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Emery-Dreifuss Muscular Dystrophy

, PhD, , MD, and , MD.

Author Information

Initial Posting: ; Last Update: August 15, 2019.

Estimated reading time: 37 minutes

Summary

Clinical characteristics.

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

Diagnosis/testing.

The diagnosis of EDMD is established in a proband with:

  • A clearly relevant clinical picture including limb muscle wasting and/or weakness and elbow or neck/spine joint contractures (cardiac disease may be missing in the first decades of life); AND
  • A hemizygous pathogenic variant in EMD or FHL1, a heterozygous pathogenic variant in LMNA, or (more rarely) biallelic pathogenic variants in LMNA identified by molecular genetic testing.

Management.

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

Surveillance: At a minimum, annual cardiac assessment (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: Molecular genetic testing if the pathogenic variant(s) in the family are known; clinical evaluation, including at least muscular and cardiac assessments if the pathogenic variant(s) in the family are not known.

Genetic counseling.

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

  • XL-EDMD. If the mother of a proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous. Heterozygous females are usually asymptomatic but are at risk of developing a cardiac disease, progressive muscular dystrophy, and/or an EDMD phenotype.
  • AD-EDMD. 65% of probands with AD-EDMD have a de novo LMNA pathogenic variant. Each child of an individual with AD-EDMD has a 50% chance of inheriting the pathogenic variant.
  • AR-EDMD. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier.

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

Diagnosis

Suggestive Findings

Emery-Dreifuss muscular dystrophy (EDMD) should be suspected in individuals with 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.

Age of onset. Onset usually occurs between age five and ten years, rarely before age five years.

Family history. May be positive (autosomal dominant, X-linked, or, rarely, autosomal recessive). However, simplex cases due to de novo genetic events are not rare.

Note: Diagnosis guidelines have been published [Emery 1997, Bonne et al 2002b, Madej-Pilarczyk 2018].

Establishing the Diagnosis

The diagnosis of EDMD is established in a proband with a clearly relevant clinical picture including limb muscle wasting and/or weakness and elbow or neck/spine joint contractures (cardiac disease may be missing in the first decades of life) and a hemizygous pathogenic variant in EMD or FHL1, a heterozygous pathogenic variant in LMNA, or (more rarely) biallelic pathogenic variants in LMNA identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of EDMD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical features in whom the diagnosis of EDMD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of EDMD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

The likelihood of identifying a causative variant in EMD, FHL1, or LMNA is dependent on known or suspected mode of inheritance.

  • In cases of X-linked inheritance, EMD-related disease is most likely, followed by FHL1.
  • In cases of autosomal dominant or recessive inheritance, LMNA-related disease is most likely.
  • In the absence of a clear inheritance pattern, LMNA-related disease is most likely followed by EMD- and then FHL1-related disease.

In an affected female who represents a simplex case (i.e., a single occurrence in a family) LMNA-related disease is more likely than an X-linked disorder. Carrier females rarely manifest X-linked EDMD (XL-EDMD); thus, affected females are much more likely to have AD-EDMD.

A multigene panel that includes EMD, FHL1, LMNA, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of EDMD is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Emery-Dreifuss Muscular Dystrophy (EDMD)

Gene 1, 2Proportion of EDMD Attributed to Pathogenic Variants in Gene 3Proportion of Pathogenic Variants 4 Detectable by This Method
Sequence analysis 5Gene-targeted deletion/duplication analysis 6
EMD8.5%99% 7Rare 8, 9
FHL11.2%99% 10Rare 7, 11
LMNA26.5%%99% 12None reported 13
Unknown63.4%NA
1.

Genes are listed in alphabetic order.

2.
3.
4.

See Molecular Genetics for information on allelic variants detected in this gene.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.
8.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by deletion/duplication analysis.

9.
10.
11.
12.
13.

Intragenic LMNA deletions and duplications have been associated with cardiomyopathy.

