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 humeroperoneal 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 clinical diagnosis of EDMD can be established in a proband with characteristic early and prominent joint contractures, humeroperoneal (or more rarely limb-girdle) muscle weakness and wasting, and later-onset cardiac disease. The molecular diagnosis is established in a proband with characteristic clinical findings and a hemizygous pathogenic variant in EMD or FHL1, a heterozygous pathogenic variant in LMNA, SUN2, SYNE1, SYNE2, or TMEM43, or (more rarely) biallelic pathogenic variants in LMNA or SUN1 identified by molecular genetic testing.

Management.

Treatment of manifestations: 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. Treatment for cardiac disease can include antiarrhythmic drugs, oral anticoagulation, ablation procedures, cardiac pacemaker, implantable cardioverter-defibrillator, pharmacologic and nonpharmacologic therapy for heart failure; heart transplantation for the end stages of heart failure as appropriate; respiratory aids (respiratory muscle training, assisted coughing techniques, mechanical ventilation) as needed; in those with associated metabolic features, treatment may include dietary modification, medications to improve hypertriglyceridemia and hypercholesterolemia, and diabetes / insulin resistance medications.

Surveillance: Assess joints for contractures and mobility, and spine for rigidity, posture, flexibility, swallowing function, and muscle strength at each visit; EKG, Holter monitor, and echocardiography at least annually; additional cardiac surveillance as needed; pulmonary function tests every two to three years and annually in those with respiratory compromise; cholesterol panel with triglycerides, hemoglobin A1c, and blood glucose every two to three years or more frequently in those with abnormalities.

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 musculoskeletal evaluation and cardiac assessment, if the pathogenic variant(s) in the family are not known.

Genetic counseling.

EDMD is inherited in an X-linked (XL), autosomal dominant (AD), or (rarely) autosomal recessive (AR) 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 cardiac disease, progressive muscular dystrophy (rare), and/or an EDMD phenotype (exceedingly rare).

AD-EDMD: Sixty-five percent of individuals with LMNA-related AD-EDMD have a de novo pathogenic variant. Each child of an individual with AD-EDMD has a 50% chance of inheriting the pathogenic variant.

AR-EDMD: If both parents are known to be heterozygous for a pathogenic variant associated with AR-EDMD, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.

Once the EDMD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for EDMD are possible.

Suggestive Findings

EDMD should be suspected in probands with the following clinical, electrophysiologic, imaging, and laboratory findings and family history.

Clinical findings

• Age of onset is typically between age five and ten years, rarely before age five or after ten years.
• Joint contractures of the elbow flexors, Achilles tendons, and neck extensors resulting in limitation of neck flexion, followed by limitation of extension of the entire spine
• Muscle wasting and weakness that is slowly progressive, with humeroperoneal/scapuloperoneal muscles typically affected first
• Cardiac disease symptoms including palpitations, presyncope, syncope, and poor exercise tolerance

EKG findings. Atrial fibrillation, flutter, and standstill, supraventricular and ventricular arrhythmias, and atrioventricular and bundle branch blocks

Echocardiogram findings. Dilated or hypertrophic cardiomyopathy

Laboratory findings. Serum creatine kinase (CK) concentration is normal or moderately elevated (2x-10x upper normal level). The highest serum CK concentration is usually found at disease onset.

Family history of EDMD can present in an autosomal dominant, X-linked, or (rarely) autosomal recessive pattern. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Clinical Description

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures, muscle weakness and wasting, and cardiac disease. Respiratory function may be impaired in some individuals. Age of onset, severity, and progression of 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 onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, concomitantly 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. Onset after age 20 years is exceedingly rare.

Joint contractures begin in early childhood and can be the first clinical manifestation of EDMD or 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. They usually develop before any significant weakness and may extend to fingers and wrists. Severe contractures may lead to loss of ambulation by limitation of movement of the spine and lower limbs.

Muscle weakness and wasting is bilateral and approximatively symmetric, typically initially involving the humeral (biceps and triceps brachialis muscles) and peroneal (peroneal and tibialis anterior muscles) compartments and can later extend to the scapular, pelvic girdle, and axial 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 as a result of muscle weakness progression.

