Emery Dreifuse

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Bookshelf ID: NBK1436PMID: 20301609

Emery-Dreifuss Muscular Dystrophy

Gisle Bonne, PhD, France Leturcq, MD, and Rabah Ben Yaou, MD.

Author Information

Initial Posting: September 29, 2004; Last Revision: August 24, 2010.

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Summary

Disease characteristics. Emery-Dreifuss muscular dystrophy (EDMD) is characterized bythe 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 known to be associated with EDMD areEMD (encodingemerin) andFHL1 (encoding FHL1), which cause X-linked EDMD (XL-EDMD); andLMNA

(encoding lamin A and C), which causes autosomal dominant EDMD (AD-EDMD) and

autosomal recessiveEDMD (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 ofEMD or

FHL1. The diagnosis of AD-EDMD and AR-EDMD also relies on molecular genetic testing

ofLMNA.

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 of sudden death.

Prevention of secondary complications: antithromboembolic drugs to prevent cerebral

thromboembolism of cardiac origin in those with decreased left ventricular function or atrialarrhythmias.
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Surveillance: 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.

Testing 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, orautosomal

recessive manner. XL-EDMD: If the mother of aproband 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 EDMDphenotype.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 has been identified in

a family member.

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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

o 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.

o Dilated or hypertrophic cardiomyopathy may be detected by the performance

of echocardiographic evaluation.

Other clinical findings are nonspecific:

Electromyogram (EMG) usually shows myopathic features with normal nerve

conduction studies, but neuropathic patterns have been described for X-linked EDMD
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(XL-EDMD) [Hopkins et al 1981] and forautosomal dominantEDMD (AD-EDMD)

[Witt et al 1988].

CT scan of muscle shows a diffuse pattern of involvement affecting the biceps,

soleus, peroneal, external vasti, gluteus, and paravertebral muscles [Graux et al 1993].

Characteristic findings in the calf muscles on MRI have been reported in AD-EDMD

[Mercuri et al 2002].

Testing

Other nonspecific laboratory findings:

Serum CK concentration is normal or moderately elevated (2-20 times 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].

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 blotin various tissues: exfoliative buccal

cells, lymphocytes, lymphoblastoid cell lines, skin biopsy, or muscle biopsy [Manilal

et al 1997,Mora et al 1997] (see GeneTests Laboratory Directory).

o

In individuals with XL-EDMD, emerin is absent in 95% [Yates & Wehnert1999].

o 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 carrierdetection because it may show either a normal amount or

reduced amount of emerin, depending on the proportion of nuclei expressing

emerin.

o 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/orwestern blot in fresh muscle biopsy or

myoblasts, fibroblasts, and cardiomyocytes [Sheikh et al 2008,Gueneau et al 2009].o In individuals withFHL1-related XL-EDMD, FHL1 is absent or significantly

decreased [Gueneau et al 2009].

o In female carriers ofFHL1-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

because of the expression of the wild typeallele at the nuclear membrane and in the

nuclear matrix.
http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hopkins.1981.230http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.witt.1988.230http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.graux.1993.554http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2002.10http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2002.187http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2002.187http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.fidzianska.1998.88http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sabatelli.2001.826http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sabatelli.2001.826http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sewry.2001.281http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sewry.2001.281http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sewry.2001.281http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.fidzianska.2003.47http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.fidzianska.2007.47http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/specificity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/western-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/western-blot/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.manilal.1997.63http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.manilal.1997.63http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.manilal.1997.63http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mora.1997.249http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.yates.1999.199http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.yates.1999.199http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/western-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/western-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isoforms/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/western-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/western-blot/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sheikh.2008.3870http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sheikh.2008.3870http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hopkins.1981.230http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.witt.1988.230http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.graux.1993.554http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2002.10http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2002.187http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.fidzianska.1998.88http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sabatelli.2001.826http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sewry.2001.281http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sewry.2001.281http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.fidzianska.2003.47http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.fidzianska.2007.47http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/specificity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/western-blot/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.manilal.1997.63http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.manilal.1997.63http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mora.1997.249http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.yates.1999.199http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.yates.1999.199http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/western-blot/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isoforms/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/western-blot/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sheikh.2008.3870http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/


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Molecular Genetic Testing

Genes. The three genes known to be associated with EDMD encode ubiquitous proteins

localized either in the nuclear membrane or in the cytoplasm and nucleoplasm.

