DiagnosisClinical DiagnosisThe clinical diagnosis of Emery-Dreifuss muscular dystrophy (EDMD) is based on the presence of the following triad [Emery 2000]:Early contractures of the elbow flexors, Achilles tendons (heels), and neck extensors resulting in limitation of neck flexion, followed by limitation of extension of the entire spine Slowly progressive wasting and weakness typically of the humero-peroneal/scapulo-peroneal muscles in the early stages Cardiac disease with conduction defects and arrhythmias Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (ECG) or by 24-hour ambulatory ECG. Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation. Other clinical findings are nonspecific:Electromyogram (EMG) usually shows myopathic features with normal nerve conduction studies, but neuropathic patterns have been described for X-linked EDMD (XL-EDMD) [Hopkins et al 1981] and for autosomal dominant EDMD (AD-EDMD) [Witt et al 1988]. CT scan of muscle shows a diffuse pattern of involvement affecting the biceps, soleus, peroneal, external vasti, gluteus, and paravertebral muscles [Graux et al 1993]. Characteristic findings in the calf and posterior thigh muscles on MRI or CT scan have been reported in AD-EDMD [Mercuri et al 2002, Deconinck et al 2010, Carboni et al 2012]. TestingOther nonspecific laboratory findings: Serum CK concentration is normal or moderately elevated (2-20x upper normal level). Increases in serum CK concentration are more often seen at the beginning of the disease than in later stages [Bonne et al 2000, Bonne et al 2002]. Muscle histopathology shows nonspecific myopathic or dystrophic changes, including variation in fiber size, increase in internal nuclei, increase in endomysial connective tissue, and necrotic fibers. Electron microscopy may reveal specific alterations in nuclear architecture [Fidzianska et al 1998, Sabatelli et al 2001, Sewry et al 2001, Fidzianska & Hausmanowa-Petrusewicz 2003, Fidzianska & Glinka 2007]. Inflammatory changes may also be found in LMNA-related myopathies including EDMD [Komaki et al 2011]. Muscle biopsy is now rarely performed for diagnostic purposes because of the lack of specificity of the dystrophic changes observed. Immunodetection of emerin. In normal individuals, the protein emerin is ubiquitously expressed on the nuclear membrane. Emerin can be detected by immunofluorescence and/or by western blot in various tissues: exfoliative buccal cells, lymphocytes, lymphoblastoid cell lines, skin biopsy, or muscle biopsy [Manilal et al 1997, Mora et al 1997]. In individuals with XL-EDMD, emerin is absent in 95% [Yates & Wehnert 1999]. In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin.In individuals with AD-EDMD, emerin is normally expressed.Immunodetection of FHL1. In controls, the three FHL1 isoforms (A, B, and C) are ubiquitously expressed in the cytoplasm as well as in the nucleus. The isoforms can be detected by immunofluorescence and/or western blot in fresh muscle biopsy or myoblasts, fibroblasts, and cardiomyocytes [Sheikh et al 2008, Gueneau et al 2009].In individuals with FHL1-related XL-EDMD, FHL1 is absent or significantly decreased [Gueneau et al 2009]. In female carriers of FHL1-related XL-EDMD, FHL1 is expected to be variably expressed. Immunodetection of lamins A/C. Lamins A/C are expressed at the nuclear rim (i.e., nuclear membrane) and within the nucleoplasm (i.e., nuclear matrix). Depending on the antibody used, lamins A/C can be localized to both the nuclear membrane and matrix or to the nuclear matrix only. However, this test is not reliable for confirmation of the diagnosis of AD-EDMD because in AD-EDMD lamins A/C are always present due to expression of the wild-type allele at the nuclear membrane and in the nuclear matrix. Western blot analysis for lamin A/C may contribute to the diagnosis, but yields normal results in many affected individuals [Menezes et al 2012]. Molecular Genetic TestingGenes. Mutations in three genes are known to cause EDMD. These genes encode ubiquitous proteins localized either in the nuclear membrane or in the cytoplasm and nucleoplasm. EMD (in which mutation causes XL-EDMD) encodes emerin [Bione et al 1994]. FHL1 (XL-EDMD) encodes FHL1 [Gueneau et al 2009]. LMNA (AD-EDMD and AR-EDMD) encodes lamins A and C [Bonne et al 1999].Evidence for locus heterogeneity. About 64% of individuals with a diagnosis of EDMD who have emerin detected on immunocytochemistry and/or immunoblotting have no mutation identified in EMD, FHL1, or LMNA, suggesting that these individuals are either misdiagnosed or that other, as-yet unidentified genes are involved in EDMD [Gueneau et al 2009]. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Emery-Dreifuss Muscular DystrophyView in own windowGene Symbol% of EDMD Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency ¹ Test AvailabilityEMD~61% of XL-EDMD ^{2Sequence analysis or mutation scanning 3Sequence variants 499% 5, 6, 7, 8Clinical Deletion / duplication analysis 9, 10Deletion of exon(s) or entire geneFHL1~10% of XL-EDMD 2Sequence analysis or mutation scanning 3Sequence variants 499% 6, 7, 8, 11ClinicalLMNA~45% of AD-EDMD; unknown for AR-EDMD 12Sequence analysis or mutation scanning 3Sequence variants 499% 13, 14ClinicalDeletion / duplication analysis 9, 10Deletion of exon(s) or entire gene 15Unknown 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Estimates are based on the published experience in France [Gueneau et al 2009]. Since FHL1 was only recently reported as causative of XL-EDMD, a better understanding of its prevalence will emerge with time and expanded use of testing. 3. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably among laboratories based on specific protocols used. 4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.5. Sequencing of EMD (6 exons, 5 short introns, and promoter region) detects an EMD mutation in more than 99% of individuals with established X-linked inheritance and/or with no emerin detected by immunodetection methods [Manilal et al 1998].6. Males with an established X-linked inheritance or individuals with no emerin expression as determined by immunodetection studies of muscle tissue7. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. 8. Sequence analysis of genomic DNA cannot detect exonic, multiexonic, or whole-gene deletions on the X chromosome in carrier females.9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.10. Extent of deletion detected may vary by method and by laboratory.11. Males with an established X-linked inheritance or individuals with no or highly reduced FHL1 expression as determined by immunodetection studies of muscle tissue [Gueneau et al 2009].12. AR-EDMD is very rare. To date only one LMNA mutation in a homozygous state leading to AR-EDMD has been reported [Raffaele Di Barletta et al 2000]. 13. Sequence analysis of the coding regions of LMNA (12 exons and their flanking intronic regions) detects mutations in 100% of individuals with LMNA sequence variants (missense and nonsense mutations, small deletions/insertions); however, this represents only about 45% of individuals with AD-EDMD because (a) large deletions and duplications involving one or several exons are not detected and (b) other as-yet undiscovered genes could be implicated in AD-EDMD [Bonne et al 2000, Brown et al 2001, Bonne et al 2003, Vytopil et al 2003]. Mutations in TMEM43 were reported by Liang et al [2011] in EDMD-like patients, but other genes remain to be identified.14. Complementary DNA (cDNA) sequencing may be helpful to confirm the transcript variants resulting from splice-site mutations.15. Four large deletions have been identified to date. One encompasses the promoter region and the beginning of exon 1 and is responsible for a neurogenic variant of EDMD [Walter et al 2005]. The three others – deletion of exon 1 [van Tintelen et al 2007], deletion of exons 3 to 12 [Gupta et al 2010], and a complex rearrangement involving a double deletion [Marsman et al 2011] – are responsible for isolated cardiac disease.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband If the family history clarifies the mode of inheritance, testing of EMD and FHL1 should be performed for XL-EDMD and LMNA for AD-EDMD or AR-EDMD. In the absence of an informative family history:Affected males. Emerin and FHL1 immunodetection studies help to distinguish between XL- and AD-EDMD and thus determine the appropriate gene for molecular genetic testing. Affected females who are simplex cases (i.e., a single occurrence in a family). Carrier females rarely manifest X-linked EDMD; thus, affected females are much more likely to have AD-EDMD and LMNA should be analyzed before considering analysis of the X-linked genes. If sequence analysis does not identify an EMD mutation in those with possible XL-EDMD, deletion/duplication analysis should be considered. If sequence analysis does not identify an LMNA mutation in those with suspected AD-EDMD or AR-EDMD, deletion/duplication analysis may be appropriate; however, whole-exon or multiexon deletions of LMNA are rare.Carrier testingX-linked EDMD. Carrier testing for at-risk relatives requires prior identification of the EMD or FHL1 disease-causing mutation in the family.
Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.Autosomal recessive EDMD. Carrier testing for at-risk relatives requires prior identification of the disease-causing LMNA mutations in the family.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in families with X-linked EDMD and autosomal dominant EDMD, and of the disease-causing mutations in families with autosomal recessive EDMD.Genetically Related (Allelic) DisordersEMDThe disorders caused by mutations in EMD are called “emerinopathies” and affect striated muscles:X-linked LGMD (limb-girdle muscular dystrophy) phenotype caused by mutation in EMD; rarely reported [Ura et al 2007, Fanin et al 2009]X-linked isolated cardiac disease with prominent sinus node disease and atrial fibrillation [Ben Yaou et al 2007, Karst et al 2008]FHL1FHL1-related diseases include three allelic disorders characterized by the presence of reducing bodies detected on histopathology: Reducing body myopathy [Schessl et al 2008] X-linked scapuloperoneal myopathy [Quinzii et al 2008] Some cases of rigid spine syndrome [Shalaby et al 2008]Other allelic FHL1-related diseases:X-linked myopathy with postural muscle atrophy (X-MPMA) and generalized muscle hypertrophy or X-MPMA in which reducing bodies are absent and FHL1 protein is reduced on immunodetection (making this disorder similar to FHL1-related EDMD) [Windpassinger et al 2008]X-linked hypertrophic cardiomyopathy [Gueneau et al 2009, Friedrich et al 2012]LMNAThe disorders caused by mutations in LMNA are called "laminopathies." Disorders of striated muscle *LGMD1B, an autosomal dominant form of limb-girdle muscular dystrophy associated with atrioventricular conduction defect [van der Kooi et al 1996, Muchir et al 2000] CMD1A or DCM-CD, an autosomal dominant form of dilated cardiomyopathy with cardiac conduction defects [Fatkin et al 1999, Bécane et al 2000] Autosomal dominant dilated cardiomyopathy (DCM) with apical left ventricular aneurysm without atrio-ventricular block [Forissier et al 2003]; DCM with early atrial fibrillation [Sebillon et al 2003]; DCM with left ventricular non-compaction [Hermida-Prieto et al 2004] Arrhythmogenic right ventricular cardiomyopathy [Quarta et al 2012] Autosomal dominant quadriceps myopathy associated with dilated cardiomyopathy and cardiac conduction defects [Charniot et al 2003] Neurogenic variant of EDMD [Walter et al 2005] LMNA-related congenital muscular dystrophy (L-CMD) [Quijano-Roy et al 2008]* Note: (1) These may not truly be allelic disorders because the phenotype overlaps with EDMD. See comments in Genotype-Phenotype Correlations. (2) Laminopathies affecting striated muscles are important to recognize because of the severity of the dilated cardiomyopathy associated with conduction/rhythm (DCM-CD) disorders, and the high frequency of sudden death [van Berlo et al 2005]. (3) See also Dilated Cardiomyopathy Overview.Disorders of peripheral nerve CMT2B1, an autosomal recessive form of axonal Charcot-Marie-Tooth disease with the founder mutation p.Arg298Cys [De Sandre-Giovannoli et al 2002] (see Charcot-Marie-Tooth Neuropathy Type 2) Autosomal dominant CMT2 associated with muscular dystrophy, cardiomyopathy and leukonychia [Goizet et al 2004]. Autosomal dominant CMT2 associated with myopathy [Benedetti et al 2005]. Disorders of fatty tissues. Autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD) [Shackleton et al 2000]. The majority of FPLD cases are caused by LMNA mutations affecting arginine codon 482, leading to several amino acid substitutions [Bonne et al 2003]. Isolated metabolic manifestations without lipodystrophy have been also reported [Young et al 2005, Decaudain et al 2007].Disorders involving several tissues Autosomal dominant muscular dystrophy, dilated cardiomyopathy, and partial lipodystrophy [Garg et al 2002, van der Kooi et al 2002] Mandibuloacral dysplasia (MAD) (autosomal recessive). Founder mutations are reported in MAD (p.Arg527His) [Novelli et al 2002]. Generalized lipoatrophy, insulin-resistant diabetes mellitus, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy (LDHCP) [Caux et al 2003] Hutchinson-Gilford progeria syndrome (HGPS) (autosomal dominant). Mutations in codon 608 are associated with HGPS [De Sandre-Giovannoli et al 2003, Eriksson et al 2003]. Atypical Werner syndrome (autosomal dominant) [Chen et al 2003] Restrictive dermopathy [Navarro et al 2004] Progeria, arthropathy, and calcinosis of tendons [Van Esch et al 2006] Heart-hand syndrome, Slovenian type [Renou et al 2008]Silent normal allelic variants of LMNA. Some silent normal sequence variants of LMNA are also reported to be related to susceptibility to obesity and to insulin resistance [Hegele et al 2001a, Hegele et al 2001b, Murase et al 2002].}

