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Emery-Dreifuss Muscular Dystrophy

, PhD, , MD, and , MD.

Author Information
, PhD
INSERM, UMRS974
Université Pierre et Marie Curie-Paris 6, UM 76, CNRS, UMR7215, Institut de Myologie, IFR14
AP-HP, Groupe Hospitalier Pitié-Salpêtrière
UF Cardiogénétique et Myogénétique
Service de Biochimie Métabolique
Paris, France
, MD
AP-HP, Laboratoire de Biochimie & Génétique Moléculaire
Hôpital Cochin
Paris, France
, MD
INSERM, UMRS974
Université Pierre et Marie Curie-Paris 6, UM 76, CNRS, UMR7215, Service des Essais Cliniques et des Bases de Données
Institut de Myologie
Paris, France

Initial Posting: ; Last Update: January 17, 2013.

Summary

Disease 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. 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.

Diagnosis/testing. The three genes in which mutations are known to cause EDMD are EMD (encoding emerin) and FHL1 (encoding FHL1), which cause X-linked EDMD (XL-EDMD); and LMNA (encoding lamin A and C), which causes autosomal dominant EDMD (AD-EDMD) and autosomal recessive EDMD (AR-EDMD). For all forms of EDMD the diagnosis is based on clinical findings and family history. The diagnosis of X-linked EDMD also relies on failure to detect emerin or FHL1 protein in various tissues and molecular genetic testing of EMD or FHL1. The diagnosis of AD-EDMD and AR-EDMD also relies on molecular genetic testing of LMNA.

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

Prevention of primary manifestations: Physical therapy and stretching to prevent contractures; implantation of cardiac defibrillators to reduce risk for sudden death.

Prevention of secondary complications: Antithromboembolic drugs to prevent cerebral thromboembolism of cardiac origin in those with decreased left ventricular function or atrial arrhythmias.

Surveillance: At a minimum, annual cardiac assessment (ECG, 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: Cardiac evaluation for relatives at risk for AD-EDMD and female carriers of XL-EDMD.

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

  • XL-EDMD. If the mother of a proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers. Female carriers are usually asymptomatic, but they are at risk of developing a cardiac disease, progressive muscular dystrophy, and/or an EDMD phenotype.
  • AD-EDMD. 76% of probands with AD-EDMD have a de novo LMNA mutation. Each child of an individual with AD-EDMD has a 50% chance of inheriting the mutation.
  • 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.

Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in a family member.

Diagnosis

Clinical Diagnosis

The 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:

Testing

Other 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 Testing

Genes. 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.

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 Dystrophy

Gene Symbol% of EDMD Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency 1
EMD~61% of XL-EDMD 2Sequence analysis or mutation scanning 3Sequence variants 499% 5, 6, 7, 8
Deletion / duplication analysis 9, 10Deletion of exon(s) or entire gene
FHL1~10% of XL-EDMD 2Sequence analysis or mutation scanning 3Sequence variants 499% 6, 7, 8, 11
LMNA~45% of AD-EDMD; unknown for AR-EDMD 12Sequence analysis or mutation scanning 3Sequence variants 499% 13, 14
Deletion / 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 gene

2. 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 tissue

7. 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 Strategy

To 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 testing

  • X-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.

Clinical Description

Natural History

AD-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 Correlations

EMD. 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].

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].

Penetrance

Five LMNA mutations were reported with incomplete penetrance in families with AD-EDMD or other LMNA-related disorders [Vytopil et al 2002, Rankin et al 2008].

Anticipation

Anticipation has not been observed to date.

Prevalence

The overall prevalence of EDMD is not known.

The prevalence of XL-EDMD is estimated at 1:100,000.

Heterozygous LMNA mutations causing AD-EDMD are more common than EMD mutations causing XL-EDMD.

Hopkins & Warren [1992] estimated EDMD to be the third most prevalent muscular dystrophy, with the two dystrophinopathies, Duchenne muscular dystrophy and Becker muscular dystrophy, being the two most prevalent.

Differential Diagnosis

Some 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

Other myopathies with or without contractures and/or cardiac disease that can resemble AD-EDMD but have distinguishing features

Other disorders with distinguishing features

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 consultation

Treatment of Manifestations

The 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 Complications

Physical 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].

Surveillance

The 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 Avoid

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). 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 Risk

Because 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 Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Emery-Dreifuss muscular dystrophy (EDMD) is inherited in an X-linked (XL-EDMD), autosomal dominant (AD-EDMD), or autosomal recessive (AR-EDMD) manner.

Note: Because AR-EDMD is rare, details of genetic counseling issues are not provided here.

