areflexia in weak muscles. Patients with DMD often require a wheelchair by about age 12 to 13 years and die in their late teens or twenties from respiratory insufficiency or cardiomyopathy. Rarely, patients survive in their early thirties. (See 'Clinical phenotypes' above and 'Duchenne muscular dystrophy' above.)
●Clinical features of BMD – Compared with DMD, the age of onset of symptoms of those with BMD is usually later and the degree of clinical involvement milder (table 3). Patients with BMD typically remain ambulatory beyond the age of 16 years and often well into adult life, and usually survive beyond the age of 30 years. (See 'Becker muscular dystrophy' above.)
●DMD-associated cardiomyopathy – Dystrophinopathy can present in adulthood with DMD-associated dilated cardiomyopathy, which is the term used when the heart is primarily affected and skeletal muscle is relatively spared, with little or no weakness. (See 'DMD-associated dilated cardiomyopathy' above.)
●Symptomatic females – Some female carriers are symptomatic, with a high variability in age at onset and severity of weakness. (See 'Symptomatic females' above.)
●Diagnosis – A dystrophinopathy is usually suspected in a boy with muscle weakness, myopathic signs, and (possibly) a family history of the illness. Molecular genetic testing is indicated for patients with an elevated serum CK level and clinical findings suggestive of a dystrophinopathy. The diagnosis is established if a disease-causing mutation of the DMD gene is identified (table 2). Although seldom necessary, a muscle biopsy with dystrophin analysis can confirm the diagnosis if the genetic studies are negative or equivocal. (See 'Evaluation and diagnosis' above and 'Genetic analysis' above and 'Muscle biopsy and dystrophin analysis' above.)
●Differential diagnosis – The differential diagnosis of DMD includes several conditions that cause progressive neuromuscular weakness, particularly limb-girdle muscular dystrophy. These are usually diagnosed by genetic testing in patients who do not have a disease-causing DMD mutation. In addition, the differential diagnosis of isolated DMD-associated dilated cardiomyopathy (DCM), which presents mainly in adults, includes multiple other causes of DCM. (See 'Differential diagnosis' above.)