Clinical Characteristics

Clinical Description

AD-EDMD and XL-EDMD

Autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) and X-linked EDMD (XL-EDMD) have similar but not identical neuromuscular and cardiac involvement [Yates et al 1999, Bonne et al 2000, Bonne et al 2002b, Boriani et al 2003, Astejada et al 2007, Gueneau et al 2009, Cowling et al 2011, Carboni et al 2012b, Madej-Pilarczyk 2018].

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 posterior 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 due to muscle weakness can occur in AD-EDMD but is rare in XL-EDMD [Bonne et al 2000].
  • Cardiac involvement usually appears within the end of the second to third decades of life and 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 [Bécane et al 2000, Boriani et al 2003, Sanna et al 2003, Sakata et al 2005, Astejada et al 2007, Carboni et al 2012b].
    • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation.
    • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent.
    • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilation and dysfunction is higher in AD-EDMD than in XL-EDMD.
    • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [Boriani et al 2003, Redondo-Vergé et al 2011, Homma et al 2018].
    • A generalized dilated (in LMNA- or EMD-related EDMD) or hypertrophic cardiomyopathy (in FHL1-related EDMD) often occurs.

Other clinical findings may be nonspecific:

  • Electromyogram usually shows myopathic features with normal nerve conduction studies, but neuropathic patterns have been described for both XL-EDMD [Hopkins et al 1981] and AD- EDMD [Witt et al 1988].
  • CT scan of muscle. 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 2012a]. A similar pattern of muscle fatty infiltration was reported and mainly involves paravertebral, gluteal, quadriceps, biceps, semitendinosus, semimembranosus, adductor major, soleus, and gastrocnemius muscles [Díaz-Manera et al 2016].

Other 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 2002a].
  • 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 [Fidziańska et al 1998, Sabatelli et al 2001, Sewry et al 2001, Fidziańska & Hausmanowa-Petrusewicz 2003, Fidziańska & 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].

Variability. 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. In a large published series of affected individuals, Astejada et al [2007] found a range of onset of 10.1 ± 9.5 and 3.3 ± 2.9 years respectively in 20 individuals with pathogenic variants in EMD and 27 individuals with pathogenic variants in LMNA.

Progression. Cardiac involvement usually arises after the second decade of life. Respiratory function can be impaired in some individuals [Emery 2000, Mercuri et al 2000, Talkop et al 2002, Mercuri et al 2004, Ben Yaou et al 2007, Gueneau et al 2009]. On occasion, sudden cardiac death is the first manifestation of the disorder [Bécane et al 2000, Kärkkäinen et al 2004, De Backer et al 2010].

AR-EDMD

Nine individuals with genetically confirmed isolated autosomal recessive EDMD (i.e., homozygous or compound heterozygous for a LMNA pathogenic variant) have been reported [Raffaele Di Barletta et al 2000, Brown et al 2001, Vytopil et al 2002, Mittelbronn et al 2006, Scharner et al 2011, Jimenez-Escrig et al 2012, Sframeli et al 2017] (see Table 2). When reported, heterozygous relatives were asymptomatic.

Table 2.

Clinical Characteristics in Ten Reported Individuals with Biallelic LMNA Pathogenic Variants

Reference# of Reported IndividualsOnsetLast Muscular AssessmentHeart Involvement
AgeSymptomsAgeFindings
Raffaele Di Barletta et al [2000]114 mosWalking difficulties40 yrsInitial wheelchair use at age 4 yrs; severe & diffuse muscle wasting, wheelchair boundNone
Brown et al [2001]13 yrsNot reported12 yrsProximal upper & distal lower limb weakness; ankle, elbow, & knee contracturesNone
Vytopil et al [2002]1ChildhoodStumbled frequently; slower than peers16 yrsHead flexion & scapulo-humero-peroneal weakness; stiff neck; ankle, hip, & elbow contracturesPolymorphic ventricular premature beats; salvos of atrial premature beats
Scharner et al [2011]1<1 yrNot reported6 yrsProximal upper & limb-girdle weakness; stiff neck; elbow, ankle, & knee contracturesCardiomyopathy from age 3 yrs
Jimenez-Escrig et al [2012]414 yrsDifficulty in running50 yrsInitial wheelchair use at age 35 yrs; stiff neck; ankle & elbow contracturesSupraventricular premature beats
12 yrsClumsy gait46 yrsStill ambulant; elbow & ankle contracturesSupraventricular & ventricular premature beats
4 yrsDifficulty rising from the floor43 yrsWheelchair use at age 25 yrs; elbow, hip, & ankle contracturesSupraventricular & ventricular premature beats
3rd decadeNot reported41 yrsStill ambulant w/cane; lower- & upper-limb proximal weakness; no contracturesSupraventricular premature beats
Sframeli et al [2017]1Early childhoodMobility difficultiesChildUpper- & lower-limb weakness; elbow & ankle contracturesNone

