Emery-Dreifuss Muscular Dystrophy

Excerpt

Clinical characteristics: Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of: joint contractures that begin in early childhood; slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles; and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure along with variable cardiac rhythm disturbances. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. 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. Cardiac involvement usually occurs after the second decade and respiratory function may be impaired in some individuals.

Diagnosis/testing: The diagnosis of EDMD is established in a proband with:

1. A clearly relevant clinical picture including limb muscle wasting and/or weakness and elbow or neck/spine joint contractures (cardiac disease may be missing in the first decades of life); AND

2. A hemizygous pathogenic variant in EMD or FHL1, a heterozygous pathogenic variant in LMNA, or (more rarely) biallelic pathogenic variants in LMNA identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment for cardiac arrhythmias, AV conduction disorders, congestive heart failure, including antiarrhythmic drugs, cardiac pacemaker, implantable cardioverter defibrillator; heart transplantation for the end stages of heart failure as appropriate; respiratory aids (respiratory muscle training, assisted coughing techniques, mechanical ventilation) as needed. Surgery to release contractures and manage scoliosis as needed; aids (canes, walkers, orthoses, wheelchairs) as needed to help ambulation; physical therapy and stretching to prevent contractures.

Surveillance: At a minimum, annual cardiac assessment (EKG, Holter monitoring, echocardiography); monitoring of respiratory function.

Agents/circumstances to avoid: Triggering agents for malignant hyperthermia, such as depolarizing muscle relaxants (succinylcholine) and volatile anesthetic drugs (halothane, isoflurane); obesity.

Evaluation of relatives at risk: Molecular genetic testing if the pathogenic variant(s) in the family are known; clinical evaluation, including at least muscular and cardiac assessments if the pathogenic variant(s) in the family are not known.

Genetic counseling: EDMD is inherited in an X-linked, autosomal dominant, or, rarely, autosomal recessive manner.

1. XL-EDMD. If the mother of a proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous. Heterozygous females are usually asymptomatic but are at risk of developing a cardiac disease, progressive muscular dystrophy, and/or an EDMD phenotype.

2. AD-EDMD. 65% of probands with AD-EDMD have a de novo LMNA pathogenic variant. Each child of an individual with AD-EDMD has a 50% chance of inheriting the pathogenic variant.

3. AR-EDMD. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier.

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for EDMD are possible.