clinical features and diagnosis of duchenne and becker muscular dystrophy

8/17/2019 Clinical Features and Diagnosis of Duchenne and Becker Muscular Dystrophy

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Clinical features and diagnosis of Duchenne and Beckermuscular dystrophy

Clinical features and diagnosis of Duchenne and Becker muscular dystrophyAuthorBasil T Darras, MDSection EditorsMarc C Patterson, MD, FRACPHelen V Firth, DM, FRCP, DCHDeputy EditorJohn F Dashe, MD, PhDDisclosures

All topics are updated as new evidence becomes available and our peer reviewprocess is complete.Literature review current through: Mar 2013. | This topic last updated: Sep 30, 2012.

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 [ 1 ]. Some of the genes responsible for these conditions have been

identified. Muscle weakness is the primary symptom.

The genetics, pathogenesis, and clinical characteristics of the Duchenne and Becker

muscular dystrophies are reviewed here. The management and treatment of these

conditions are discussed separately. (See "Treatment of Duchenne and Becker

muscular dystrophy" .)

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 dystrophin gene and are therefore

named dystrophinopathies. 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:

Duchenne muscular dystrophy (DMD) is associated with the most severe clinicalsymptoms

Becker muscular dystrophy (BMD) has a similar presentation to DMD, buttypically has a later onset and a milder clinical course

Patients with an intermediate phenotype (outliers) may be classified clinically ashaving either mild DMD or severe BMD.

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GENETICS AND PATHOGENESIS — Duchenne muscular dystrophy is caused by a

defective gene located on the X chromosome that is responsible for the production of

dystrophin [ 2-4 ]. The dystrophin gene is the largest gene yet identified in humans,

spanning approximately 2.3 megabases at chromosome Xp21.2. The protein product is

also extremely large, weighing 427 kilodaltons (kD) [ 5 ].

Mutations — The vast majority of mutations of the dystrophin gene are deletions,

which are found in approximately 72 and 85 percent of patients with DMD and BMD,

respectively [ 6,7 ]. Partial gene duplications have also been reported in a small

proportion of affected individuals (approximately 6 to 10 percent).

The genetic lesions in the remaining 15 to 20 percent of patients are point mutations in

the coding sequence or the splicing sites. In addition, patients with clinical phenotypes

suggestive of DMD or BMD, but without a clear X-linked pattern of inheritance, may

have defects in other genes, including those encoding the dystrophin-associated

glycoproteins.

The molecular basis for the phenotypic differences among the dystrophinopathies is

related in part to whether the reading frame for dystrophin is preserved. In most

cases, patients with DMD have lesions that disrupt the reading frame for dystrophin,

while those with BMD have mutations that maintain the amino acid coding sequence

[ 8 ].

Dystrophin — Dystrophin is located on the cytoplasmic face of the plasma membrane

of muscle fibers, functioning as a component of a large, tightly associated glycoprotein

complex ( figure 1 ) [ 4 ]. Dystrophin normally provides mechanical reinforcement to

the sarcolemma and stabilizes the glycoprotein complex, thereby shielding it from

degradation. In its absence, the glycoprotein complex is digested by proteases. Loss of

these membrane proteins may initiate the degeneration of muscle fibers, resulting in

muscle weakness.

The loss of dystrophin in mdx mice leads to myofibril membrane instability [ 9 ].

However, genetic disruption of the dystrophin gene in mdx mice is associated with only

a mild dystrophy [ 10 ]. Although the reduced disease severity in mdx mice compared

with human DMD is not fully understood, several possible explanations are postulated:

A homolog of dystrophin called utrophin is present in mice and humans. Itsexpression in muscle can compensate physiologically for the absence ofdystrophin in mice, but this compensation does not occur in humans. Thishypothesis is supported by the finding that mice lacking both dystrophin andutrophin have a severe dystrophy that phenotypically resembles DMD [ 10 ].

Further, the selective expression in skeletal muscle of utrophin via the use ofa transgene completely rescues these double-knockout mice from early deathand the DMD phenotype [ 11 ].

The sialic acid N-glycolylneuraminic acid (Neu5Gc) is absent in all humans dueto an inactivating deletion in the cytidine monophosphate–sialic acidhydroxylase gene (CMAH) required for its expression [ 12 ]. However, mostmammals, including mice, are able to express Neu5Gc and incorporate it ontoglycoproteins and glycolipids in skeletal and cardiac muscle, a factor that mayameliorate disease expression in mdx mice [ 13 ]. In support of this theory,

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disease severity is accelerated and more closely resembles human DMD inmdx mice that also carry a human-like mutation in the Cmah gene [ 13 ].