EMD, a cause of XL-EDMD, encodes emerin [Bione et al 1994]. FHL1, a cause of XL-EDMD, encodes FHL1 [Gueneau et al 2009].

LMNA, a cause of AD-EDMD and AR-EDMD, encodes lamins A and C [Bonne et al

1999].

Other loci. About 64% of individuals with a diagnosis of EDMD who have emerin detected

on immunocytochemistry and/or immunoblotting have nomutationidentified inEMD,

FHL1, orLMNA, suggesting that these individuals are either misdiagnosed or that other as-

yet unidentified genes are involved in EDMD [Gueneau et al 2009].

Clinical testing

EMD

Sequence analysis/mutation scanning. Sequencing ofEMD (6 exons, 5 short

introns, andpromoter region) detects anEMD 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]. Note: Sequence analysis of genomic

DNA cannot detect deletionof an exon(s) or whole-gene deletions on the X

chromosome in carrierfemales.

Deletion/duplication analysis detects exonic, multiexonic, or whole-gene deletions

ofEMD.

LMNA

Sequence analysis of the coding regions ofLMNA (12 exons and their flanking

intronic regions) detects mutations in 100% of individuals withLMNA sequence

variants (missense and nonsense mutations, small deletions/insertions); however, this

represents only about 45% of individuals with AD-EDMD because (1) large deletions

and duplications involving one or several exons are not detected and (2) other not-yet

discovered genes could be implicated in AD-EDMD [Bonne et al 2000,Brown et al

2001, Bonne et al 2003, Vytopil et al 2003].

Complementary DNA(cDNA) sequencing may be helpful to confirm the transcript

variants resulting from splice-site mutations.

Deletion/duplication analysis detects exonic, multiexonic or whole-gene deletions of

LMNA. Three large deletions have been identified to date. One of them encompasses

thepromoter regionand the beginning ofexon 1 and is responsible for a neurogenic

variant of EDMD [Walter et al 2005]. The two others, deleting exon 1 [van Tintelen

et al 2007] and exons 3 to 12 [Gupta et al 2010] respectively, are responsible for

isolatedcardiac disease.

FHL1

Sequence analysis of the eight exons, seven introns, andpromoter region detects a
http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bione.1994.323http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.1999.285http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.1999.285http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.manilal.1998.855http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.brown.2001.359http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.brown.2001.359http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.brown.2001.359http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2003.508http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vytopil.2003.e132http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.walter.2005.40http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vantintelen.2007.2430http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vantintelen.2007.2430http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gupta.2010.365http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isolated/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isolated/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bione.1994.323http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.1999.285http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.1999.285http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.manilal.1998.855http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.brown.2001.359http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.brown.2001.359http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2003.508http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vytopil.2003.e132http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.walter.2005.40http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vantintelen.2007.2430http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vantintelen.2007.2430http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gupta.2010.365http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isolated/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/promoter-region/


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mutation in more than 99% of individuals with established X-linked inheritance and

with reduced or absent FHL1 by immunodetection methods [Gueneau et al 2009].

Table 1. Summary of Molecular Genetic Testing Used in Emery-Dreifuss Muscular

Dystrophy

Gene

Symbol

% of EDMD

Attributed to

Mutations in

This Gene

Test MethodMutations

Detected

Mutation

Detection

Frequency 1

Test

Availability

EMD~61% of X-

linked EDMD 2

Sequence analysis or

mutation scanning3Sequence

variants 4, 5

99% 6, 7 8Clinical

Deletion/duplication

analysis 9, 10

Deletion of

exon(s) or

entiregene

FHL1 ~10% of X-linked EDMD 2 Sequence analysis ormutation scanning3 Sequencevariants 4, 5 99%6, 7, 8, 11 Clinical

LMNA

~45% AD-

EDMD;

Unknown for

AR-EDMD 12

Sequence analysis or

mutation scanning3Sequence

variants 4, 599%

Clinical

Deletion/duplication

analysis 9, 10

Deletion of

exon(s) or

entiregene13Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory.

