Emery-Dreifuss Muscular Dystrophy (AD, XL)

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: LMNA (HGNC:6636) EMD (HGNC:3331) FHL1 (HGNC:3702)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 07/13/2017
• Curation Status: Released - Under Revision

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
LMNA	Emery-Dreifuss muscular dystrophy (0016830)	181350	Assertion Pending
EMD	Emery-Dreifuss muscular dystrophy (0016830)	310300	Limited Actionability
FHL1	Emery-Dreifuss muscular dystrophy (0016830)	300696	Limited Actionability

Actionability Assertion Rationale

• All experts agreed with the limited assertion computed according to the rubric for the EMD and FHL1 genes. The experts refrained from providing an assertion for LMNA given its stronger association with dilated cardiomyopathy than with just muscular dystrophy.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Complications from pregnancy / Pregnancy management	2	0D	2C	3	7DC
Scoliosis / Glucocorticoids	1	0D	2A	2	5DA
Cerebral thromboembolism / Antithrombotic medications	2	0D	2C	2	6DC
Arrhythmias / Defibrillator/cardiac surveillance	3	0D	2C	2	7DC
Congestive heart failure / Pharmacotherapy/cardiac surveillance	2	0D	2C	3	7DC
Complications from anesthesia/surgery / Anesthesia management	2	0D	2C	3	7DC
Morbidity due to disorders of glucose and lipid metabolism associated with partial lipodystrophy / Metabolic evaluation	2	0D	2C	3	7DC

Severity of Outcome

Prevalence of the Genetic Condition

Sources differ regarding the prevalence of Emery-Dreifuss muscular dystrophy (EDMD). The overall prevalence has been cited at 0.13-0.3 per 100,000.

Clinical Features (Signs / symptoms)

EDMD is clinically characterized by the presence of the clinical triad of joint contractures, slowly progressive muscle weakness and wasting, and cardiac involvement. Autosomal dominant EDMD (AD-EDMD) and X-linked EDMD (XL-EDMD) have similar, but not identical, neuromuscular and cardiac involvement. Joint contractures predominate in the elbows, ankles, and post-cervical muscles. Contractures in the post-cervical muscles are responsible for limitation of neck flexion followed by limitation in movement of the entire spine. Slowly progressive muscle weakness and wasting is initially in humero-peroneal distribution but can later extend to the scapular and pelvic girdle muscles. Cardiac involvement may include palpitations, presyncope and syncope, poor exercise tolerance, congestive heart failure, and a variable combination of supraventricular arrhythmias, disorders of atrioventricular conduction, ventricular arrhythmias, dilated cardiomyopathy, and sudden death despite pacemaker implantation. Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, Wenckebach phenomenon, third-degree atrioventricular block, and bundle-branch block. Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. A generalized dilated or hypertrophic cardiomyopathy often occurs. In AD-EDMD, the risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilation and dysfunction is higher than in XL-EDMD. Individuals are at risk for cerebral emboli and sudden death. Respiratory function may also be impaired. In a woman with EDMD, pregnancy complications may include the development of cardiomyopathy or progression of preexisting cardiomyopathy, preterm delivery, respiratory involvement, cephalopelvic disproportion, and delivery of a low birth-weight infant. Heterozygous females with XL-EDMD are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype. AD-EDMD is caused by mutations in LMNA while XL-EDMD is caused by mutation of EDMD or FHL1. Even in the same family, mutations in LMNA (OMIM: 150330) are also responsible for other phenotypic presentations, such as dilated cardiomyopathy 1A and limb-girdle muscular dystrophy 1B. Dilated cardiomyopathy 1A is addressed in a separate report.

Natural History (Important subgroups & survival / recovery)

Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. The degree and progression of contractures are variable and not always age related. In XL-EDMD, joint contractures are typically the first sign, but in AD-EDMD, muscle weakness may onset prior to joint contractures. Severe contractures may lead to loss of ambulation by limitation of movement of the spine and lower limbs. Progression of muscle wasting is usually slow in the first three decades of life, after which it becomes more rapid. Loss of ambulation can occur in AD-EDMD but is rare in XL-EDMD. Cardiac involvement usually occurs after the second decade. On occasion, sudden cardiac death is the first manifestation of the disorder.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Autosomal Dominant (LMNA) or X-linked recessive (EMD; FHL1)

Prevalence of Genetic Variants

Unknown

Information regarding prevalence of pathogenic variants associated with EDMD in the general population was not identified. However, roughly 45% of AD-EMDM is attributed to pathogenic variants in LMNA, roughly 61% of XL-EMDM is attributed to EMD, and roughly 10% of XL-EMDM is attributed to FHL1.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

Five LMNA pathogenic variants were reported with reduced penetrance in families with AD-EDMD or other LMNA-related disorders. One study summarized clinical outcomes 4 families that harbored 4 unique missense pathogenic variants, where 2 in 2 (100%), 2 in 3 (67%), 1 in 3 (33%), and 0 in 4 (0%) individuals who harbored the familial variant in each family, respectively, were affected, indicating that variants could range from silent to fully penetrant. A second study focused on the R644C variant of LMNA reported penetrance rates across 5 families with more than one individual harboring the variant: 1 in 4 (25%), 1 in 2 (50%), 1 in 2 (50%), 2 in 5 (60%), and 2 in 3 (67%).