Compared with the murine type, human muscle stem cells have shortertelomeres, which results in progressive loss of muscle stem cell function. Theseverity of human DMD may be due in part to the loss of functional musclestem cells, leading to an inability to repair the accelerated muscle injury that

occurs as part of this disease [ 14 ]. In support of this hypothesis, doubleknockout mdx/mTRmice that lack the RNA component of telomerase haveshortened telomeres in muscle cells and develop a severe musculardystrophy similar to human DMD.

As part of the glycoprotein complex, dystrophin secures a number of dystrophin-

associated proteins, including neuronal nitric oxide synthase (nNOS), to the

sarcolemma [ 15 ]. Sarcolemmal nNOS is necessary for the production of nitric oxide,

which regulates vasodilation and increased blood flow into muscle, and is important for

the prevention of early muscle fatigue with exercise [ 16-18 ]. The absence of

dystrophin in humans with DMD or mdx mice is associated with a loss of muscle nNOS

[ 15,19 ], resulting in exercise-induced muscle fatigue [ 16-18,20 ].

Disruption of calcium regulation may also play a role in the pathogenesis of DMD [ 21-

24 ]. Muscle cell membrane damage related to the loss of dystrophin may permit the

pathologic entry of extracellular calcium into muscle fibers. In addition, inflammatory

mediators in dystrophic muscle may increase the expression of inducible nitric oxide

synthase (iNOS), which binds to and destabilizes ryanodine receptors of the

sarcoplasmic reticulum that regulate calcium ion flow [ 25,26 ]. The result is calcium

leakage from the SR into the cytosol. The excess cytosolic calcium can activate

calpains, which promote muscle proteolysis [ 27,28 ].

Genes other than dystrophin may affect disease severity and response to treatment. A

preliminary study found that a variant of the SPP1 gene promotor region (the G alleleof the polymorphism rs28357094) is associated with decreased muscle strength and

younger age at loss of ambulation in patients with DMD [ 29 ]. However, this finding

requires confirmation in larger genetic studies [ 30 ].

CLINICAL ASPECTS — The prevalence of DMD detected by a newborn screening

program in Wales was 1 in 5867 live male births (1.7 per 10,000) [ 31 ]. Some cases

may have been missed, since approximately 5 percent of families declined to

participate. In the United States, a population-based surveillance study of males (5 to

24 years old) in four states – Arizona, Colorado, Iowa, and western New York – found

that the overall prevalence of Duchenne/Becker muscular dystrophy ranged from 1.3

to 1.8 per 10,000 [ 32 ]. The overall annual incidence of DMD among males born

between 1968 and 2008 in Nova Scotia was 1 in 4700 (2.1 per 10,000) [ 33 ].

Duchenne muscular dystrophy — 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 [ 34 ]. In some

cases, the onset of symptoms occurs later. Children also frequently have varying

degrees of mild cognitive impairment. However, an occasional child may have average

or above-average intelligence.

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Weakness — 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.Patients are usually wheelchair bound by the age of twelve.

Cardiomyopathy — DMD causes a primary dilated cardiomyopathy (DCM) and

conduction abnormalities, especially intraatrial and interatrial but also involving the AV

node, and a variety of arrhythmias, primarily supraventricular [ 35 ]. 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 ) [ 36 ]. 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 [ 37 ].

The incidence of symptomatic cardiomyopathy in patients with DMD increases

gradually in the teenage years. 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 [ 38 ].

Ultrasonography can detect structural changes in the myocardium well before the

onset of systolic dysfunction and overt cardiomyopathy [ 39 ].

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 [ 40 ]. Heart failure and arrhythmias may develop in the late stages of the

disease, especially during intercurrent infections or surgery. In rare cases, heart failuredominates the picture and can be the immediate cause of death without marked

compromise of respiratory function [ 41 ].

The possible role of therapy in slowing progression of the cardiomyopathy is discussed

separately. (See "Treatment of Duchenne and Becker muscular dystrophy", section on

'Cardiac disease' .)

Orthopedic complications — Fractures involving the arms and legs are frequent

[ 42 ]. One series of 378 patients (ages 1 to 25 years) with DMD found that 79 (21

percent) had experienced fractures [ 43 ]. The most common mechanism was falling;

about half of the fractures occurred among patients who were independent with

ambulation.