GeneReviews designates a molecular genetic test as clinically available only if the test

is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed

laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or

performance. Clinicians must communicate directly with the laboratories to verify

information.

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].

SinceFHL1 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 scanningof 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 bysequence analysismay include small intragenic

deletions/insertions and missense, nonsense, and splice site mutations.

5. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations.

6. Males with an established X-linked inheritance or individuals with no emerinexpression as determined by immunodetection studies of muscle tissue
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/221498?db=genetestshttp://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/319279?db=genetestshttp://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/2378?db=genetestshttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation-scanning/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/


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7. Lack of amplification by PCRprior to sequence analysis can suggest a putative

exonic or whole-genedeletion on the X chromosome in affected males; confirmation

may require additional testing bydeletion/duplication analysis.

8. Sequence analysis of genomic DNA cannot detectdeletionof anexon(s) or whole-

gene deletions on the X chromosomein carrierfemales.

9. Testing that identifies deletions/duplications not readily detectable by sequence

analysis of genomic DNA; a variety of methods including quantitative PCR, long-

range PCR, multiplex ligation-dependentprobe amplification (MLPA), or targeted

array GH (gene/segment-specific) may be used. A full array GH analysis that detects

deletions/duplications across the genome may also include this gene/segment. See

array GH.

10. Extent ofdeletion detected may vary by method and by laboratory.

11. Males with an established X-linked inheritance or individuals with no or highlyreduced FHL1 expression as determined by immunodetection studies of muscle tissue

12. AR-EDMD is very rare. To date only oneLMNAmutation in a homozygous state

leading to AR-EDMD has been reported [Raffaele Di Barletta et al 2000].

13. Only three large deletions have been identified to date.

Interpretation of test results. For issues to consider in interpretation ofsequence analysis

results, clickhere.

Testing Strategy

To confirm/establish the diagnosis in a proband

If the family historyclarifies themode of inheritance, testing ofEMD andFHL1

should be performed for XL-EDMD andLMNA for AD-EDMD or AR-EDMD.

In the absence of an informative family history:

o Foraffected males: Emerin and FHL1 immunodetection studies help to

distinguish between XL- and AD-EDMD and thus determine the appropriate

gene formolecular genetic testing.

o Foraffected females who are simplex cases (i.e., a single occurrence in afamily): Carrier females rarely manifest X-linked EDMD; thus, affected

females are much more likely to have AD-EDMD andLMNA should be

analyzed before considering analysis of the X-linked genes.

Ifsequence analysis does not identify aEMDmutationin those with possible XL-

EDMD, deletion/duplication analysis should be considered.

Ifsequence analysis does not identify aLMNAmutationin those with suspected AD-

EDMD or AR-EDMD, deletion/duplication analysis may be appropriate even though

whole-exon or multi-exon deletions ofLMNA are rare.

Carrier testing
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/quantitative-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/quantitative-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/probe/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genome/http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_lab_service_id/234754?db=genetestshttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.raffaeledibarletta.2000.1407http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/app2/http://www.ncbi.nlm.nih.gov/books/n/gene/app2/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mode-of-inheritance/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mode-of-inheritance/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/polymerase-chain-reaction-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/quantitative-pcr/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/probe/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genome/http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_lab_service_id/234754?db=genetestshttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.raffaeledibarletta.2000.1407http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/app2/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mode-of-inheritance/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion-duplication-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/


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X-linked EDMD. Carrier testing for at-risk relatives requires prior identification of

theEMD orFHL1disease-causing mutationin 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 anaffected male is not available for testing,molecular genetic testingfirst bysequence

analysis, and then, if no mutation is identified, by methods to detect gross structural

abnormalities.

Autosomalrecessive EDMD. Carrier testing for at-risk relatives requires prior

identification of the disease-causingLMNA mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessivedisorder 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 EDMDandautosomal dominant EDMD, and of the disease-causing mutations in families with

autosomal recessiveEDMD.