Natural HistoryAD-EDMD and XL-EDMD have similar, but not identical, neuromuscular and cardiac involvement [Wulff et al 1997, Manilal et al 1998, Yates et al 1999, Bécane et al 2000, Bonne et al 2000, Felice et al 2000, Raffaele Di Barletta et al 2000, Brown et al 2001, Boriani et al 2003, Vytopil et al 2003, Gueneau et al 2009, Knoblauch et al 2010, Cowling et al 2011, Schessl et al 2011]. EDMD is characterized by the presence of the following clinical triad: Joint contractures that begin in early childhood in both XL-EDMD and AD-EDMD. In XL-EDMD, joint contractures are usually the first sign, whereas in AD-EDMD, joint contractures may appear after the onset of muscle weakness. Joint contractures predominate in the elbows, ankles, and post-cervical muscles (responsible for limitation of neck flexion followed by limitation in movement of the entire spine). The degree and the progression of contractures are variable and not always age related [Bonne et al 2000]. Severe contractures may lead to loss of ambulation by limitation of movement of the spine and lower limbs. Slowly progressive muscle weakness and wasting that are initially in a humero-peroneal distribution and can later extend to the scapular and pelvic girdle muscles. The 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 [Bonne et al 2000]. Cardiac involvement that 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 [Sanna et al 2003]. 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. In AD-EDMD, the risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilation and dysfunction is higher than in XL-EDMD [Bécane et al 2000, Bonne et al 2003, Boriani et al 2003, Draminska et al 2005, Pasotti et al 2008]. Individuals are at risk for cerebral emboli and sudden death [Boriani et al 2003]. A generalized dilated or hypertrophic cardiomyopathy often occurs. Age of onset, severity, and progression of the muscle and cardiac involvement demonstrate both inter- and intrafamilial variability [Mercuri et al 2000, Mercuri et al 2004, Carboni et al 2010]. Clinical variability ranges from early and severe presentation in childhood to late onset and a slowly progressive course. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually arises after the second decade of life. Respiratory function can be impaired in some individuals [Emery 2000, Mercuri et al 2000, Ben Yaou et al 2002, Talkop et al 2002, Mercuri et al 2004, Gueneau et al 2009]. On occasion, sudden cardiac death is the first manifestation of the disorder [Bécane et al 2000, Karkkainen et al 2004, De Backer et al 2010]. AR-EDMD. Only five individuals with genetically proven AR-EDMD (i.e., homozygous for a LMNA mutation) have been reported [Raffaele Di Barletta et al 2000, Jimenez-Escrig et al 2012]. The first reported individual, who had a homozygous c.664C>T LMNA mutation, initially experienced difficulties when he started walking at age 14 months as a result of severe muscular dystrophy and joint contractures. He was confined to a wheelchair by age 40 years but has had no known cardiac abnormalities [Raffaele Di Barletta et al 2000]. The four other individuals carrying a homozygous c.674G>A LMNA mutation belong to a Spanish family, in which one sibling [Jimenez-Escrig et al 2012] was incidentally diagnosed with AR-EDMD through exome sequencing. These individuals have severe muscular dystrophy in a limb-girdle distribution with joint contractures leading to ambulation loss in two of them at ages 25 and 35 years. Cardiac disease consists mainly of premature atrial and ventricular contractions and conduction defects.