A progressive scoliosis develops in nearly all children with DMD [ 44-47 ]. Scoliosis, in

combination with progressive weakness, results in impaired pulmonary function. With

progressive disease, patients may eventually suffer acute respiratory failure.

(See "Respiratory muscle weakness due to neuromuscular disease: Clinical

manifestations and evaluation" .)

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Examination — 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. Wheelchair-bound children in particular

tend to have evidence of scoliosis with poor pulmonary function.

Becker muscular dystrophy — Compared with DMD, the age of onset of symptoms

of those with BMD is usually later and the degree of clinical involvement milder [ 48 ].

Patients typically remain ambulatory at least until age 15 and commonly well into adult

life. Some patients maintain ambulation into old age. This retained strength permits

the clinical distinction between BMD and DMD. Mental retardation and contractures are

also not as common or severe and there is relative preservation of neck flexor muscle

strength in BMD and intermediate types of muscular dystrophy.

The distinction between BMD and limb-girdle dystrophy 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 limb-girdle dystrophy.

Although muscle involvement is less severe than in DMD, cardiac involvement in BMD

is often more evident [ 49 ]. 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 [ 50 ]. 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 [ 50 ]. 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 [ 51 ]. Discontinuous immunostaining of cardiac

dystrophin is characteristic of BMD and the absence of immunostaining may be

associated with more severe cardiac disease.

Intermediate phenotype — The intermediate group of patients, also known as

outliers, have a clinical phenotype best characterized as mild DMD or severe BMD;

these individuals usually become confined to wheelchairs between the ages of 12 and

16 years.

Prognosis — Patients with DMD are often confined to wheelchair by about age 12years and die in their late teens or twenties from respiratory insufficiency or

cardiomyopathy. 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 "Treatment of Duchenne and Becker muscular dystrophy", section on

'Prognosis' .)

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LABORATORY AND PATHOLOGIC FINDINGS — Elevated levels of serum creatine

kinase, ECG abnormalities, and skeletal muscle biopsy findings are similar in both

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). They

may be distinguished by marked differences in dystrophin expression in skeletal

muscle as detected by immunoblotting.

Creatine kinase — Serum creatine kinase (CK) concentrations are elevated in

patients with DMD and BMD prior to the appearance of any clinical signs of disease;

increased levels are even observed among newborns. Serum CK peaks by age two; it

is usually 10 to 20 times the upper limit of normal and may be higher. 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 are also elevated.

Serum CK is also increased in approximately 70 and 50 percent of Duchenne and

Becker female carriers, respectively [ 52 ]. 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. (See"Muscle enzymes in the evaluation of neuromuscular diseases" .)

Electrocardiogram — Electrocardiographic abnormalities are frequent among

patients with DMD [ 53 ]. Extensive fibrosis of the posterobasal left ventricular wall

may result 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 ). DMD is also associated with conduction disturbances, especially

intraatrial and interatrial, leading to a variety of arrhythmias, primarily

supraventricular [ 35 ]. Intraatrial conduction defects are more common than AV or

infranodal defects in DMD.

Electromyography — With both DMD and BMD, the EMG reveals myopathic changes,

usually consisting of small polyphasic potentials.

Muscle biopsy — Muscle biopsy demonstrates degeneration, regeneration, isolated

"opaque" hypertrophic fibers, and significant replacement of muscle by fat and

connective tissue.

Dystrophin analysis — In normal individuals, dystrophin may easily be detected on

immunoblots of 100 µg 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 [54 ]. 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 isalso frequently reduced in quantity among these individuals. The remaining15 percent have a normal sized protein of reduced quantity.

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Dystrophin immunoblotting may be used to predict the severity of the evolving

muscular dystrophy phenotype. The quantity of the dystrophin molecule, rather than

its size, determines disease severity ( table 1 ) [ 55 ]:

Less than 5 percent of the normal quantity of dystrophin is associated withDMD.

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 are associated with mild to moderate BMD

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS — A dystrophinopathy is usually

suspected in a boy with muscle weakness, myopathic signs, and (possibly) a family

history of the illness. As with all suspected myopathies, a thorough history, physical

examination, and laboratory analysis of serum muscle enzymes are performed to

investigate the possibility of a pathologic process in muscle. (See "Approach to the

patient with muscle weakness" and "Muscle enzymes in the evaluation of

neuromuscular diseases" .)

When a clinical diagnosis of suspected dystrophinopathy is made based on the history,

examination, and creatinine kinase level, genetic investigations may establish a

definitive diagnosis without recourse to muscle biopsy. However, a muscle biopsy is

often performed to confirm the diagnosis if the genetic studies are negative.