Note: It is the policy ofGeneReviews to include information on preimplantation genetic

diagnosis available from laboratories listed in the GeneTests Laboratory Directory; inclusion

does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or

reviewer(s).

Genetically Related (Allelic) Disorders

EMD

The disorders caused by mutations inEMD are called emerinopathies and affect striated

muscles:

X-linked LGMD (limb-girdle muscular dystrophy)phenotype caused bymutationin

EMD; rarely reported [Ura et al 2007,Fanin et al 2009]

X-linked isolated cardiac disease with prominent sinus node disease and atrial

fibrillation [Ben Yaou et al 2007, Karst et al 2008]

FHL1

FHL1-related diseases include three allelic disorders characterized by the presence of

reducing bodies detected on histopathology:

Reducing body myopathy [Schessl et al 2008]

X-linked scapuloperoneal myopathy [Quinzii et al 2008]

Some cases of rigid spine syndrome [Shalaby et al 2008]

Other allelicFHL1-related diseases:

X-linked myopathy with postural muscle atrophy (X-MPMA) and generalized musclehypertrophy or X-MPMA in which reducing bodies are absent and FHL1 protein is
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reduced on immunodetection (making this disorder similar toFHL1-related EDMD)

[Windpassinger et al 2008]

X-linked hypertrophic cardiomyopathy [Gueneau et al 2009]

LMNA

The disorders caused by mutations inLMNA are called "laminopathies:"

Disorders of striated muscle *

LGMD1B, an autosomal dominantform oflimb-girdle muscular dystrophy associated

with atrioventricular conduction defect [van der Kooi et al 1996, Muchir et al 2000]

CMD1A or DCM-CD, anautosomal dominant form of dilated cardiomyopathy with

cardiac conduction defects [Fatkin et al 1999, Bcane et al 2000]

Autosomal dominant dilated cardiomyopathy (DCM) with apical left ventricular

aneurysm without atrio-ventricular block [Forissier et al 2003] or early atrial

fibrillation [Sebillon et al 2003] or left ventricular non-compaction [Hermida-Prieto etal 2004]

Autosomal dominant quadriceps myopathy associated with dilated cardiomyopathy

and cardiac conduction defects [Charniot et al 2003]

Neurogenic variant of EDMD [Walter et al 2005]

LMNA-related congenital muscular dystrophy (L-CMD) [Quijano-Roy et al 2008]

* Note: (1) These may not truly be allelic disorders because the phenotypeoverlaps with

EDMD. See comments in Genotype-Phenotype Correlations. (2) Laminopathies affecting

striated muscles are important to recognize because of the severity of the dilated

cardiomyopathy associated with conduction/rhythm (DCM-CD) disorders, and the high

frequency of sudden death [van Berlo et al 2005]. (3) See also Dilated Cardiomyopathy

Overview.

Disorders of peripheral nerve

CMT2B1, an autosomal recessive form of axonal Charcot-Marie-Tooth disease with

the foundermutation p.Arg298Cys [De Sandre-Giovannoli et al 2002] (see Charcot-

Marie-Tooth type 2)

Autosomal dominant CMT2 associated with muscular dystrophy, cardiomyopathy and

leukonychia [Goizet et al 2004].

Autosomal dominant CMT2 associated with myopathy [Benedetti et al 2005].

Disorders of fatty tissues. Autosomal dominantDunnigan type familial partial lipodystrophy

(FPLD) [Shackleton et al 2000]. The majority of FPLD cases are caused byLMNA mutations

affecting arginine codon482, leading to several amino acid substitutions [Bonne et al 2003].

