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 humeroperoneal 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 clinical diagnosis of EDMD can be established in a proband with characteristic early and prominent joint contractures, humeroperoneal (or more rarely limb-girdle) muscle weakness and wasting, and later-onset cardiac disease. The molecular diagnosis is established in a proband with characteristic clinical findings and a hemizygous pathogenic variant in EMD or FHL1, a heterozygous pathogenic variant in LMNA, SUN2, SYNE1, SYNE2, or TMEM43, or (more rarely) biallelic pathogenic variants in LMNA or SUN1 identified by molecular genetic testing.

Management: Treatment of manifestations: 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. Treatment for cardiac disease can include antiarrhythmic drugs, oral anticoagulation, ablation procedures, cardiac pacemaker, implantable cardioverter-defibrillator, pharmacologic and nonpharmacologic therapy for heart failure; heart transplantation for the end stages of heart failure as appropriate; respiratory aids (respiratory muscle training, assisted coughing techniques, mechanical ventilation) as needed; in those with associated metabolic features, treatment may include dietary modification, medications to improve hypertriglyceridemia and hypercholesterolemia, and diabetes / insulin resistance medications.

Surveillance: Assess joints for contractures and mobility, and spine for rigidity, posture, flexibility, swallowing function, and muscle strength at each visit; EKG, Holter monitor, and echocardiography at least annually; additional cardiac surveillance as needed; pulmonary function tests every two to three years and annually in those with respiratory compromise; cholesterol panel with triglycerides, hemoglobin A1c, and blood glucose every two to three years or more frequently in those with abnormalities.

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 musculoskeletal evaluation and cardiac assessment, if the pathogenic variant(s) in the family are not known.

Genetic counseling: EDMD is inherited in an X-linked (XL), autosomal dominant (AD), or (rarely) autosomal recessive (AR) manner.

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 cardiac disease, progressive muscular dystrophy (rare), and/or an EDMD phenotype (exceedingly rare).

AD-EDMD: Sixty-five percent of individuals with LMNA-related AD-EDMD have a de novo pathogenic variant. Each child of an individual with AD-EDMD has a 50% chance of inheriting the pathogenic variant.

AR-EDMD: If both parents are known to be heterozygous for a pathogenic variant associated with AR-EDMD, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.

Once the EDMD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for EDMD are possible.