The diagnosis of a dystrophinopathy is suspected based upon the following:

Characteristic age and sex Presence of symptoms and signs suggestive of a myopathic process Markedly increased serum creatinine kinase values Myopathic changes on electromyography and muscle biopsy

A positive family history suggesting X-linked recessive inheritance

The cloning of the dystrophin gene and the ability to characterize its protein product

provide the tools for an accurate diagnosis [ 56 ]. The choice of immunoblotting for

dystrophin or genetic testing as the initial diagnostic and/or confirmatory examination,

or whether such testing must be performed varies based upon the clinical presentation

and the presence or absence of a family history of a dystrophinopathy (algorithm 1 ).

Biopsy evidence of total absence of dystrophin in Duchenne muscular dystrophy (DMD)

or reduced dystrophin in Becker muscular dystrophy (BMD) has historically been the

gold standard for the diagnosis of these disorders because of the technical difficulty in

detecting point mutations of the dystrophin gene [ 57,58 ]. (See 'Dystrophin

analysis' above and 'Genetic 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 dystrophin gene (DMD) is

identified ( table 2 ).

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When a clinical diagnosis of DMD or BMD is made in younger patients who have a

negative family history, muscle biopsy may be obtained for Western blot and

immunohistochemistry studies of dystrophin if molecular genetic testing does not

identify a disease-causing mutation

A number of methods are available for molecular genetic analysis of the DMD gene,

including:

Analysis for deletions/duplications (the most common form of mutation seen in80 to 85 percent of cases)

Mutation scanning and sequence analysis to detect point mutations (found in 15to 20 percent of cases)

Deletions account for approximately 72 percent of DMD mutations and 85 percent of

BMD mutations. MLPA is the main technique for the detection of deletions and

duplications of the DMD gene. It can be performed in both probands and carrier

females, using either MLPA [ 59-61 ] or array-MLPA [ 62 ]. Approximately 98 percent

of deletions can be detected by multiplex PCR [ 63 ]. FISH is used much less often butis still available, and some exon-specific FISH probes can detect small deletions

[ 64,65 ].

Approximately 6 to 10 percent of males with DMD or BMD have disease-causing

mutations due to duplications that lead to in-frame or out-of-frame transcripts [ 66 ].

In a study that evaluated patients who had already been screened for deletions and

point mutations, duplications were detected in 87 percent [ 67 ]. Duplication analysis

can be performed with Southern blotting and quantitative PCR analysis.

Approximately 15 to 20 percent of DMD/BMD mutations are small deletions or

insertions, single-base changes, and splicing mutations. These are difficult to identify

by routine assays but may be detected by other methods, including DHPLC screeningand direct sequencing [ 68 ], SSCP analysis [ 69 ], DOVAM-S [ 70 ], SCAIP [ 71 ],

DGGE-based whole-gene mutation scanning [ 72,73 ], and microarray-based

methodologies [ 74 ]. 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 cDNA sequencing [ 75 ].

When carrier testing is done for a known DMD deletion/duplication in the proband,

MLPA can also be used for the detection of carriers. Deletions and duplications may be

detected through quantitative analysis for gene dosage by Southern blot. However, a

reliable method based on quantitative real-time PCR is easier to perform and interpret,

and detects deletions or duplications in 100 percent of such DMD/BMDcarriers [ 76 ].As discussed, carrier testing using sequence analysis is possible if the proband is

known to have a point mutation.

When the proband has an unknown DMD mutation, the carrier status of at-risk females

may be determined through linkage analysis.

LGMD2I presenting as DMD or BMD — Limb-girdle muscular dystrophy type 2I

(LGMD2I) is caused by a mutation in the FKRP gene and phenotypically

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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) [ 77 ]. 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" .)

Unclear clinical presentation and negative family history — For patients with an

unclear clinical phenotype that is suggestive ofDMD/BMD or limb girdle muscular

dystrophy (LGMD) and no family history, genetic testing for mutations in the

dystrophin (DMD) gene should be performed first. If positive, it will confirm the

diagnosis of DMD/BMD. If negative, genetic testing targeted at certain gene mutations

that cause LGMD is the next step (see "Limb-girdle muscular dystrophy", section on

'Diagnosis' ). If that is also negative, a muscle biopsy for histology,

immunohistochemistry with multiple antibodies and Western blot analysis of skeletal

muscle for dystrophin should be performed ( algorithm 1 ). An immunoblot assay of

dystrophin derived from a muscle biopsy specimen may confirm the clinical diagnosis

ofDMD/BMD in rare mutation-negative cases and can be used to predict the severity of

the disease. (See 'Dystrophin analysis' above.)