Genotype-Phenotype Correlations

EMD. Intra- and interfamilial variability in the severity of clinical features are observed. However,

LMNA. Marked intra- and interfamilial variability is observed for the same LMNA pathogenic variant [Bécane et al 2000, Bonne et al 2000, Mercuri et al 2005, Carboni et al 2010]. For example, within the same family the same pathogenic variant can lead to AD-EDMD, LGMD1B, or isolated DCM-CD (i.e., laminopathies involving striated muscle) [Bécane et al 2000, Brodsky et al 2000, Granger et al 2011]. However,

EMD and LMNA. Severe EDMD has been reported in individuals with pathogenic variants in both EMD and LMNA [Muntoni et al 2006, Meinke et al 2011]. A range of clinical presentations (i.e., CMT2, CMT2-EDMD, and isolated cardiomyopathy) were found in a large family in which pathogenic variants in EMD and LMNA cosegregate [Ben Yaou et al 2007, Meinke et al 2011].

FHL. No definite genotype-phenotype correlations for FHL1 have been identified.

Penetrance

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

Prevalence

The prevalence of XL-EDMD has been estimated at 0.13:100,000-0.2:100,000 [Norwood et al 2009]. This form of EDMD accounts for approximately 10% of the total cases of EDMD (see Table 1). Therefore, the prevalence of EDMD of all types is estimated to be 1.3:100,000-2:100,000.

Differential Diagnosis

Some neuromuscular disorders result in a similar pattern of muscle involvement, joint contractures, or cardiac disease, but most do not feature the complete triad observed in Emery-Dreifuss muscular dystrophy (EDMD).

Table 3.

Disorders to Consider in the Differential Diagnosis of Emery-Dreifuss Muscular Dystrophy