Genotype-Phenotype CorrelationsEMD. The majority of EMD mutations are null mutations that result in complete absence of emerin expression in nuclei; however, intra- and interfamilial variability in the severity of the phenotype associated with null mutations may be observed [Muntoni et al 1998, Hoeltzenbein et al 1999, Canki-Klain et al 2000, Ellis et al 2000]. The few missense mutations that have been identified are associated with decreased or normal amounts of emerin and result in a milder phenotype [Yates et al 1999]. LMNA mutations do not show a clear genotype/phenotype correlation with regard to EDMD [Bonne et al 2000, Genschel & Schmidt 2000, Bonne et al 2003, Scharner et al 2010, Bertrand et al 2011]. Benedetti et al reported that individuals with early skeletal muscle involvement frequently have missense mutations, whereas those with later-onset muscle symptoms often have frameshift mutations, presumably leading to truncated protein or to nonsense-mediated decay [Benedetti et al 2007].Marked intra- and interfamilial variability is observed for the same LMNA mutation [Bécane et al 2000, Bonne et al 2000, Mercuri et al 2005, Carboni et al 2010]. For example, within the same family the same mutation can lead to AD-EDMD, LGMD1B, or isolated DCM-CD, i.e., laminopathies involving striated muscle [Bécane et al 2000, Brodsky et al 2000]. Homozygous LMNA mutations seem to lead to a more severe muscular phenotype, as three of the five reported individuals with homozygous LMNA mutations lost ambulation within the third to fifth decades of life [Raffaele Di Barletta et al 2000, Jimenez-Escrig et al 2012]. EMD and LMNA. Severe EDMD has been reported in individuals with mutations in both EMD and LMNA [Muntoni et al 2006]. A range of clinical presentations (i.e. CMT2, CMT2-EDMD, and isolated cardiomyopathy) were found in a large family in which mutations in EMD and LMNA cosegregate [Ben Yaou et al 2007, Meinke et al 2011].Modifier gene: A recent study showed that a possible modifier gene could modulate the age of onset of myopathic symptoms [Granger et al 2011].

Differential DiagnosisSome neuromuscular disorders result in a similar pattern of muscle involvement, joint contractures, or cardiac disease, but none features the triad observed in Emery-Dreifuss muscular dystrophy (EDMD). Scapulo-peroneal syndromes without contractures or cardiac disease Facioscapulohumeral muscular dystrophy (FSHD) Adult-onset scapulo-peroneal myopathy X-linked scapulo-peroneal muscular dystrophy linked to chromosome 12 [Wilhelmsen et al 1996, Quinzii et al 2008] Scapulo-peroneal spinal muscle atrophy linked to chromosome 12 [Isozumi et al 1996] Spinal muscle atrophy of Stark-Kaeser type [Kaeser 1965] Some forms of hyaline body myopathy [Masuzugawa et al 1997, Onengut et al 2004] Other myopathies with or without contractures and/or cardiac disease that can resemble AD-EDMD but have distinguishing featuresSYNE1- and SYNE2-related EDMD-like [Zhang et al 2007]. The cardiomuscular features associated with SYNE1 and SYNE2 variants reported in four families were reminiscent of those observed in EDMD (i.e., mainly cardiac disease) but do not fully fit with the typical EDMD phenotype [Zhang et al 2007 (see Supplementary Material)]. TMEM43-related myopathies. Liang et al reported two families in which three individuals had an "EDMD-related myopathy" caused by mutations in TMEM43 (encoding LUMA protein) [Liang et al 2011]. Due to the lack of detailed clinical information in two of these individuals and a patently non-EDMD phenotype in the third, these individuals should not be characterized as having EDMD until the phenotype of TMEM43-related myopathy has been more clearly delineated. Rigid spine syndrome [Moghadaszadeh et al 1999], especially selenopathies [Moghadaszadeh et al 2001, Ferreiro et al 2002] FKRP-related muscle diseases [Poppe et al 2003] (see Congenital Muscular Dystrophy Overview and Limb-Girdle Muscular Dystrophy Overview)Bethlem myopathy caused by collagen VI gene mutations [Bertini & Pepe 2002] (see Collagen Type VI-Related Disorders) Myotonic dystrophy type 1DystrophinopathiesLimb-girdle muscular dystrophies with cardiac involvement [Muntoni 2003] (see Limb-Girdle Muscular Dystrophy Overview) Desmin-related myopathies [Goldfarb et al 2004] (see Myofibrillar Myopathy) X-linked vacuolar myopathies with cardiomyopathy or Danon disease [Danon et al 1981] Myotonic dystrophy type 2 (proximal myotonic myopathy [PROMM]) [Udd et al 2003] Myopathy with maltase acid deficiency [Laforêt et al 2010]BAG3-related myofibrillar myopathy [Selcen et al 2009]Other disorders with distinguishing features Ankylosing spondylitis [Goncu et al 2003] Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).XL-EDMDAD-EDMD