Isolated metabolic manifestations without lipodystrophy have been also reported [Young et al

2005, Decaudain et al 2007]

Disorders involving several tissues

Autosomal dominant muscular dystrophy, dilated cardiomyopathy, and partial

lipodystrophy [Garg et al 2002, van der Kooi et al 2002]
http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.windpassinger.2008.88http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/lgmd-overview/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vanderkooi.1996.636http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.muchir.2000.1453http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.fatkin.1999.1715http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/n/gene/dcm-lmna/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.forissier.2003.821http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sebillon.2003.560http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hermidaprieto.2004.50http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hermidaprieto.2004.50http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.charniot.2003.473http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.walter.2005.40http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/congenital/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.quijanoroy.2008.177http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.GenotypePhenotype_Correlationshttp://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vanberlo.2005.79http://www.ncbi.nlm.nih.gov/books/n/gene/dcm-ov/http://www.ncbi.nlm.nih.gov/books/n/gene/dcm-ov/http://www.ncbi.nlm.nih.gov/books/n/gene/dcm-ov/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.desandregiovannoli.2002.726http://www.ncbi.nlm.nih.gov/books/n/gene/cmt2/http://www.ncbi.nlm.nih.gov/books/n/gene/cmt2/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.goizet.2004.E29http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.benedetti.2005.1019http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.shackleton.2000.153http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/codon/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/codon/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2003.508http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.young.2005.1873http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.young.2005.1873http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.decaudain.2007.4835http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.garg.2002.549http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vanderkooi.2002.620http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.windpassinger.2008.88http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/lgmd-overview/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vanderkooi.1996.636http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.muchir.2000.1453http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.fatkin.1999.1715http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/n/gene/dcm-lmna/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.forissier.2003.821http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sebillon.2003.560http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hermidaprieto.2004.50http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hermidaprieto.2004.50http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.charniot.2003.473http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.walter.2005.40http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/congenital/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.quijanoroy.2008.177http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.GenotypePhenotype_Correlationshttp://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vanberlo.2005.79http://www.ncbi.nlm.nih.gov/books/n/gene/dcm-ov/http://www.ncbi.nlm.nih.gov/books/n/gene/dcm-ov/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.desandregiovannoli.2002.726http://www.ncbi.nlm.nih.gov/books/n/gene/cmt2/http://www.ncbi.nlm.nih.gov/books/n/gene/cmt2/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.goizet.2004.E29http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.benedetti.2005.1019http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.shackleton.2000.153http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/codon/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2003.508http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.young.2005.1873http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.young.2005.1873http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.decaudain.2007.4835http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.garg.2002.549http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vanderkooi.2002.620


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Mandibuloacral dysplasia (MAD) (autosomal recessive). Founder mutations are

reported in MAD (p.Arg527His) [De Sandre-Giovannoli et al 2002,Novelli et al

2002].

Generalized lipoatrophy, insulin-resistant diabetes mellitus, disseminated

leukomelanodermic papules, liver steatosis, and cardiomyopathy (LDHCP) [Caux et

al 2003] Hutchinson-Gilford progeria syndrome (HGPS) (autosomal dominant). Mutations in

codon 608 are associated with HGPS [De Sandre-Giovannoli et al 2003, Eriksson et al

2003].

Atypical Werner syndrome (autosomal dominant) [Chen et al 2003]

Restrictive dermopathies such as a lethal neonatal laminopathy [Navarro et al 2004]

Progeria, arthropathy, and calcinosis of tendons [Van Esch et al 2006]

Heart-hand syndrome, Slovenian type [Renou et al 2008]

Silent normal allelic variants ofLMNA. Some silent normal sequence variants ofLMNA are

also reported to be related to susceptibility to obesity and to insulin resistance [Hegele et al

2001a,Hegele et al 2001b, Murase et al 2002].

Go to:

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,Bcane et al 2000,

Bonne et al 2000, Felice et al 2000,Raffaele Di Barletta et al 2000,Brown et al 2001,Borianiet al 2003,Vytopil et al 2003,Gueneau et al 2009,Knoblauch et al 2010].