Disorder NameGene(s)MOI 1Clinical Findings
Muscle involvementJoint contracturesCardiac diseaseDistinguishing feature(s)
Facioscapulohumeral muscular dystrophyDNMT3B
DUX4L1
SMCHD1
AD+++ (scapulo-peroneal)No joint contractures or cardiac disease
Other scapuloperoneal syndromes
(neurogenic & myopathic types)
(OMIM 181400, 181405, 181430, 608358, 255160)
DES
MYH7
TRPV4
AD
AR
+++
(DES, MYH)
++
(DES, MYH)
  • No joint contractures (DES, MYH)
  • No cardiac disease (TRPV4)
SYNE1-related disorders
(OMIM 612998)
SYNE1AD±++±Unavailable (pending description of clear phenotype)
SYNE2-related disorders
(OMIM 612999)
SYNE2AD±_±No joint contractures
TMEM43-related myopathies
(OMIM 614302)
TMEM43AD+++±±Unavailable (pending description of clear phenotype)
SUN1-related disorders
(OMIM 613569)
SUN1AD++++No cardiac disease
Multiminicore disease (rigid spine syndrome)
(OMIM 602771)
SELENON
(SEPN1)
AR+++++
  • No cardiac disease
  • Early & severe respiratory failure
TTN-related myopathies
(see Salih Myopathy, Hereditary Myopathy w/Early Respiratory Failure, Udd Distal Myopathy)
TTNAD
AR
++++++±
  • Variably present cardiac disease
  • Severe respiratory involvement
  • Specific muscle pathology
LAMA2-related muscular dystrophyLAMA2AR+++++±Leukodystrophy
FKRP-related muscle diseases
(OMIM 606596)
FKRPAR+++±±
  • Variably present cardiac disease
  • Possible CNS involvement
Collagen type VI-related Bethlem myopathyCOL6A1
COL6A2
COL6A3
AD+++++
  • No cardiac disease
  • Specific muscle imaging pattern
Myotonic dystrophy type 1DMPKAD+++++
  • No joint contractures
  • Myotonia
DystrophinopathiesDMDXL+++++No joint contractures or conduction defects / arrhythmias
Limb-girdle muscular dystrophies w/cardiac involvement>50 genes 2AR
AD
+++++No joint contractures
Desmin-related myopathies (OMIM 601419)DESAD+++++No joint contractures
X-linked vacuolar myopathies w/ cardiomyopathy
(OMIM 300257)
LAMP2XL+++++No joint contractures
Myotonic dystrophy type 2CNBPAD+++++No joint contractures
Myopathy with maltase acid deficiencyGAAAR+++++ (rare cases)
  • No joint contractures
  • Peculiar muscle pathology
BAG3-related myofibrillar myopathy
(OMIM 612954)
BAG3AD+++++++
  • Peculiar muscle pathology
  • Peripheral neuropathy
Ankylosing spondylitisAcquired disease++ (spine)±No overt muscle involvement or limb joint contractures

AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; XL = X-linked

1.

Typical MOI; exceptions occur

2.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Emery-Dreifuss muscular dystrophy (EDMD), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Emery-Dreifuss Muscular Dystrophy

System/ConcernEvaluationComment
Cardiac
  • ECG
  • Holter-ECG monitoring
  • Echocardiography
  • Cardiac MRI
  • Electrophysiologic study
RespiratoryEvaluation of respiratory function (vital capacity measurement & other pulmonary volume measurements)
MusculoskeletalEvaluation of joints by a physical therapist or orthopedist to determine need for appropriate therapiesTherapies may incl physiotherapy, mechanical aids, orthopedic surgeries
Metabolic functionsEvaluation of metabolic functions (glycemia, insulinemia, cholesterolemia, trigylceridemia)Rarely, an individual w/LMNA EDMD has overlapping LMNA phenotype & partial lipodystrophy features, requiring careful metabolic assessment [Garg et al 2002, van der Kooi et al 2002].
OtherConsultation w/clinical geneticist &/or genetic counselor

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with Emery-Dreifuss Muscular Dystrophy

Manifestation/
Concern
TreatmentConsiderations/Other
CardiacSpecific for cardiac issue in the individual; can include antiarrhythmic drugs, cardiac pacemaker, implantable cardioverter defibrillator, & both pharmacologic & non-pharmacologic therapy for heart failureHeart transplantation may be necessary in end stages of heart failure; some individuals may not be candidates for transplantation because of associated severe skeletal muscle & respiratory involvement.
RespiratoryUse of respiratory aids (respiratory muscle training & assisted coughing techniques, mechanical ventilation) if indicated in late stages
Musculoskeletal
  • Orthopedic surgeries to release Achilles tendons & other contractures or scoliosis as needed
  • Mechanical aids (canes, walkers, orthoses, wheelchairs) as needed to help ambulation
  • Physical therapy & stretching exercises to promote mobility & help prevent contractures

Surveillance

Table 6.

Recommended Surveillance for Individuals with Emery-Dreifuss Muscular Dystrophy

System/ConcernEvaluationFrequency
Cardiac
  • ECG, Holter monitoring, & echocardiography to detect asymptomatic cardiac disease
  • More advanced & invasive cardiac assessment may be required for those w/cardiac disease.
Annual
RespiratoryPulmonary function testsIf normal, every 2-3 yrs; if abnormal, annually

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 must be considered [Aldwinckle & Carr 2002].