Electromyogram usually shows myopathic features with normal nerve conduction studies. Muscle MRI or CT scans show fatty infiltration mainly involving the paravertebral, gluteal, quadriceps, biceps, semitendinosus, semimembranosus, adductor major, soleus, and gastrocnemius muscles [Díaz-Manera et al 2016, Pinto et al 2022, Panicucci et al 2023].

Cardiac involvement usually appears within the end of the second to third decades of life. Symptoms may include palpitations, presyncope, syncope, and poor exercise tolerance. Sudden cardiac death may also occur as an inaugural event in some individuals.

Cardiac conduction defects can include sinus bradycardia, sinoatrial blocks, atrial standstill, first-degree atrioventricular block, bundle branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker or implantable cardioverter-defibrillator.

Atrial arrhythmias (extrasystoles, atrial fibrillation, and flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent [Valenti et al 2022, Cannie et al 2023]. Affected individuals are at risk for cerebral emboli and sudden death [Boriani et al 2003, Redondo-Vergé et al 2011, Maggi et al 2014, Homma et al 2018].

Congestive heart failure, cardiomyopathy (dilated or hypertrophic), sudden death despite pacemaker implantation, end-stage heart failure leading to heart transplantation are usually reported [Bécane et al 2000, Boriani et al 2003, Sanna et al 2003, Sakata et al 2005, Astejada et al 2007, Carboni et al 2012, Maggi et al 2014, Valenti et al 2022, Cannie et al 2023].

Respiratory function can be impaired in some individuals and may arise in later stages [Maggi et al 2016]. Advanced respiratory dysfunction is uncommon and is mainly observed either in severe forms of LMNA-related EDMD or in FHL1-related EDMD.

Lipodystrophy. Rarely, individuals with LMNA-related EDMD may have additional lipodystrophy features [van der Kooi et al 2002, Wiltshire et al 2013]. Affected individuals usually have muscle weakness, muscle wasting, and joint contractures between childhood and adolescence, then progressively develop lipodystrophy in adolescence and, later, partial lipodystrophy-associated metabolic abnormalities (hypertriglyceridemia, insulin resistance, glucose intolerance / diabetes).

Prognosis. In addition to the severity of muscle weakness, the prognosis for motor function depends on the extent of joint contractures, specifically in the lower limbs. Life expectancy mainly depends on the presence of advanced cardiac disease (malignant ventricular arrythmias, end-stage heart failure). On occasion, sudden cardiac death is the first manifestation of the disorder typically due to malignant ventricular arrhythmias [Bécane et al 2000, Kärkkäinen et al 2004, De Backer et al 2010].

Females heterozygous for an EMD or FHL1 pathogenic variant. Female heterozygotes are usually asymptomatic, but they are at risk of developing cardiac disease usually after age 50 years, rarely a progressive muscular dystrophy, and exceptionally an EDMD phenotype [Meinke et al 2015, Viggiano et al 2019, Borch et al 2022, Simons et al 2025].

AR-EDMD. Thirteen individuals with molecularly confirmed autosomal recessive LMNA-related EDMD have been reported [Raffaele Di Barletta et al 2000, Brown et al 2001, Vytopil et al 2002, Cenni et al 2005, Mittelbronn et al 2006, Scharner et al 2011, Jimenez-Escrig et al 2012, Wiltshire et al 2013, Sframeli et al 2017, Xiao et al 2023] (see Table 2).

When reported, onset of motor manifestations ranged from early childhood [Raffaele Di Barletta et al 2000, Brown et al 2001, Scharner et al 2011, Sframeli et al 2017, Xiao et al 2023] to adolescence [Jimenez-Escrig et al 2012, Wiltshire et al 2013] or even later [Jimenez-Escrig et al 2012]. In some individuals assessed after age 30 years, muscle weakness was severe with loss of ambulation within the third to fifth decades of life [Raffaele Di Barletta et al 2000, Jimenez-Escrig et al 2012, Wiltshire et al 2013].