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Emery-Dreifuss muscular dystrophy (EDMD), the following evaluations are recommended:ECG, Holter-ECG monitoring, echocardiography, radionucleotide angiography, and cardiac MRI. Electrophysiologic study is often advisable in EDMD; however, it is performed in selected individuals on the basis of the clinical presentation and the results of noninvasive studies and not as an "evaluation at initial diagnosis" in all individuals. Evaluation of respiratory function (vital capacity measurement and other pulmonary volume measurements) Evaluation of metabolic functions (glycemia, insulinemia, trigylceridemia) Medical genetics consultationTreatment of ManifestationsThe following are appropriate:Orthopedic surgeries to release Achilles tendons and other contractures or scoliosis as needed Use of mechanical aids (canes, walkers, orthoses, wheelchairs) as needed to help ambulation Specific treatments for cardiac features (arrhythmias, AV conduction disorders, and congestive heart failure), including antiarrhythmic drugs, cardiac pacemaker, implantable cardioverter defibrillator (ICD), and both pharmacologic and non-pharmacologic therapy for heart failure [Bécane et al 2000, Bonne et al 2003, Boriani et al 2003]. Heart transplantation may be necessary in the end stages of heart failure; some individuals may not be candidates for heart transplantation because of associated severe skeletal muscle and respiratory involvement. Use of respiratory aids (respiratory muscle training and assisted coughing techniques, mechanical ventilation) if indicated in late stages Prevention of Secondary ComplicationsPhysical therapy and stretching exercises promote mobility and help prevent contractures. When indicated, implantation of cardiac defibrillators can considerably reduce the risk of sudden death [Meune et al 2006].Antithromboembolic drugs (vitamin K antagonists, warfarin, heparin) are probably required to prevent cerebral thromboembolism of cardiac origin in those individuals with either decreased left ventricular function or atrial arrhythmias [Boriani et al 2003].SurveillanceThe following are appropriate:Annual cardiac assessment consisting of ECG, Holter monitoring, and echocardiography in order to detect asymptomatic cardiac disease. More advanced and invasive cardiac assessment may be required. Monitoring of respiratory function Agents/Circumstances to AvoidAlthough 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 have to be considered [Aldwinckle & Carr 2002]. Body weight should be monitored, as affected individuals may be predisposed to obesity.Evaluation of Relatives at RiskBecause of the high risk for cardiac complications (including sudden death) observed in individuals with LMNA mutations, cardiac evaluation of relatives is recommended [Bécane et al 2000, Boriani et al 2003, Taylor et al 2003]; however, in families with AD-EDMD and incomplete penetrance, no cardiac complications were reported in asymptomatic relatives [Vytopil et al 2002]. Cardiac evaluation is recommended for female carriers of an EMD or FHL1 mutation as they are at increased risk of developing cardiac complications [Manilal et al 1998, Canki-Klain et al 2000, Gueneau et al 2009, Knoblauch et al 2010]. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management In a woman with EDMD, pregnancy complications may include the development of cardiomyopathy or the 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.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Emery-Dreifuss Muscular Dystrophy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDEMDXq28EmerinThe UMD-EMD mutations database
EMD homepage - Leiden Muscular Dystrophy pagesEMDLMNA1q22Prelamin-A​/CHuman Intermediate Filament Database LMNA (lamin C1)
Human Intermediate Filament Database LMNA (lamin A)
Human Intermediate Filament Database LMNA (lamin C2)
IPN Mutations, LMNA
LMNA homepage - Leiden Muscular Dystrophy pagesLMNAFHL1Xq26​.3Four and a half LIM domains protein 1FHL1 homepage - Leiden Muscular Dystrophy pagesFHL1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Emery-Dreifuss Muscular Dystrophy (View All in OMIM) View in own window 150330LAMIN A/C; LMNA 181350EMERY-DREIFUSS MUSCULAR DYSTROPHY 2, AUTOSOMAL DOMINANT; EDMD2 300163FOUR-AND-A-HALF LIM DOMAINS 1; FHL1 300384EMERIN; EMD 300696MYOPATHY, X-LINKED, WITH POSTURAL MUSCLE ATROPHY; XMPMA 310300EMERY-DREIFUSS MUSCULAR DYSTROPHY 1, X-LINKED; EDMD1Molecular Genetic PathogenesisElucidation of the pathophysiology of Emery-Dreifuss muscular dystrophy (EDMD), caused by mutations in EMD, LMNA, SYNE1, SYNE2, and FHL1, still requires deciphering of the role of the proteins that they encode in the functional organization of the nuclear envelope.EMD and FHL1 mutations cause, in most cases, absence of emerin or FHL1 isoforms [Manilal et al 1998, Gueneau et al 2009]; a few EMD missense or in-frame deletions or insertions lead to aberrant targeting at the inner nuclear membrane and binding of emerin to lamins [Fairley et al 1999]. Missense LMNA mutations lead to expression of abnormal lamins A/C [Muchir et al 2004], whereas nonsense LMNA mutations result in haploinsufficiency with decreased amount of normal lamins A/C [Bonne et al 1999, Bécane et al 2000]. Analysis of cells or tissues from affected individuals have demonstrated an abnormal nuclear envelope with increased fragility [Manilal et al 1999, Muchir et al 2004, Reichart et al 2004] as well as chromatin alterations [Ognibene et al 1999, Sabatelli et al 2001, Sewry et al 2001, Fidzianska & Hausmanowa-Petrusewicz 2003, Fidzianska & Glinka 2007]. While hypotheses such as an increased susceptibility to apoptosis [Morris 2000] of muscle cell nuclei cannot be completely ruled out, two mechanisms (not necessarily mutually exclusive) could be involved in EDMD pathogenesis [Broers et al 2006, Worman & Bonne 2007, Worman et al 2009]: Structural mechanisms caused by mechanical stress present in skeletal muscle and cardiac muscleModification of gene expression relative to abnormal chromatin organization associated with alteration of proliferation/differentiation of muscle cellsIn line with the mechanical stress hypothesis, variants in SYNE1 and SYNE2 encoding nesprin proteins were identified in EDMD-like patients through a candidate gene approach; the nesprins link the cytoskeletal network to emerin and lamins proteins. Analysis of skin fibroblasts from affected individuals with SYNE mutations revealed nuclear morphology defects with diminished nuclear envelope localization of nesprins and impaired nesprin-/emerin-/lamin-binding interactions [Zhang et al 2007].Interactions of these nuclear envelope proteins with chromatin- and nuclear matrix-associated proteins are of particular interest. Both emerin and lamin A/C interact with nuclear actin, a component of the chromatin remodeling complex associated with the nuclear matrix, suggesting that either chromatin arrangement or gene transcription or both could be impaired in the disease [Maraldi et al 2002]. Numerous other interactions have been analyzed resulting in identification of transcription factors such as c-fos, pRb, and Lco1 as binding partners of Lamin A/C. These point toward possible deregulation of signaling pathways and alteration of proliferation/differentiation of muscle cells [Broers et al 2006, Vlcek & Foisner 2007, Worman & Bonne 2007].EMDNormal allelic variants. The gene has six exons; normal allelic variants have been identified.Pathologic allelic variants. More than 134 different mutations have been reported to date. See the UMD-EMD Database. The majority of mutations (95%) are null mutations: nonsense mutations, deletions/insertions, and splice site mutations that lead to exon skipping, frameshift, and premature arrest of translation and, thus to absence of emerin. A few missense mutations and in-frame deletions also exist, leading to decreased expression of emerin or to normal expression of a nonfunctional protein [Ellis et al 1998, Yates et al 1999, Yates & Wehnert 1999, Ellis et al 2000]. Most mutations are unique to a single family. On occasion, two or three families have the same mutation. No “hot-spot” for mutation is observed in EMD; mutations are nearly randomly spread out along the gene. (For more information, see Table A.) Normal gene product. Emerin is a 254-amino acid serine-rich protein expressed in most tissue. It belongs to a family of type II integral membrane proteins, including lamina-associated protein 2 (LP2; β-thymopoietin) and lamin B receptor. The hydrophobic tail anchors the protein to the inner nuclear membrane and the hydrophilic remainder of the molecule projects into the nucleoplasm, where it interacts with the nuclear lamina [Manilal et al 1996, Yorifuji et al 1997]. Emerin binds directly to lamins A/C and to BAF (BANF1; OMIM 603811), a DNA-bridging protein. This binding requires conserved residues in a central lamin A-binding domain and the N-terminal LEM domain of emerin, respectively [Clements et al 2000, Lee et al 2001]. BAF is required for the assembly of emerin and A-type lamins at the reforming nuclear envelope during telophase of mitosis and may mediate their stability in the subsequent interphase [Haraguchi et al 2001]. Abnormal gene product. In most cases, null mutations lead to premature arrest of translation with no protein product. In the rare cases in which protein is expressed, either the gene product is lacking the transmembrane domain (in-frame distal deletions) and is not able to target the nuclear membrane and thus is delocalized in the nucleoplasm or cytoplasm, or the