Clinical Guidance

If a pathogenic variant is identified, the diagnosis of a dystrophinopathy is established, but the distinction between DMD and BMD can be difficult in some cases. For example, deletion of exons 3-7, the most extensively investigated deletion associated with both phenotypes, has been found in males with DMD and also with BMD . Reading frame rule. This "rule" states that pathogenic variants that do not alter the reading frame (in-frame deletions/duplications) generally correlate with the milder BMD phenotype, whereas those that alter the reading frame (out-of-frame) generally correlate with the more severe DMD phenotype . Therefore, the type of deletion/duplication can distinguish between the DMD and BMD phenotypes with 91%-92% accuracy in young children who represent simplex cases (i.e.

Source: GeneReviews — "Dystrophinopathies"

Penetrance

Penetrance of dystrophinopathies is complete in males. Penetrance in heterozygous females varies, and may depend in part on patterns of X-chromosome inactivation (XCI).

Source: GeneReviews — "Dystrophinopathies"

Diagnostic Criteria

The dystrophinopathies cover a spectrum of X-linked muscle disease that ranges from mild to severe and includes Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy (DCM). Suggestive Findings A dystrophinopathy should be suspected in an individual with the following and findings that support the diagnosis of DMD, BMD, or DMD-associated DCM – especially when they occur in addition to a positive family history compatible with X-linked inheritance. Findings are most commonly noted in males, but females may also be affected. Clinical Findings Duchenne muscular dystrophy (DMD) • Progressive symmetric muscle weakness (proximal distal) often with calf hypertrophy • Symptoms present before age five years • Wheelchair dependency before age 13 years Becker muscular dystrophy (BMD) • Progressive symmetric muscle weakness (proximal distal) often with calf hypertrophy; weakness of quadriceps femoris in some cases the only sign • Activity-induced cramping (present in some individuals) • Flexion contractures of the elbows (if present, late in the course) • Wheelchair dependency (after age 16 years); although some individuals remain ambulatory into their 30s and in rare cases into their 40s and beyond • Preservation of neck flexor muscle strength (differentiates BMD from DMD) Note: The presence of fasciculations or loss of sensory modalities excludes a suspected diagnosis of a dystrophinopathy. Individuals with an intermediate phenotype (outliers) have symptoms of intermediate severity and become wheelchair dependent between ages 13 and 16 years. DMD-associated dilated cardiomyopathy (DCM) • DCM with congestive heart failure, with males typically presenting between ages 20 and 40 years and females presenting later in life • Usually no clinical evidence of skeletal muscle disease; may be classified as "subclinical" BMD • Rapid progression to death in several years in males and slower progression over a decade or more in females See also Dilated Cardiomyopathy Overview. Laboratory Testing Serum creatine phosphokinase (CK) concentration. See . Table 1. Serum Creatine Phosphokinase (CK) Concentration in the Dystrophinopathies

Source: GeneReviews — "Dystrophinopathies"

Differential Diagnosis

Limb-girdle muscular dystrophy

(LGMD) is a group of autosomal recessive and autosomal dominant disorders that are clinically similar to DMD but occur in both sexes. Limb-girdle dystrophies are caused by mutation of genes that encode sarcoglycans and other proteins associated with the muscle cell membrane that interact with dystrophin . Testing for deficiency of proteins from the transmembrane sarcoglycan complex and of other proteins is indicated in individuals with dystrophin-positive dystrophies. LGMD type 2I phenotypically resembles DMD and BMD and is caused by biallelic pathogenic variants in FKRP (encoding fukutin-related protein).

Source: GeneReviews — "Dystrophinopathies"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a dystrophinopathy, the following evaluations are recommended if they have not already been completed:

• Physical therapy assessment

• Developmental evaluation before entering elementary school for the purpose of designing an individualized educational plan, as necessary

• At the time of diagnosis or by age six years, evaluation for cardiomyopathy by electrocardiography, cardiac echocardiography, and/or MRI

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Appropriate management of individuals with a dystrophinopathy can prolong survival and improve quality of life.

Duchenne Muscular Dystrophy (DMD) / Becker Muscular Dystrophy (BMD) Phenotypes

Cardiomyopathy in DMD and BMD. Recommendations are based on an American Academy of Pediatrics policy statement and various additional publications and apply to patients with the DMD or BMD phenotype.

Source: GeneReviews — "Dystrophinopathies"

Clinical Guidance

Individuals with dystrophinopathy should avoid botulinum toxin injections. Although it is recommended that triggering agents like succinylcholine and inhalational anesthetics be avoided in patients with dystrophinopathy because of susceptibility to malignant hyperthermia or malignant hyperthermia-like reactions (rhabdomyolysis, cardiac complications, hyperkalemia), it should be noted that an extensive literature search did not find an increased risk for malignant hyperthermia susceptibility in individuals with dystrophinopathy when compared with the general population . However, individuals with DMD have been reported to have severe reactions to anesthesia (malignant hyperthermia-like) that did not meet the criteria for true malignant hyperthermia .

Source: GeneReviews — "Dystrophinopathies"

Therapies Under Investigation

See also . Gene therapy. Clinical studies in gene therapy currently focus on restoring dystrophin expression by administering recombinant adeno-associated virus vectors that deliver either functional dystrophin transgene (micro- or minidystrophin genes) or gene-editing components [, , , ]. Gene repair. CRISPR (clustered regularly interspaced short palindromic repeats)-associated protein 9 (CRISPR/Cas9)-mediated genome editing in mdx mice has been shown to partially restore dystrophin protein expression in cardiac and skeletal muscle by cutting the noncoding introns that flank the mutated sequence-containing exon 23 . Ataluren.

Source: GeneReviews — "Dystrophinopathies"

Surveillance Guidelines

Cardiac

The American Academy of Pediatrics (AAP) has published recommendations for optimal cardiac care in persons with dystrophinopathy (full text) and consensus guidelines .

DMD

• Complete cardiac evaluation at least every two years, beginning at the time of diagnosis

• Note: At minimum, the evaluation should include an electrocardiogram and a noninvasive cardiac imaging study such as echocardiography or cardiac MRI.

• At approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation

• Note: Most individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course.

• If evaluation reveals ventricular dysfunction, initiation of pharmacologic therapy and surveillance at least every six months

BMD. Complete cardiac evaluation at least every two years, beginning at the time of diagnosis. Evaluations should continue at least every two years. DMD-related DCM. There are no consensus guidelines regarding the optimal cardiac care of patients with DMD-related DCM. However, once the diagnosis of DCM is made, patients will need complete cardiac evaluations at intervals defined by experienced cardiac specialists. Asymptomatic females. The AAP recommendations for optimal cardiac care of asymptomatic females with a heterozygous DMD pathogenic variant include the following:

Source: GeneReviews — "Dystrophinopathies"