Body weight should be monitored, as affected individuals may be predisposed to obesity.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic at-risk sibs, parents, and relatives of individuals with EDMD because of the high risk for cardiac complications (including sudden death) associated with EDMD. Evaluation may allow early identification of family members who would benefit from initiation of treatment and preventive measures [Manilal et al 1998, Bécane et al 2000, Boriani et al 2003, Maioli et al 2007, Gueneau et al 2009, Scharner et al 2011, Jimenez-Escrig et al 2012, Stallmeyer et al 2012, Madej-Pilarczyk et al 2018].

Evaluations can include:

  • Molecular genetic testing if the pathogenic variant(s) in the family are known;
  • Clinical evaluation, including at least muscular and cardiac assessments if the pathogenic variant(s) in the family are not known.

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 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 in the US and EU Clinical Trials Register in Europe for 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), an autosomal dominant (AD-EDMD), or, rarely, an autosomal recessive (AR-EDMD) manner.

X-Linked Inheritance

Risk to Family Members

Parents of a male proband

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

Offspring of a proband. Affected males transmit the EMD or FHL1 pathogenic variant to:

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 heterozygotes or of being affected.

Heterozygote Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the EMD or FHL1 pathogenic variant has been identified in the proband.

Note: Females heterozygous for an EMD or FHL1 pathogenic variant are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [Gueneau et al 2009, Knoblauch et al 2010]. (See Evaluation of Relatives at Risk.)

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
  • If the LMNA pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but slightly greater than that of the general population because of the possibility of parental germline mosaicism.
  • If the parents have not been tested for the LMNA pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for AD-EDMD because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

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

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 and/or has the pathogenic variant, his or her family members are at risk.

Autosomal Recessive Inheritance

Risk to Family Members

Parents of a proband

Sibs of a proband

  • 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 unaffected and not a carrier.
  • Heterozygotes are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [Jimenez-Escrig et al 2012]. (See Evaluation of Relatives at Risk.)

Offspring of a proband. The offspring of an individual with AR-EDMD are obligate heterozygotes for a pathogenic variant in LMNA.

Other family members. Each sib of the proband’s parents is at a 50% risk of being heterozygous for an LMNA pathogenic variant.

Heterozygote Detection

Molecular genetic testing for at-risk relatives requires prior identification of the LMNA pathogenic variants in the family.

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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with AD-EDMD has the LMNA pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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 heterozygotes, or are at risk of being heterozygotes.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

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

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 cedex 91002
    France
    Phone: +33 01 69 47 28 28
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Netherlands
    Phone: 31 35 5480481
    Fax: 31 35 5480499
    Email: enmc@enmc.org
  • Japan Muscular Dystrophy Association
    3-43-11 Fukushi Zaidan Bldg
    Tokyo 170-0005
    Japan
    Phone: 81-3-6907-3521
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.org

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 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 Pathogenesis

The genes EMD, LMNA, and FHL1 – pathogenic variants in which cause Emery-Dreifuss muscular dystrophy (EDMD) – encode proteins critical for the organization of the nuclear envelope. Although not entirely elucidated, two main mechanisms (not necessarily mutually exclusive) are thought to be involved in EDMD pathogenesis [Broers et al 2006, Worman & Bonne 2007, Worman et al 2009]:

  • Structural strain caused by mechanical stress present in skeletal muscle and cardiac muscle
  • Modification of gene expression caused by abnormal chromatin organization associated with alteration of proliferation/differentiation and/or signaling pathways of muscle cells

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].

EMD

Gene structure. The gene has six exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 130 different pathogenic variants have been reported to date (see the UMD-EMD Database). The majority of pathogenic variants (95%) are null variants: nonsense variants, deletions/insertions, and splice site variants. A few reported missense variants and in-frame deletions lead 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 pathogenic variants are unique to a single family. On occasion, two or three families have the same pathogenic variant. No "hot spot" for pathogenic variants is observed in EMD; pathogenic variants 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 tissues. 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 (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. Most pathogenic variants result in no emerin production. In the rare cases in which protein is expressed, either the gene product is lacking the transmembrane domain (in-frame distal deletions) resulting in mislocalization of the protein in the nucleoplasm or cytoplasm, or the abnormal protein is present at the nuclear rim (missense variants) but has weakened interactions with the lamina components [Ellis et al 1999, Fairley et al 1999, Ellis et al 2000].