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 limb-girdle muscular dystrophy or other neuromuscular diseases

(eg, acid maltase deficiency). (See "Approach to the metabolic

myopathies" and "Approach to the patient with muscle weakness" .)

When genetic testing detects a deletion, duplication, or pathologic point mutation in

the dystrophin gene, thus confirming the diagnosis of DMD or BMD ( algorithm 1 ), theresult may be used as a marker for testing other family members at risk, including

carrier detection of at-risk females. Prenatal diagnosis also becomes possible [ 78 ].

If a dystrophin gene deletion, duplication, or point mutation is not uncovered, and the

diagnosis of DMD/BMD is secure by immunoblot assay demonstrating deficient

dystrophin from muscle biopsy, linkage analysis may be attempted for detection of at-

risk female relatives and for prenatal diagnosis. Such analysis, which some families

may consider, requires the cooperation of several family members.

Clear clinical presentation and negative family history — When the clinical

phenotype of DMD or BMD is apparent at presentation in a patient with possibly

sporadic disease (eg, family history negative for DMD/BMD), genetic testing on DNAextracted from a peripheral blood sample may be performed first; this will confirm the

diagnosis of DMD/BMD if a deletion/duplication is detected ( algorithm 1 ).

However, failure to detect a deletion with PCR does not exclude the diagnosis. An

immunoassay should be done to exclude or confirm the diagnosis if a mutation is not

uncovered. If a diagnosis of DMD/BMD is confirmed, genetic analysis for point

mutations in the dystrophin gene can be performed. In addition, patients with a clinical

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phenotype of DMD or BMD who are negative for dystrophin gene mutations should be

tested for the FKRP gene mutation that causes LGMD2I as noted above. (See 'LGMD2I

presenting as DMD or BMD' above.)

Familial cases — In cases of typical DMD or BMD with a family history of X-linked

dystrophinopathy, molecular diagnosis is very straightforward if the familial mutation

has already been defined, and 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.

If the diagnosis has not previously been confirmed by analysis of dystrophin or DNA in

the proband, then DNA-based deletion/duplication(and sometimes DMD gene

sequencing) test should be attempted first, since it is less invasive. If such analysis

fails to detect a dystrophin gene abnormality, a muscle biopsy for dystrophin assay is

indicated, particularly in the following settings:

Clinically atypical cases Families without a clear X-linked pattern of inheritance Families with affected male and female siblings, suggesting an autosomal

recessive form of muscular dystrophy.

Symptomatic female carriers — Clinically apparent muscle weakness occurs in 2.5

to 20 percent of female carriers of a mutated dystrophin gene [ 79 ]. In about 70

percent of such individuals, serum CK concentrations are also elevated, although the

values decline with age.

Female carriers may have an early onset, progressive muscular dystrophy if one of the

following genetic abnormalities is also present:

45X, 46XY, or Turner mosaic karyotypes Apparently balanced X/autosome translocations with breakpoints in Xp21,

within the dystrophin gene, and preferential inactivation of the normal X A normal karyotype but non-random (skewed) X-chromosome inactivation,

thereby leading to diminished expression of the normal dystrophin allele.

After excluding other neuromuscular diseases (eg, polymyositis, spinal muscular

atrophy) by electromyography and/or muscle biopsy, chromosomal analysis is

indicated in all symptomatic females, particularly those with markedly elevated serum

CK levels.

Further study with a dystrophin assay and/or a DNA deletion test may be diagnostic inthose with 45X, 46XY, or Turner mosaic karyotypes. However, the relationship

between X-inactivation status, dystrophin analysis and phenotype is complex [ 80 ].

Quantitative analysis of dystrophin in female carriers is not useful in clinical practice

because of the wide range of values and the significant overlap with normal values.

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Immunofluorescence testing of muscle biopsies for dystrophin expression from

symptomatic carriers generally shows high proportions of dystrophin-negative fibers

(mosaic pattern).

Female carriers and prenatal diagnosis — Carrier detection of at risk females and

prenatal diagnosis becomes possible after the detection of a DNA deletion, duplication,

or point mutation in an affected family member ( algorithm 1 ) [ 78 ]. 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.

MANAGEMENT — The management of DMD/BMD is discussed separately.

