Clinical Guidance

EMD. Intra- and interfamilial variability in the severity of clinical features are observed.

• Null variants tend to have a more severe phenotype [, , , ].

• Missense variants are associated with decreased or normal amounts of emerin and result in a milder EDMD phenotype . Otherwise, EMD missense variants frequently lead to isolated cardiac disease .

LMNA. Marked intra- and interfamilial variability is observed for the same LMNA pathogenic variant . For example, within the same family the same pathogenic variant can lead to AD-EDMD, limb-girdle muscular type, or isolated dilated cardiomyopathy with conduction system disease (i.e., laminopathies involving striated muscle) .

Source: GeneReviews — "Emery-Dreifuss Muscular Dystrophy"

Penetrance

Penetrance is usually complete in EMD- and FHL1-related EDMD except for females heterozygous for an EMD or FHL1 pathogenic variant, who are usually asymptomatic but are at risk of developing cardiac disease (usually after age 50 years), progressive muscular dystrophy (rare), or EDMD (exceedingly rare) [, , , ]. Reduced penetrance has been occasionally reported in LMNA-related EDMD . In SUN1-, SUN2-, SYNE1-, SYNE2-, and TMEM43-related EDMD, penetrance appears complete but reported data are limited.

Source: GeneReviews — "Emery-Dreifuss Muscular Dystrophy"

Diagnostic Criteria

Consensus clinical diagnostic criteria for Emery-Dreifuss muscular dystrophy (EDMD) have been published .

Suggestive Findings

EDMD should be suspected in probands with the following clinical, electrophysiologic, imaging, and laboratory findings and family history.

Clinical findings

• Age of onset is typically between age five and ten years, rarely before age five or after ten years.

• Joint contractures of the elbow flexors, Achilles tendons, and neck extensors resulting in limitation of neck flexion, followed by limitation of extension of the entire spine

• Muscle wasting and weakness that is slowly progressive, with humeroperoneal/scapuloperoneal muscles typically affected first

• Cardiac disease symptoms including palpitations, presyncope, syncope, and poor exercise tolerance

Source: GeneReviews — "Emery-Dreifuss Muscular Dystrophy"

Differential Diagnosis

Some neuromuscular disorders result in a similar pattern of muscle involvement, joint contractures, or cardiac disease, but most do not feature the complete triad observed in Emery-Dreifuss muscular dystrophy (EDMD). Because overt joint contractures may be absent to slight within the first decade of life and cardiac disease is usually absent within the first two decades of life, it may be difficult to clinically distinguish EDMD from other neuromuscular disorders. Table 4. Disorders to Consider in the Differential Diagnosis of Emery-Dreifuss Muscular Dystrophy

Management Guidelines

For individuals with Emery-Dreifuss muscular dystrophy (EDMD) and cardiac involvement, risk stratification guidelines for primary prevention of sudden cardiac death have been reported for laminopathies including autosomal dominant and autosomal recessive LMNA-related EDMD [, , , ] and emerinopathies including EMD-related EDMD . For deficiencies resulting from skeletal muscle involvement, no specific clinical practice guidelines for EDMD have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder and reported literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EDMD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Emery-Dreifuss Muscular Dystrophy: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Musculoskeletal

| Eval of joints by PMR specialist, orthopedist, or PT to determine extent of musculoskeletal deficits need for therapies |

Cardiac

| • Referral to cardiologist

• EKG/ Holter-EKG monitoring

• Echocardiography

• Cardiac MRI electrophysiologic study

|

Respiratory

| • Referral to pulmonologist

• Eval of respiratory function (vital capacity measurement other pulmonary volume measurements)

|

Metabolic functions

| • Cholesterol panel incl triglycerides

Source: GeneReviews — "Emery-Dreifuss Muscular Dystrophy"

Clinical Guidance

Although malignant hyperthermia susceptibility has not been described in EDMD, it is appropriate to anticipate a possible malignant hyperthermia reaction and to avoid triggering agents such as depolarizing muscle relaxants (succinylcholine) and volatile anesthetic drugs (halothane, isoflurane). Other anesthetic precautions must be considered . Obesity should be avoided to decrease negative impact on ambulation and joints.

Source: GeneReviews — "Emery-Dreifuss Muscular Dystrophy"

Therapies Under Investigation

Several therapeutic approaches (pharmacologic treatments, gene therapy) are still under evaluation in mice models such as mTOR and p38 inhibitors. So far, only one therapy has reached a human trial (REALM-DCM; NCT03439514) , which enrolled 12 individuals with LMNA-related cardiac disease with or without skeletal muscle involvement. After 48 weeks of treatment with either 100 mg or 400 mg of ARRY-371797 (a p38 inhibitor) twice daily, there were no safety concerns and an overall positive outcome in the primary and secondary end points, leading to a Phase III clinical trial. However, the sponsor decided to stop the Phase III trial due to futility. Search ClinicalTrials.

Source: GeneReviews — "Emery-Dreifuss Muscular Dystrophy"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended in a multidisciplinary setting.

Table 7.

Emery-Dreifuss Muscular Dystrophy: Recommended Surveillance

System/Concern | Evaluation | Frequency

Musculoskeletal

| • Assess joints for contractures mobility.

• Assess spine for rigidity, posture, flexibility, swallowing function.

• Assess muscle strength.

| At each visit

Cardiac

| • EKG, Holter monitoring, echocardiography to detect asymptomatic cardiac disease

• More advanced invasive cardiac assessment may be required for those w/cardiac disease.

| At least annually; more frequently as needed

Respiratory

| Pulmonary function tests | If normal, every 2-3 yrs; if abnormal, annually

Endocrine

| • Cholesterol panel w/triglycerides

• Hgb A1c blood glucose

| If normal, every 2-3 yrs; if abnormal, annually or more frequently as needed

Hgb = hemoglobin

Source: GeneReviews — "Emery-Dreifuss Muscular Dystrophy"