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 postcervical 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 pacemakerimplantation [Sanna et al 2003]. Cardiac conduction defects can include sinus
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.desandregiovannoli.2002.726http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.desandregiovannoli.2002.726http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.novelli.2002.426http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.novelli.2002.426http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.caux.2003.1006http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.caux.2003.1006http://www.ncbi.nlm.nih.gov/books/n/gene/hgps/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/codon/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.desandregiovannoli.2003.2055http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.eriksson.2003.293http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.eriksson.2003.293http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.chen.2003.440http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.navarro.2004.2493http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vanesch.2006.517http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.renou.2008.666http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hegele.2001a.1707http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hegele.2001a.1707http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hegele.2001b.2747http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hegele.2001b.2747http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.murase.2002.1017http://www.ncbi.nlm.nih.gov/books/NBK1436/#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.wulff.1997.526http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.manilal.1998.855http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.yates.1999.159http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.yates.1999.159http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.yates.1999.159http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.felice.2000.275http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.felice.2000.275http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.raffaeledibarletta.2000.1407http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.raffaeledibarletta.2000.1407http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.brown.2001.359http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.brown.2001.359http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.boriani.2003.901http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.boriani.2003.901http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.boriani.2003.901http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vytopil.2003.e132http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vytopil.2003.e132http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.knoblauch.2010.136http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sanna.2003.2227http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.desandregiovannoli.2002.726http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.novelli.2002.426http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.novelli.2002.426http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.caux.2003.1006http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.caux.2003.1006http://www.ncbi.nlm.nih.gov/books/n/gene/hgps/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/codon/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.desandregiovannoli.2003.2055http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.eriksson.2003.293http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.eriksson.2003.293http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.chen.2003.440http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.navarro.2004.2493http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vanesch.2006.517http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.renou.2008.666http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hegele.2001a.1707http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hegele.2001a.1707http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hegele.2001b.2747http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.murase.2002.1017http://www.ncbi.nlm.nih.gov/books/NBK1436/#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.wulff.1997.526http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.manilal.1998.855http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.yates.1999.159http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.felice.2000.275http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.raffaeledibarletta.2000.1407http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.brown.2001.359http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.boriani.2003.901http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.boriani.2003.901http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vytopil.2003.e132http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.knoblauch.2010.136http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.sanna.2003.2227


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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 of ventricular

tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilation

and dysfunction is higher than in XL-EDMD [Bcane 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 canbe 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 [Bcane et al 2000, Karkkainen et al 2004,De

Backer et al 2010].

AR-EDMD. Only one individual with genetically proven AR-EDMD (i.e., homozygous for a

LMNAmutation) has been reported [Raffaele Di Barletta et al 2000]. He had severe muscular

dystrophy. He experienced difficulties when he started walking at age 14 months; at age five

years, contractures prevented him from standing. By age 40 years, he had severe and diffuse

muscle wasting and was confined to a wheelchair. Cardiac evaluation revealed no

abnormalities [Raffaele Di Barletta et al 2000].

Genotype-Phenotype Correlations

EMD. The majority ofEMD 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 milderphenotype [Yates et al 1999].

LMNA mutations do not show a clear correlation between genotypeandphenotype [Bonne et

al 2000, Genschel & Schmidt 2000, Bonne et al 2003].

Marked intra- and interfamilial variabilityis observed for the sameLMNAmutation [Bcane

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, orisolatedDCM-CD, i.e.,

laminopathies involving striated muscle [Bcane et al 2000,Brodsky et al 2000].

Because only one individual with AR-EDMD and a homozygousp.His222Tyr

mutation ofLMNA has been reported [Raffaele Di Barletta et al 2000], no genotype-phenotype correlations can be made.
http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2003.508http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2003.508http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2003.508http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.boriani.2003.901http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.boriani.2003.901http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.draminska.2005.207http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.draminska.2005.207http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.pasotti.2008.1250http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.boriani.2003.901http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/intrafamilial-variability/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/intrafamilial-variability/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2000.1704http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2000.1704http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2004.690http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2004.690http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.carboni.2010.85http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.carboni.2010.85http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.emery.2000.228http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2000.1704http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.benyaou.2002.721http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.talkop.2002.878http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.talkop.2002.878http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2004.690http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2004.690http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.gueneau.2009.338http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.karkkainen.2004.885http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.karkkainen.2004.885http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.debacker.2010.97http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.debacker.2010.97http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.raffaeledibarletta.2000.1407http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.raffaeledibarletta.2000.1407http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/interfamilial-variability/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.muntoni.1998.72http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hoeltzenbein.1999.166http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hoeltzenbein.1999.166http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.cankiklain.2000.389http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.ellis.2000.24http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.yates.1999.159http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.genschel.2000.451http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2003.508http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/interfamilial-variability/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/interfamilial-variability/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bonne.2000.170http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.mercuri.2005.602http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.carboni.2010.85http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isolated/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isolated/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.becane.2000.1661http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.brodsky.2000.473http://www.ncbi.nlm.nih.gov/books/NBK1436/table/edmd.T.selected_lmna_pathologic_allelic_/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK1436/table/edmd.T.selected_lmna_pathologic_allelic_/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.raffaeledibarletta.2000.1407http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genotype/http://www.ncbi.nlm.nih.gov/books/n/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EMD and LMNA. Severe EDMD has been reported in individuals with mutations in both