Cardiac involvement was variable, either minimal or absent in nine individuals age six to 50 years [Raffaele Di Barletta et al 2000, Brown et al 2001, Vytopil et al 2002, Jimenez-Escrig et al 2012, Wiltshire et al 2013]. More significant cardiac disease was reported in four individuals [Cenni et al 2005, Scharner et al 2011, Wiltshire et al 2013, Xiao et al 2023] with atrial arrhythmias and cardiomyopathy responsible for heart failure requiring heart transplantation at age 48 years in one individual [Cenni et al 2005].

Among the 13 reported individuals, three were homozygous for LMNA pathogenic variants p.Arg482Gln or p.Arg482Trp [Wiltshire et al 2013, Xiao et al 2023], which are known to be hot spot LMNA pathogenic variants for autosomal dominant partial lipodystrophy. These three individuals had EDMD features associated with lipodystrophy. Their heterozygous parents and sibs had only lipodystrophy.

When reported, heterozygous relatives of individuals with AR-EDMD were usually asymptomatic except for heterozygous individuals from two reported families [Wiltshire et al 2013, Xiao et al 2023]. Late-onset cardiac disease occurred in heterozygous individuals in one additional family with LMNA-related AR-EDMD [Jimenez-Escrig et al 2012].

Note: A second LMNA pathogenic variant was identified in one of the probands (family MBr) initially reported by Vytopil et al [2002] with autosomal dominant EDMD; this proband in fact had compound heterozygous LMNA pathogenic variants [G Bonne, unpublished data].

Phenotype Correlations by Gene

Genotype-Phenotype Correlations

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

• Null variants tend to have a more severe phenotype [Muntoni et al 1998, Hoeltzenbein et al 1999, Canki-Klain et al 2000, Ellis et al 2000].
• Missense variants are associated with decreased or normal amounts of emerin and result in a milder EDMD phenotype [Yates et al 1999]. Otherwise, EMD missense variants frequently lead to isolated cardiac disease [Báez-Ferrer et al 2023].

LMNA. Marked intra- and interfamilial variability is observed for the same LMNA pathogenic variant [Carboni et al 2010, Cotta et al 2019]. For example, within the same family the same pathogenic variant can lead to AD-EDMD, limb-girdle muscular type, or isolated dilated cardiomyopathy with conduction system disease (i.e., laminopathies involving striated muscle) [Carboni et al 2008, Cotta et al 2019].

• Missense variants have been associated with early skeletal muscle involvement and joint contractures (i.e., EDMD type), while frameshift variants have been associated with later-onset muscle symptoms, limb-girdle type [Benedetti et al 2007].
• Pathogenic variants destabilizing the 3D structure of the C-terminal domain of lamin-A/C lead predominantly to EDMD [Krimm et al 2002].

Co-occurrence of EMD and LMNA pathogenic variant(s). Severe EDMD has been reported in individuals with pathogenic variants in both EMD (hemizygous or heterozygous) and LMNA (heterozygous or homozygous) [Muntoni et al 2006, Ben Yaou et al 2007, Meinke et al 2011].

FHL1, SUN1, SUN2, SYNE1, SYNE2, and TMEM43. Due to a limited number of reported individuals, no definite genotype-phenotype correlations have been identified.

Penetrance

Penetrance is usually complete in EMD- and FHL1-related EDMD except for females heterozygous for an EMD or FHL1 pathogenic variant, who are usually asymptomatic but are at risk of developing cardiac disease (usually after age 50 years), progressive muscular dystrophy (rare), or EDMD (exceedingly rare) [Meinke et al 2015, Viggiano et al 2019, Borch et al 2022, Simons et al 2025].

Reduced penetrance has been occasionally reported in LMNA-related EDMD [Vytopil et al 2002, Rankin et al 2008].

In SUN1-, SUN2-, SYNE1-, SYNE2-, and TMEM43-related EDMD, penetrance appears complete but reported data are limited.

Prevalence

The prevalence of XL-EDMD has been estimated at 0.13-0.2:100,000 [Deenen et al 2015]. As XL-EDMD accounts for approximately 10% of all EDMD (see Table 1), the prevalence of EDMD of all types is estimated to be 1.3-2:100,000. Moreover, male predominance has been observed [Deenen et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EDMD, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Timely supportive care to improve quality of life and prognosis, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended in a multidisciplinary setting.