Risk to Family Members — XL-EDMD

Parents of a proband

Sibs of a proband

Offspring of a proband

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation has been identified in the family.

Risk to Family Members — AD-EDMD

Parents of a proband

  • Some individuals diagnosed with AD-EDMD have an affected parent.
  • A proband with AD-EDMD often has the disorder as the result of a de novo mutation. Bonne et al [2000] reported that 76% of mutations were de novo.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical evaluation – in particular, cardiac investigations and molecular genetic testing.

Note: Although some individuals diagnosed with AD-EDMD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

Offspring of a proband. Each child of an individual with AD-EDMD has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

X-linked EDMD. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in a family member. The usual procedure is to determine the sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

AD-EDMD and AR-EDMD. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in a family member. Analysis of DNA extracted from fetal cells obtained by amniocentesis is usually performed at about 15 to 18 weeks' gestation or CVS at about ten to 12 weeks' gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry 91002
    France
    Phone: +33 01 69 47 28 28
    Fax: 01 69 47 77 12 16
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    JN Baarn 3743
    Netherlands
    Phone: 035 54 80 481
    Fax: 035 54 80 499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • World Muscle Society (WMS)
    ICSM Hammersmith Campus
    Du Cane Road
    London W12 ONN
    United Kingdom
    Email: j.miller@ic.ac.uk

Molecular Genetics

Information 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 Databases

Data 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)

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; EDMD1

Molecular Genetic Pathogenesis

Elucidation 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 muscle
  • Modification of gene expression relative to abnormal chromatin organization associated with alteration of proliferation/differentiation of muscle cells

In 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].

EMD

Normal 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].

FHL1

Normal 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].

LMNA

Normal 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 Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.664C>Tp.His222Tyr 1NM_005572​.3
c.674G>Ap.Arg225Gln

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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].

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Suggested Reading

  1. Ben Yaou R, Gueneau L, Demay L, Stora S, Chikhaoui K, Richard P, Bonne G. Heart involvement in lamin A/C related diseases. Arch Mal Coeur Vaiss. 2006;99:848–55. [PubMed: 17067107]
  2. Ben Yaou R, Muchir A, Arimura T, Massart C, Demay L, Richard P, Bonne G. Genetics of laminopathies. Novartis Found Symp. 2005;264:81–90. [PubMed: 15773749]
  3. Bonne G, Lampe AK. Muscle diseases with prominent muscle contractures. In: Karpati G, Hilton-Jones D, Griggs RC, Bushby K, eds. Disorders of Voluntary Muscle. 8 ed. Cambridge, UK: Cambridge University Press; 2010:299-313.
  4. Decostre V, Ben Yaou R, Bonne G. Laminopathies affecting skeletal and cardiac muscles: clinical and pathophysiological aspects. Acta Myol. 2005;24:104–9. [PubMed: 16550926]
  5. Gruenbaum Y, Margalit A, Goldman RD, Shumaker DK, Wilson KL. The nuclear lamina comes of age. Nat Rev Mol Cell Biol. 2005;6:21–31. [PubMed: 15688064]
  6. Worman HJ, Ostlund C, Wang Y. Diseases of the nuclear envelope. Cold Spring Harb Perspect Biol. 2010;2:a000760. [PMC free article: PMC2828284] [PubMed: 20182615]

Chapter Notes

Acknowledgments

Authors are coordinators (GB, FL) or members (RBY) of the French networks for rare diseases on "EDMD and other nuclear envelope pathologies," network supported by AFM (Association Française contre les Myopathies, grant #10722 and #12325). GB and RBY are members of the European consortium "Euro-Laminopathies" supported by an EU-FP7 grant (#018690). GB, FL, RBY are supported by the Institut National de la Santé et de la Recherche Médicale, the Assistance Publique des Hôpitaux de Paris, the Centre National de la Recherche Scientifique and the Universités Paris V and Paris VI.

Author History

Rabah Ben Yaou, MD (2004-present)
Gisèle Bonne, PhD (2004-present)
France Leturcq, MD (2004-present)
Dominique Récan-Budiartha, MD; Hôpital Cochin (2004-2010)

Revision History

  • 17 January 2013 (me) Comprehensive update posted live
  • 24 August 2010 (cd) Revision: sequence analysis and prenatal testing for FHL1 mutations available clinically
  • 15 June 2010 (me) Comprehensive update posted live
  • 21 November 2007 (cd) Revision: LMNA deletion/duplication testing available clinically
  • 26 April 2007 (me) Comprehensive update posted to live Web site
  • 29 September 2004 (me) Review posted to live Web site
  • 27 January 2004 (gb) Original submission
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