FHL1

Gene structure. The gene has eight exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Of the more than 40 disease-associated variants reported in FHL1, seven have been associated with EDMD [Gueneau et al 2009, Knoblauch et al 2010]. EDMD-associated variants are localized in the distal exons (5-8) of FHL1: two missense variants affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions [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 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]. 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].

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. FHL1B and FHL1C have different C-terminal domains, 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].

Abnormal gene product. Pathogenic variants in FHL1 affect FHL1 isoforms differently since they are located in alternatively spliced exons:

  • Missense variants affect highly conserved cysteine residues important for the zinc finger conformation and lead to variable expression level of mutated protein in muscles of affected individuals.
  • Loss-of-function variants are expressed at a very low level. In myoblasts from affected individuals myotube formation was severely delayed [Gueneau et al 2009].

LMNA

Gene structure. LMNA encodes four transcripts via alternative splicing – two major transcripts: the full-length lamin A (exon 1-12) and a shorter transcript lamin C (exon 1-10); and two minor transcripts: lamin A-delta-10, which lacks exon 10, and lamin C2, which has a different N-terminal start (alternative exon 1) from lamin C. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 450 LMNA pathogenic variants are reported to date. See the UMD-LMNA Database [Bonne et al 2003] and Leiden Muscular Dystrophy pages©. The majority (85%) of pathogenic variants are missense variants. Nonsense variants, small deletions/insertions in-frame or with frameshift, and splice site variants also occur. Pathogenic variants are distributed along the length of the gene [Bonne et al 2000, Brown et al 2001]. A few recurrent pathogenic variants exist [Broers et al 2006]. (For more information, see Table A.)

Pathogenic variants associated with autosomal recessive (AR) disease generally occur at different residues from those responsible for autosomal dominant (AD) disease. As yet, variants cannot be predicted to cause AR or AD disease.

Table 7.

Selected LMNA Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.664C>Tp.His222Tyr 1NM_005572​.3
c.674G>Ap.Arg225Gln

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

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

1.

Normal gene product. Four A-type lamins (A, AΔ10, C, and C2) are produced by LMNA 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. A few myeloid and lymphoid cell lines have no lamins.

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 [Alsheimer & Benavente 1996, 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.

Transcription factors such as c-fos, pRb, and Lco1 have been identified as binding partners of Lamin A/C, suggesting possible deregulation of signaling pathways and alteration of proliferation/differentiation of muscle cells [Broers et al 2006, Vlcek & Foisner 2007, Worman & Bonne 2007, Azibani et al 2014].

Abnormal gene product. Missense variants are reported in the majority of cases. Western blot analysis on fibroblasts of affected individuals demonstrates a normal level of protein expression, strongly suggesting that abnormal proteins are expressed [Muchir et al 2004]. Nonsense variants resulting in approximately 50% of normal protein levels have also been described [Bécane et al 2000, Muchir et al 2003].

References

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Chapter Notes

Acknowledgments

Authors are coordinators (GB, FL, 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 have been members of the European consortium "Euro-Laminopathies" supported by an EU-FP7 grant (#018690) and are currently members of SOLVE-RD, an European Union's Horizon 2020 research and innovation programme under grant agreement No. 779257. GB, FL, RBY are supported by the Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, the Assistance Publique des Hôpitaux de Paris.

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

  • 15 August 2019 (ha) Comprehensive update posted live
  • 25 November 2015 (me) Comprehensive update posted live
  • 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 live
  • 29 September 2004 (me) Review posted live
  • 27 January 2004 (gb) Original submission
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Bookshelf ID: NBK1436PMID: 20301609

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