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 [ Funnell et al 2012].

Obesity should be avoided to decrease negative impact on ambulation and joints.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic at-risk sibs, parents, and relatives of individuals with EDMD (including female relatives of male individuals with XL-EDMD) because of the high risk for cardiac complications associated with EDMD (including sudden cardiac death, which may be the first manifestation of the disorder). Evaluation may allow early identification of family members who would benefit from initiation of treatment and preventive measures [Heller et al 2020, Valenti et al 2022, Cannie et al 2023]. Evaluations can include:

• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Clinical evaluation, including musculoskeletal evaluation and cardiac assessment (including both EKG and echocardiography), if the pathogenic variant(s) in the family are not known (see Table 5.)

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. Cesarean 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

Several therapeutic approaches (pharmacologic treatments, gene therapy) are still under evaluation in mice models [Benarroch et al 2021, Rawls et al 2023, Leconte et al 2024] such as mTOR and p38 inhibitors. So far, only one therapy has reached a human trial (REALM-DCM; NCT03439514) [MacRae et al 2023], which enrolled 12 individuals with LMNA-related cardiac disease with or without skeletal muscle involvement. After 48 weeks of treatment with either 100 mg or 400 mg of ARRY-371797 (a p38 inhibitor) twice daily, there were no safety concerns and an overall positive outcome in the primary and secondary end points, leading to a Phase III clinical trial. However, the sponsor decided to stop the Phase III trial due to futility.

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.

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 (see Table 8). Autosomal dominant transmission of EDMD is the most frequently observed mode of inheritance. Genetic counseling and risk assessment depend on determination of the specific genetic cause of EDMD in an affected family member.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the EMD or FHL1 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the EMD or FHL1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism.
• If a male is the only affected family member (i.e., a simplex case):
  • The mother may be a heterozygote. Female heterozygotes are usually asymptomatic, but they are at risk of developing cardiac disease (usually after age 50 years), progressive muscular dystrophy (rare), or EDMD (exceedingly rare) [Meinke et al 2015, Viggiano et al 2019, Borch et al 2022, Simons et al 2025].
  • The affected male may have a de novo EMD or FHL1 pathogenic variant (in which case the mother is not a heterozygote). The frequency of de novo pathogenic variants is unknown.
  • The mother may have somatic/gonadal mosaicism. One instance of gonadal mosaicism in XL-EDMD has been reported [Manilal et al 1998].
• Molecular genetic testing of the mother is recommended to confirm her genetic status, allow reliable recurrence risk assessment, and determine her need for muscular and cardiac assessment [Viggiano et al 2019] (see Evaluation of Relatives at Risk). Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

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

• If the mother of the proband has an EMD or FHL1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Variability in the age of onset, severity, and progression of muscle and cardiac involvement is observed among family members with an EMD or FHL1 pathogenic variant.
  • Males who inherit the pathogenic variant will be affected.
  • Females who inherit the pathogenic variant are usually asymptomatic but are at risk of developing cardiac disease (usually after age 50 years), progressive muscular dystrophy (rare), or EDMD (exceedingly rare).
• If the proband represents a simplex case and if the EMD or FHL1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal gonadal mosaicism. Gonadal mosaicism has been reported in XL-EDMD [Manilal et al 1998].

Offspring of a male proband. Affected males transmit the EMD or FHL1 pathogenic variant to all of their daughters (who will be heterozygotes) and none of their sons.

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of having an EMD or FHL1 pathogenic variant.

Heterozygote detection. Identification of female heterozygotes requires prior identification of the EMD or FHL1 pathogenic variant in the family.

Note: Females heterozygous for an EMD or FHL1 pathogenic variant are usually asymptomatic but are at risk of developing cardiac disease (usually after age 50 years), progressive muscular dystrophy (rare), or EDMD (exceedingly rare).