Tier 3

Unknown

Additional information on penetrance was not identified.

Tier Not provided

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information regarding relative risk was not identified.

Expressivity

LMNA variants do not show a clear genotype/phenotype correlation, with marked intra- and interfamilial variability observed. Note that pathogenic variants in LMNA can result in variable phenotypes with different clinical designations. The same pathogenic variant may lead to different diagnostic phenotypes (AD-EDMD, LGMD1B, or isolated DCM-CD) in the same family.

Tier 3

Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability.

Tier 3

Intervention Effectiveness

Patient Management

Clinicians should refer patients to a clinic that has access to multiple specialties designed specifically to care for patients with muscular dystrophy and other neuromuscular disorders to provide efficient and effective long-term care. Evidence from studies in other neuromuscular diseases, such as amyotrophic lateral sclerosis, indicates that a multidisciplinary approach is the most effective way to deliver care and is associated with improved survival, higher quality of life, increased use of treatments and interventions, and increased use of adaptive equipment.

Tier 1

Patients newly diagnosed should be referred for cardiology evaluation, including electrocardiogram (ECG) and structural evaluation (echocardiography or cardiac MRI), even if they are asymptomatic, to guide appropriate management. Patients with cardiac involvement often do not have symptoms that precede cardiac morbidity or sudden cardiac death and serious cardiac manifestations are often identified only with cardiology testing. Thus the detection and appropriate management of cardiac dysfunction are important to reduce morbidity and mortality. Patients with muscular dystrophy often have improved quality of life following appropriate pharmacologic treatment, device placement, or surgical intervention for their cardiac involvement.

Tier 1

At the time of diagnosis, patients should be referred for pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright and, if normal, supine positions) or pulmonary evaluation (to identify and treat respiratory insufficiency). Patients with respiratory failure from neuromuscular-related weakness often do not have symptoms that precede the onset of respiratory failure. Impending respiratory failure is often identified only with pulmonary function tests. Patients with respiratory failure secondary to muscle weakness often have improved quality of life with noninvasive pulmonary ventilation due to improvement in energy, vitality, shortness of breath, daytime somnolence, depression, concentration problems, sleep quality, and physical fatigue.

Tier 1

At the time of diagnosis, individuals with LMNA-linked EDMD should undergo evaluation of metabolic functions (glycemia, insulinemia, triglyceridemia), as rarely this phenotype can overlap with features of partial lipodystrophy.

Tier 3

Clinicians may advise patients that gentle, low impact aerobic exercise improves cardiovascular performance, increases muscle efficiency, and lessens fatigue. In a study of 27 patients with undescribed slowly progressive neuromuscular disease, moderate resistance exercise resulted in significantly improved strength equal to that of healthy control subjects. Another study of 8 subjects with progressive neuromuscular disease diagnoses that did not include EDMD demonstrated increased aerobic capacity and power output after a 12-week moderate intensity aerobic walking program.

Tier 2

The following are recommended to prevent primary manifestations and secondary complications:

- Implantation of cardiac defibrillators to reduce the risk of sudden death. In a prospective study of 19 patients with LMNA mutations, including 9 patients with EDMD, who received ICD implantation, 8 patients received appropriate ICD shocks which may have prevented sudden death due to lethal tachyarrhythmias. Six patients received ICD shocks for ventricular fibrillation, 2 received shocks for ventricular tachycardia, and one received antitachycardia pacing for ventricular tachycardia. It is unclear how many patients with EDMD received a shock.

- Anithromboembolic drugs to prevent cerebral thromboembolism of cardiac origin in individuals with decreased left ventricular function or atrial arrhythmias. In a case series of patients with EDMD, 4 of 11 patients with atrial arrhythmia incurred thromboembolic events, indicating a high risk for thromboembolic events in this subset of patients. None were on anticoagulant prophylaxis.