mutated protein is present at the nuclear rim (missense mutations) but has weakened interactions with the lamina components [Ellis et al 1999, Fairley et al 1999, Ellis et al 2000]. FHL1Normal allelic variants. The gene has eight exons; normal allelic variants have been identified. Pathologic allelic variants. Seven EDMD-causing mutations in FHL1 are reported to date [Gueneau et al 2009, Knoblauch et al 2010], localized in the distal exons of FHL1: two missense mutations affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions. Mutations were preferentially located in the most distal exons of FHL1 (exons 5-8), thus affecting the three isoforms [Gueneau et al 2009]. (For more information, see Table A.)Normal gene product. Three FHL1 isoforms are produced by alternative splicing of FHL1. FHL1 proteins belong to a protein family containing four and a half LIM domains (Lin-11, Isl-1, Mec3), which are highly conserved sequences comprising two zinc fingers in tandem, implicated in numerous interactions. Each of the two zinc fingers contains four highly conserved cysteines linking together one zinc ion [Kadrmas & Beckerle 2004]. The main isoform FHL1A is predominantly expressed in striated muscles [Lee et al 1998, Taniguchi et al 1998]. The two other (less abundant) isoforms, FHL1B and FHL1C, are expressed in striated muscles [Brown et al 1999, Ng et al 2001]. FHL1A, FHL1B, and FHL1C are, respectively, composed of 4.5, 3.5, and 2.5 LIM domains. Alternative splicing leads to different domains in the C-terminal part of FHL1B and FHL1C, which correspond to nuclear import and export signals in FHL1B and to the RBP-J binding domain in FHL1B and FHL1C [Brown et al 1999, Ng et al 2001]. FHL1A can be localized to the sarcolemma, sarcomere, and nucleus of muscle cells [Brown et al 1999, Ng et al 2001]. It has been implicated in sarcomere assembly by interacting with myosin binding protein-C [McGrath et al 2006]. Abnormal gene product. The EDMD-causing mutations in FHL1 differently affect the three FHL1 protein isoforms, being located in alternatively spliced exons. The missense mutations affect highly conserved cysteine important for the zinc finger conformation and lead to variable expression level of mutant protein in muscles of affected individuals. The out-of-frame insertions or deletions give rise to truncated mutant proteins that are expressed in tissues of affected individuals at a very low level. In two individuals for whom myoblasts were available, functional studies demonstrated severe delay in myotube formation [Gueneau et al 2009].LMNANormal allelic variants. An incomplete list of normal allelic variants is available at Leiden Muscular Dystrophy pages^©.Pathologic allelic variants. More than 458 LMNA mutations are reported to date. See the UMD-LMNA Database [Bonne et al 2003], Leiden Muscular Dystrophy pages^©, and Table A. The majority of mutations (85%) are missense mutations. Nonsense mutations, small deletions/insertions in-frame or with frameshift, and splice-site mutations also occur. Mutations are distributed along the length of the gene [Bonne et al 2000, Brown et al 2001]. A few recurrent mutations exist [Broers et al 2006]. (For more information, see Table A.)Table 2. Selected LMNA Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.664C>Tp.His222Tyr ^{1NM_005572​.3c.674G>Ap.Arg225GlnSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. See Genotype-Phenotype Correlations.Normal gene product. Four A-type lamins (A, AΔ10, C, and C2) exist and are products of LMNA by alternative splicing. Lamin A and lamin C are the two main isoforms. They are initially expressed in muscle of the trunk, head, and appendages. Later, they are ubiquitously expressed. However, a few myeloid and lymphoid cell lines have no lamins. Lamin C2 was described in murine and human germ cells [Alsheimer & Benavente 1996]. The promoter 1C2 located in the first intron of LMNA allows transcription of lamin C2. The fourth lamin is lamin AΔ10 (missing exon 10) described in cancer cells [Machiels et al 1996]. Lamins are type-V intermediate filaments that form the nuclear lamina, a fibrous network underlying the inner face of the internal nuclear membrane. Abnormal gene product. Missense mutations (majority of cases) lead to mutant protein of normal size carrying one modified amino acid. Western blot analysis of fibroblasts of affected individuals demonstrates a normal level of protein expression, strongly suggesting that mutant proteins are expressed [Muchir et al 2004]. Nonsense mutations lead to haploinsufficency with expression of only the normal allele (~50% of normal protein levels); the mutant allele is either not translated (because of degradation of abnormal mRNA) or is translated and degraded [Bécane et al 2000, Muchir et al 2003].}