This study characterizes a multigenerational family with X-linked Emery-Dreifuss muscular dystrophy associated with a novel FHL1 mutation (c.746G>A, p.Cys249Tyr). Among 21 family members, 5 were affected and 3 had died. The affected individuals exhibited progressive limb weakness and muscle atrophy; classical joint contractures were absent or minimal. The proband presented with mild muscle wasting and sinus tachycardia without structural cardiac abnormalities. Electromyography revealed myopathic changes with preserved nerve conduction. Thigh magnetic resonance imaging demonstrated bilateral reduction of muscle volume with fatty infiltration, and muscle biopsy confirmed variable fiber size, degeneration, and mild fibrosis consistent with a myogenic pattern. Genetic testing identified six affected members carrying the hemizygous FHL1 c.746G>A variant, resulting in a cysteine-to-tyrosine substitution at codon 249. These findings expand the genotypic and phenotypic spectrum of FHL1-related X-linked Emery-Dreifuss muscular dystrophy, highlight the marked clinical and genetic heterogeneity of the disorder, and provide important insights into early diagnosis, phenotype prediction, and genetic counseling of the affected families.

Pathogenic variants in the EMD gene cause X-linked Emery-Dreifuss muscular dystrophy type 1 (EDMD1), typically presenting with joint contractures and skeletal muscle atrophy, followed by atrial arrhythmias, cardiac conduction defects, and atrial dilatation. Although an association with isolated dilated cardiomyopathy (DCM) has been suggested, evidence is currently insufficient to verify the gene-disease association. We investigated the causality of a missense variant, c.23C>G, p.Ser8Trp, in EMD in a large family with a history of DCM and suspected sudden cardiac death (SCD) in males. DCM was diagnosed in six hemizygous males aged 36-50 and detailed phenotyping identified end-stage heart failure, cardiac conduction defects, and ventricular arrhythmias as prominent features. Cardiac magnetic resonance imaging showed late gadolinium enhancement with mixed ischemic and non-ischemic patterns. Muscular dystrophy was absent in all six males, of whom five underwent neuromuscular examination including serum-creatine kinase measurement. Immunohistochemical analysis showed greatly reduced levels of emerin in both cardiac and skeletal muscle samples. The EMD variant c.23C>G co-segregated with DCM, with an estimated LOD score of 3.9 and full-likelihood Bayes factor of >2500:1 in favor of causality. Among the 17 heterozygous females, ages 20-87, one developed DCM at age 72. We concluded that the EMD c.23C>G missense variant is associated with DCM in the absence of muscular dystrophy, thereby providing new evidence of isolated DCM as a distinct cardiac EMD-phenotype, separate from EDMD1. The phenotypic similarities with LMNA-DCM, with a high risk of cardiac conduction defects and ventricular arrhythmias, might warrant early interventions to prevent SCD.

Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants. Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09). Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare disease characterized by early contractures, progressive muscle weakness, and cardiac abnormalities. Different subtypes of EDMD have been described, with the two most common forms represented by the X-linked EDMD1, caused by mutations in the EMD gene encoding emerin, and the autosomal EDMD2, due to mutations in the LMNA gene encoding lamin A/C. A clear definition of the magnetic resonance imaging (MRI) pattern in the two forms, and especially in the rarer EDMD1, is still lacking, although a preferential involvement of the medial head of the gastrocnemius has been suggested in EDMD2. We report a 13-year-old boy with mild limb girdle muscle weakness, elbow and ankle contractures, with absence of emerin at muscle biopsy, carrying a hemizygous frameshift mutation on the EMD gene (c.153dupC/p.Ser52Glufs*9) of maternal inheritance. Minor cardiac rhythm abnormalities were detected at 24-hour Holter electrocardiogram and required β-blocker therapy. MRI scan of the thighs showed a mild diffuse involvement, while tibialis anterior, extensor digitorum longus, peroneus longus, and medial gastrocnemius were the most affected muscles in the leg. We also provide a review of the muscular MRI data in EDMD patients and highlight the relative heterogeneity of the MRI patterns found in EDMDs, suggesting that muscle MRI should be studied in larger EDMD cohorts to better define disease patterns and to cover the wide disease spectrum.

Heart disease is an under-recognized cause of morbidity and mortality in patients with Emery-Dreifuss muscular dystrophy (EDMD). Arrhythmias and conduction delays are highly prevalent and given the rarity of this disease the patient care process remains poorly defined. This study closely followed four adult patients from the Neuromuscular Multidisciplinary Clinic (Alberta, Canada) that presented with X-linked recessive EDMD. Patients were assessed and managed on a case-by-case basis. Clinical status and cardiac function were assessed through clinical history, physical examination, and investigations (12-lead electrocardiogram, 24 hour Holter monitor, transthoracic echocardiogram, and plasma biomarkers). Conduction disease, requiring permanent pacemaker, was prevalent in all patients. With appropriate medical therapy over a median follow-up period five years the cardiac status was shown to have stabilized in all these patients. We demonstrate the presentation of arrhythmias, conduction abnormalities, and chamber dilation in adult patients with X-linked EDMD. Cardiac medications and pacemaker therapy are shown to prevent adverse outcomes from these complications. Patients with EDMD are expected to develop heart disease early and prior to the development of an overt neuromuscular phenotype. These patients should be closely monitored in a multidisciplinary setting for effective management to improve their clinical outcomes.