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Some individuals diagnosed with AD-EDMD have an affected parent.
• Individuals diagnosed with AD-EDMD often have the disorder as the result of a de novo pathogenic variant. Unpublished data indicate that 65% of individuals with LMNA-related AD-EDMD have a de novo pathogenic variant (see www.umd.be/LMNA/).
• If the proband appears to be the only affected family member (i.e., a simplex case), clinical evaluation – in particular, cardiac investigations (see Evaluation of Relatives at Risk) – and molecular genetic testing are recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for treatment/surveillance.
  Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of an AD-EDMD-related pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental mosaicism for an LMNA pathogenic variant has been reported [Bonne et al 1999, Makri et al 2009, Xie et al 2023]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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 AD-EDMD-related pathogenic variant identified in the proband, the risk to the sibs is 50%. Marked clinical variability can be observed among family members with the same LMNA pathogenic variant (see Genotype-Phenotype Correlations).
• If the AD-EDMD-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Bonne et al 1999, Makri et al 2009, Xie et al 2023].
• If the parents have not been tested for the AD-EDMD-related 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 and the possibility of parental gonadal mosaicism.

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

Other family members. 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 AD-EDMD-related pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a pathogenic variant associated with AR-EDMD.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a LMNA or SUN1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are not at risk of developing AR-EDMD.
  • If the proband is homozygous for the LMNA pathogenic variant p.Arg482Gln or p.Arg482Trp associated with an overlapping phenotype involving EDMD features and partial lipodystrophy (see Table 11), heterozygous family members may have lipodystrophy [Wiltshire et al 2013, Xiao et al 2023].
  • In rare instances, late-onset cardiac disease may occur [Jimenez-Escrig et al 2012].

Sibs of a proband

• If both parents are known to be heterozygous for a pathogenic variant associated with AR-EDMD, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes are not at risk of developing AR-EDMD.
  • If the proband is homozygous for the LMNA pathogenic variant p.Arg482Gln or p.Arg482Trp associated with an overlapping phenotype involving EDMD features and partial lipodystrophy (see Table 11), heterozygous family members may have lipodystrophy [Wiltshire et al 2013, Xiao et al 2023].
  • In rare instances, late-onset cardiac disease may occur [Jimenez-Escrig et al 2012].

Offspring of a proband. The offspring of an individual with AR-EDMD are obligate heterozygotes for a pathogenic variant in LMNA or SUN1.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an LMNA or SUN1 pathogenic variant.

Heterozygote detection. Molecular genetic testing for at-risk relatives requires prior identification of the AR-EDMD-related pathogenic variants in the family.

EDMD of Unknown Genetic Cause – Risk to Family Members

The exact risk for EDMD to the family members of a simplex proband (a single individual with a disorder in a family) with EDMD of unknown cause is uncertain but may be up to 50%.

Related Genetic Counseling Issues

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

Family planning

• The optimal time for determination of genetic risk 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 at risk of having an EDMD-related pathogenic variant(s).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the EDMD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for EDMD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

EMD, LMNA, and FHL1 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 Emery-Dreifuss muscular dystrophy (EDMD) pathogenesis [Worman & Bonne 2007, Benarroch et al 2021, Leconte et al 2024, Ben Yaou et al 2025]:

• Structural defect including nuclear envelope deformation rupture associated with DNA damage, 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].

Author Notes

Contact Dr Gisèle Bonne (rf.mresni@ennob.elesig) to inquire about review of LMNA variants of uncertain significance.

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), SOLVE-RD, a European Union's Horizon 2020 research and innovation program under grant agreement No 779257 and are currently members of ERDERA, European Rare Diseases Research Alliance and European Union's Horizon Europe research and innovation program under grant agreement N°101156595. GB is coordinating and RBY is member of PRIORITY, cardio-laminoPathy: fRom pathomechanIsms tO peRsonalIzed TherapY consortium, a Leducq Foundation International Network of Excellence (24CVD03). GB, FL, RBY are supported by the Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, and the Assistance Publique des Hôpitaux de Paris (AP-HP).

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

• 18 September 2025 (sw) Comprehensive update posted live
• 15 August 2019 (ha) Comprehensive update posted live
• 25 November 2015 (me) Comprehensive update posted live
• 17 January 2013 (me) Comprehensive update posted live
• 15 June 2010 (me) Comprehensive update posted live
• 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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