EMD andLMNA [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 andLMNA genes cosegregate [Ben Yaou et al 2007].

Penetrance

FiveLMNA mutations were reported with incompletepenetrance in families with AD-EDMD

or otherLMNA-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.

HeterozygousLMNA mutations causing AD-EDMD are more common thanEMD 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.

Go to:

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this

section, see GeneTests Laboratory Directory. ED.

Some neuromuscular disorders result in a similar pattern of muscle involvement, joint

contractures, or cardiac disease, but none associates the triad observed in Emery-Dreifuss

muscular dystrophy (EDMD).

Scapulo-peroneal syndromes without contractures or cardiac disease

Facioscapulohumeral muscular dystrophy (FSHD)

Adult-onset scapulo-peroneal myopathy

X-linked scapulo-peroneal muscular dystrophy linked to chromosome 12

[Wilhelmsen et al 1996,Quinzii et al 2008]

Scapulo-peroneal spinal muscle atrophy linked tochromosome 12 [Isozumi et al

1996]

Spinal muscle atrophy of Stark-Kaeser type [Kaeser 1965]

Some forms of hyaline body myopathy [Masuzugawa et al 1997,Onengut et al 2004]
http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.muntoni.2006.1260http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isolated/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.benyaou.2007.1883http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/penetrance/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/penetrance/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vytopil.2002.958http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vytopil.2002.958http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.rankin.2008.1530http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hopkins.1992.1http://www.ncbi.nlm.nih.gov/books/n/gene/dbmd/http://www.ncbi.nlm.nih.gov/books/n/gene/dbmd/http://www.ncbi.nlm.nih.gov/books/NBK1436/#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/books/n/gene/fsh/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.wilhelmsen.1996.507http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.wilhelmsen.1996.507http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.quinzii.2008.208http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.isozumi.1996.1377http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.isozumi.1996.1377http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.kaeser.1965.407http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.masuzugawa.1997.253http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.masuzugawa.1997.253http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.onengut.2004.4http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.muntoni.2006.1260http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isolated/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.benyaou.2007.1883http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/penetrance/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.vytopil.2002.958http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.rankin.2008.1530http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.hopkins.1992.1http://www.ncbi.nlm.nih.gov/books/n/gene/dbmd/http://www.ncbi.nlm.nih.gov/books/NBK1436/#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/books/n/gene/fsh/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.wilhelmsen.1996.507http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.quinzii.2008.208http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.isozumi.1996.1377http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.isozumi.1996.1377http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.kaeser.1965.407http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.masuzugawa.1997.253http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.onengut.2004.4


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Other myopathies with or without contractures and/or cardiac disease that can

resemble AD-EDMD but have distinguishing features

SYNE1 and SYNE2 related EDMD-like [Zhang et al 2007]. The cardiomuscular

features associated with SYNE1 and SYNE2 variants reported in four families were

reminiscent of those observed in EDMD (i.e., mainly cardiac disease) but do not fullyfit with the typical EDMDphenotype [Zhang et al 2007: Supplementary Material].