(See "Treatment of Duchenne and Becker muscular dystrophy" .)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces

are written in plain language, at the 5 th to 6 th grade reading level, and they answer

the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-

to-read materials. Beyond the Basics patient education pieces are longer, more

sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade

reading level and are best for patients who want in-depth information and are

comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage

you to print or e-mail these topics to your patients. (You can also locate patient

education articles on a variety of subjects by searching on “patient info” and the

keyword(s) of interest.)

Basics topics (See "Patient information: Muscular dystrophy (The Basics)" .) Beyond the Basics topics (See "Patient information: Overview of muscular

dystrophies (Beyond the Basics)" .)

SUMMARY AND RECOMMENDATIONS

Duchenne and Becker muscular dystrophies are caused by mutations of thedystrophin gene and are therefore named dystrophinopathies. Duchennemuscular dystrophy (DMD) is associated with the most severe clinicalsymptoms. Becker muscular dystrophy (BMD) has a similar presentation toDMD, but typically has a later onset and a milder clinical course. Patients withan intermediate phenotype (outliers) may be classified clinically as having

either mild DMD or severe BMD. (See 'Terminology' above.) Duchenne muscular dystrophy is caused by a defective gene located on the X

chromosome that is responsible for the production of dystrophin. Dystrophinis located on the cytoplasmic face of the plasma membrane of muscle fibers,functioning as a component of a large, tightly associated glycoproteincomplex ( figure 1 ). Dystrophin normally provides mechanical reinforcementto the sarcolemma and stabilizes the glycoprotein complex, thereby shieldingit from degradation. In its absence, the glycoprotein complex is digested byproteases. Loss of these membrane proteins may initiate the degeneration of

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muscle fibers, resulting in muscle weakness. (See'Genetics andpathogenesis' above and 'Dystrophin' above.)

With DMD, the clinical onset of weakness usually occurs between two and threeyears of age. Affected children frequently have varying degrees of mildcognitive impairment ( table 1 ). However, an occasional child may haveaverage or above-average intelligence. Muscle weakness affects the proximal

before the distal limb muscles. Additional features include cardiomyopathyand conduction abnormalities, bone fractures, and scoliosis. Physicalexamination reveals pseudohypertrophy of the calf and (occasionally)quadriceps muscles, lumbar lordosis, a waddling gait, shortening of theAchilles tendons, and hyporeflexia or areflexia. Wheelchair-dependentchildren in particular tend to have evidence of scoliosis with poor pulmonaryfunction. (See 'Clinical aspects' above and 'Duchenne musculardystrophy' above.)

Compared with DMD, the age of onset of symptoms of those with BMD isusually later and the degree of clinical involvement milder (table 1 ) [ 48 ].(See 'Becker muscular dystrophy' above.)

Patients with DMD are often confined to a wheelchair by about age 12 yearsand die in their late teens or twenties from respiratory insufficiency or

cardiomyopathy. Patients with BMD typically remain ambulatory beyond theage of 16 years and often well into adult life, and usually survive beyond theage of 30 years. (See "Treatment of Duchenne and Becker musculardystrophy", section on 'Prognosis' .)

Elevated levels of serum creatine kinase, abnormalities on theelectrocardiogram ( waveform 1 ) and skeletal muscle biopsy findings aresimilar in both DMD and BMD. However, the two may be distinguished bymarked differences in dystrophin expression in skeletal muscle as detected byimmunoblotting. (See 'Laboratory and pathologic findings' aboveand 'Dystrophin analysis' above.)

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 andclinical findings suggestive of a dystrophinopathy ( algorithm 1 ). Thediagnosis is established if a disease-causing mutation of the DMD gene isidentified ( table 2 ). A muscle biopsy can confirm the diagnosis if the geneticstudies are negative. (See 'Diagnosis and differential diagnosis' aboveand'Genetic analysis' above.)

The management of DMD and BMD is discussed separately. (See "Treatment ofDuchenne and Becker muscular dystrophy" .)

REFERENCES

1. Emery AE. The muscular dystrophies. Lancet 2002; 359:687.

2.

Worton R. Muscular dystrophies: diseases of the dystrophin-glycoproteincomplex. Science 1995; 270:755. 3. Kunkel LM, Hejtmancik JF, Caskey CT, et al. Analysis of deletions in DNA from

patients with Becker and Duchenne muscular dystrophy. Nature 1986;322:73.

4. Ervasti JM, Ohlendieck K, Kahl SD, et al. Deficiency of a glycoproteincomponent of the dystrophin complex in dystrophic muscle. Nature 1990;345:315.

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clinical features and diagnosis of duchenne and becker muscular dystrophy

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