Tier 3

Preoperatively, the following additional diagnostic procedures are recommended:

- ECG

- Echocardiography and 24 hour ambulatory ECG telemetry

- Cardiac electrophysiological testing should be considered for patients with conduction defects

Tier 4

Surgical and anesthesia recommendations to prevent potential complications include:

- An airway management plan to address aspiration risk and restricted neck movement

- Consideration of anti-fibrinolytics and early treatment of acquired coagulopathy

- An opioid-sparing technique and careful titrations of muscle relaxants

- Judicious use of fluids and a means of external pacing should it be necessary

- Electrolyte monitoring and DC cardioversion should be available

- Invasive arterial pressure monitoring and central venous pressure monitoring

- Neuromuscular blockade should be monitored routinely

- Potentiation of neuromuscular blockade by hypothermia should be avoided

- High dependency care should be considered particularly following intra-abdominal or thoracic surgery

Tier 4

In a woman with EDMD, pregnancy complications may include the development of cardiomyopathy or progression of preexisting cardiomyopathy, preterm delivery, respiratory involvement, cephalopelvic disproportion, and delivery of a low birth-weight infant. Pregnancy management is challenging, with very limited literature addressing the issue. Caesarean section delivery may be required. Referral of an affected pregnant woman to a specialized obstetric unit in close collaboration with a cardiologist is recommended for optimal pregnancy outcome.

Tier 4

Surveillance

Annual cardiac assessment consisting of ECG, Holter monitoring, and echocardiography is appropriate in order to detect asymptomatic cardiac disease. More advanced and invasive cardiac assessment may be required.

Tier 4

Monitoring of respiratory function should be performed.

Tier 4

Body weight should be monitored, as affected individuals may be predisposed to obesity.

Tier 4

Clinicians should monitor patients for the development of spinal deformities to prevent complications and preserve function. Management is important to reduce discomfort, maintain normal posture, assist mobility, maintain cardiopulmonary function, and optimize quality of life. Management may include daily glucocorticoid treatment, which has been shown to reduce the risk of scoliosis, with patients not treated with glucocorticoids having a 90% chance of developing significant, progressive scoliosis. Management may also include surgery such as spinal fusion to straighten the spine, which prevents worsening of deformity, eliminates pain due to vertebral fracture with osteoporosis, and slows the rate of respiratory decline.

Tier 1

Patients should have periodic assessments by physical and occupational therapist for symptomatic and preventive screening. Currently available data are not adequate to assess the effect of any rehabilitation modality (endurance and strength training, bracing, assistive devices, new computer-based technology). However, the principles of long-term management emphasize maintaining mobility and functional independence for as long as possible, with a focus on maximizing quality of life.

Tier 2

Circumstances to Avoid

Avoid dehydration, exercising to exhaustion, and supramaximal high-intensity exercise due to the risk of exercise-induced muscle damage, myoglobinuria, and subsequent overwork weakness

Tier 2

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).

Tier 3

Although evidence is lacking it may be prudent to avoid suxamethonium and inhalational anesthetics during the first decade of life to avoid anesthesia-induced rhabdomyolysis.

Tier 4

Nature of Intervention

Nature of Intervention

The nature of intervention includes surgeries to treat manifestation, ICD implantation to prevent sudden cardiac death, extensive cardiac workup and monitoring, and anesthetic precautions.

Context: Adult

Chance to Escape Clinical Detection

Because sudden cardiac death can be the first and single clinical manifestation of the disease, there is a chance to escape clinical detection prior to death due to disease.

Context: Adult

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			LMNA			181350	0016830	0021569, 0020336
EMD			310300	0016830	0010680
FHL1			300696	0016830	0010401

References List

EMERY-DREIFUSS MUSCULAR DYSTROPHY 1, X-LINKED; EDMD1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 310300, (2016) World Wide Web URL: http://omim.org/

EMERY-DREIFUSS MUSCULAR DYSTROPHY 2, AUTOSOMAL DOMINANT; EDMD2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 181350, (2015) World Wide Web URL: http://omim.org/

Emery-Dreifuss muscular dystrophy. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=261

Funnel A, Schuster F, Whabi K, Ben Yaou R.. Orphananesthesia: Anesthesia recommendations for patients suffering from Emery-Dreifuss Muscular Dystrophy. Orphananesthesia (2014) Accessed: 2017-07-13. URL: http://www.orphananesthesia.eu/en/rare-diseases/still-to-do/cat_view/61-rare-diseases/60-published-guidelines/97-emery-dreifuss-muscular-dystrophy.html

G Bonne, F Leturcq, R Ben Yaou. Emery-Dreifuss Muscular Dystrophy. (2004) [Updated Nov 25 2015]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1436/

LAMIN A/C; LMNA. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 150330, (2016) World Wide Web URL: http://omim.org/

MYOPATHY, X-LINKED, WITH POSTURAL MUSCLE ATROPHY; XMPMA. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 300696, (2011) World Wide Web URL: http://omim.org/

Narayanaswami P, Weiss M, Selcen D, David W, Raynor E, Carter G, Wicklund M, Barohn RJ, Ensrud E, Griggs RC, Gronseth G, Amato AA. (2014) Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 83(16):1453-63.