Rigid spine syndrome [Moghadaszadeh et al 1999], especially selenopathies

[Moghadaszadeh et al 2001,Ferreiro et al 2002]

FKRPgene-related disorders [Poppe et al 2003] (see Congenital Muscular Dystrophy

Overviewand Limb-Girdle Muscular Dystrophy Overview)

Bethlem myopathy caused by collagen VIgenemutations [Bertini & Pepe 2002] (see

Collagen Type VI-Related Disorders)

Myotonic dystrophy type 1

Dystrophinopathies

Limb-girdle muscular dystrophies with cardiac involvement [Muntoni 2003] (see

Limb-Girdle Muscular Dystrophy Overview) Desmin-related myopathies [Goldfarb et al 2004] (see Myofibrillar Myopathy)

X-linked vacuolar myopathies with cardiomyopathy or Danon disease [Danon et al

1981]

Myotonic dystrophy type 2 (proximal myotonic myopathy [PROMM]) [Udd et al

2003]

Myopathy with maltase acid deficiency [Lafort et al 2010]

Other disorders with distinguishing features

Ankylosing spondylitis [Goncu et al 2003]

Go to:

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)

Treatment of Manifestations

The following are appropriate:
http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.zhang.2007.901http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.zhang.2007.901http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.moghadaszadeh.1999.376http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.moghadaszadeh.2001.17http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.moghadaszadeh.2001.17http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.ferreiro.2002.739http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.poppe.2003.1246http://www.ncbi.nlm.nih.gov/books/n/gene/cmd-overview/http://www.ncbi.nlm.nih.gov/books/n/gene/cmd-overview/http://www.ncbi.nlm.nih.gov/books/n/gene/cmd-overview/http://www.ncbi.nlm.nih.gov/books/n/gene/lgmd-overview/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bertini.2002.193http://www.ncbi.nlm.nih.gov/books/n/gene/bethlem/http://www.ncbi.nlm.nih.gov/books/n/gene/myotonic-d/http://www.ncbi.nlm.nih.gov/books/n/gene/dbmd/http://www.ncbi.nlm.nih.gov/books/n/gene/lgmd-overview/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.muntoni.2003.577http://www.ncbi.nlm.nih.gov/books/n/gene/lgmd-overview/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.goldfarb.2004.723http://www.ncbi.nlm.nih.gov/books/n/gene/mfm/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.danon.1981.51http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.danon.1981.51http://www.ncbi.nlm.nih.gov/books/n/gene/myotonic-d2/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.udd.2003.589http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.udd.2003.589http://www.ncbi.nlm.nih.gov/books/n/gene/gsd2/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.laforet.2010.128http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.goncu.2003.456http://www.ncbi.nlm.nih.gov/books/NBK1436/#ui-ncbiinpagenav-2http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.zhang.2007.901http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.zhang.2007.901http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.moghadaszadeh.1999.376http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.moghadaszadeh.2001.17http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.ferreiro.2002.739http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.poppe.2003.1246http://www.ncbi.nlm.nih.gov/books/n/gene/cmd-overview/http://www.ncbi.nlm.nih.gov/books/n/gene/cmd-overview/http://www.ncbi.nlm.nih.gov/books/n/gene/lgmd-overview/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.bertini.2002.193http://www.ncbi.nlm.nih.gov/books/n/gene/bethlem/http://www.ncbi.nlm.nih.gov/books/n/gene/myotonic-d/http://www.ncbi.nlm.nih.gov/books/n/gene/dbmd/http://www.ncbi.nlm.nih.gov/books/n/gene/lgmd-overview/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.muntoni.2003.577http://www.ncbi.nlm.nih.gov/books/n/gene/lgmd-overview/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.goldfarb.2004.723http://www.ncbi.nlm.nih.gov/books/n/gene/mfm/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.danon.1981.51http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.danon.1981.51http://www.ncbi.nlm.nih.gov/books/n/gene/myotonic-d2/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.udd.2003.589http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.udd.2003.589http://www.ncbi.nlm.nih.gov/books/n/gene/gsd2/http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.laforet.2010.128http://www.ncbi.nlm.nih.gov/books/NBK1436/#edmd.REF.goncu.2003.456http://www.ncbi.nlm.nih.gov/books/NBK1436/#ui-ncbiinpagenav-2


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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 [Bcane 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 susceptibilityhas not been described in EDMD, it is

appropriate to anticipate a possible malignant hyperthermia reaction and t

Documents

Emery Dreifuse