Emery-Dreifuss muscular dystrophy is a condition that primarily affects muscles used for movement (skeletal muscles) and the heart (cardiac muscle). Among the earliest features of this disorder are joint deformities called contractures. Contractures restrict the movement of certain joints, most often the elbows, ankles, and neck, and usually become noticeable in early childhood. Most affected individuals also experience muscle weakness and wasting that worsen slowly over time, beginning in muscles of the upper arms and lower legs and later also affecting muscles in the shoulders and hips.

Almost all people with Emery-Dreifuss muscular dystrophy develop heart problems by adulthood. In many cases, these heart problems are abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects) and abnormal heart rhythms (arrhythmias). If untreated, these abnormalities can lead to a sensation of fluttering or pounding in the chest (palpitations), an unusually slow heartbeat (bradycardia), fainting (syncope), heart failure, and an increased risk of sudden death.

Researchers have identified several types of Emery-Dreifuss muscular dystrophy that are distinguished by their pattern of inheritance: X-linked, autosomal dominant, and autosomal recessive. The types usually have similar signs and symptoms, although a small percentage of people with the autosomal dominant form experience heart problems without any weakness or wasting of skeletal muscles.

Mutations in several genes, including EMD, FHL1, and LMNA, can cause Emery-Dreifuss muscular dystrophy. Mutations in the EMD gene or, less commonly, in the FHL1 gene cause the X-linked type of the condition. Mutations in the LMNA gene cause both the autosomal dominant and autosomal recessive types of the condition.

The genes associated with Emery-Dreifuss muscular dystrophy appear to be essential for the normal function of skeletal and cardiac muscle. The EMD and LMNA genes provide instructions for making proteins that are components of the nuclear envelope, which surrounds the nucleus in cells. The nuclear envelope regulates the movement of molecules into and out of the nucleus, and researchers believe it may play a role in regulating the activity of certain genes. The protein produced from the FHL1 gene appears to be involved in other muscle cell functions, including chemical signaling, maintaining the structure of these cells, and influencing muscle growth and size.

Mutations in the EMD, FHL1, and LMNA genes that cause Emery-Dreifuss muscular dystrophy prevent the production of their respective proteins or lead to abnormal or nonfunctional versions of these proteins. Researchers speculate that changes in EMD or LMNA could weaken the structure of the nuclear envelope in cells that undergo a lot of mechanical stress, such as skeletal and cardiac muscle cells, making these cells more fragile. FHL1 gene mutations also alter the structure and function of muscle cells, although little is known about the mechanism. Researchers continue to investigate how genetic changes can lead to the joint contractures, muscle weakness, and heart abnormalities characteristic of Emery-Dreifuss muscular dystrophy.

Changes in several other genes result in conditions that resemble Emery-Dreifuss muscular dystrophy, but with more variable features. Some researchers consider these to be types of Emery-Dreifuss muscular dystrophy, while others believe that they represent similar, but separate, disorders.

In more than half of all cases of Emery-Dreifuss muscular dystrophy, the genetic cause of the condition is unknown. Researchers believe that mutations in additional genes, which have not been identified, can also cause this condition.

Normal Function

The EMD gene provides instructions for making a protein called emerin. Although this protein is produced in many tissues, it appears to be particularly important for the normal function of muscles used for movement (skeletal muscles) and the heart (cardiac muscle).

Within cells, emerin is a component of the nuclear envelope. The nuclear envelope is a structure that surrounds the nucleus, acting as a barrier between the nucleus and the surrounding fluid (cytoplasm) inside the cell. The nuclear envelope has several functions, including regulating the movement of molecules into and out of the nucleus.

Emerin interacts with several other proteins on the inner surface of the nuclear envelope. Together, these proteins are involved in regulating the activity of certain genes, controlling cell division and chemical signaling, and maintaining the structure and stability of the nucleus. Emerin and related proteins also play a role in assembling the nucleus during the process of cell division.

Health Conditions Related to Genetic Changes

Emery-Dreifuss muscular dystrophy

More than 100 mutations in the EMD gene have been reported in people with Emery-Dreifuss muscular dystrophy. This condition affects skeletal and cardiac muscle, causing joint deformities called contractures, which restrict the movement of certain joints; muscle weakness and wasting that worsen over time; and heart problems, including an increased risk of sudden death.

Almost all of the EMD gene mutations prevent cells from producing any emerin protein. Researchers have not determined how a lack of this protein leads to the skeletal and cardiac muscle abnormalities characteristic of Emery-Dreifuss muscular dystrophy. Studies suggest, however, that an absence of emerin could disrupt the functions of other proteins in the nuclear envelope. These changes may alter the activity of certain genes or weaken the structure of the nucleus, making cells more fragile.

In rare cases, Emery-Dreifuss muscular dystrophy results from EMD mutations that change a single building block (amino acid) in the emerin protein. These mutations lead to the production of an abnormal version of emerin that is unable to interact with other proteins or cannot be correctly inserted into the nuclear envelope. This type of mutation may be responsible for some cases of Emery-Dreifuss muscular dystrophy with unusually mild signs and symptoms.

Other Names for This Gene

• EMD_HUMAN
• emerin (Emery-Dreifuss muscular dystrophy)
• STA

Genomic Location

Normal Function

The FHL1 gene provides instructions for making three versions (isoforms) of a protein that plays an important role in muscles used for movement (skeletal muscles) and in the heart (cardiac muscle). The full-length isoform is known as FHL1A, or sometimes just FHL1. The other two isoforms, which are shorter, are called FHL1B and FHL1C.

FHL1A is the best-studied of the three FHL1 isoforms. Studies suggest that interactions between FHL1A and other proteins play a critical role in the assembly of sarcomeres, which are structures within muscle cells that are necessary for muscle tensing (contraction). These interactions also appear to be involved in chemical signaling within muscle cells, maintaining the structure of these cells, and influencing muscle growth and size.

Less is known about the FHL1B and FHL1C isoforms. FHL1B moves in and out of the nucleus and is also part of the nuclear envelope, which is a structure that surrounds the nucleus in cells. The protein's function in this structure is unknown. FHL1B and FHL1C are suspected to play roles in the normal structure and function of skeletal and cardiac muscles.

Health Conditions Related to Genetic Changes

Emery-Dreifuss muscular dystrophy

At least seven mutations in the FHL1 gene have been found to cause Emery-Dreifuss muscular dystrophy. This condition affects skeletal and cardiac muscle, causing joint deformities called contractures, which restrict the movement of certain joints; muscle weakness and wasting that worsen over time; and heart problems, including an increased risk of sudden death.

Some of the FHL1 gene mutations that cause Emery-Dreifuss muscular dystrophy change single protein building blocks (amino acids) in the FHL1 protein, while others insert or delete a small amount of DNA from the FHL1 gene. All of the known mutations affect the FHL1A isoform. Depending on where the mutations occur, they may affect one or both of the other isoforms as well.

Studies suggest that mutations reduce the amount of functional FHL1 protein produced in cells or lead to the production of an abnormally short, nonfunctional version of the protein. A shortage of this protein disrupts the normal structure and function of cardiac and skeletal muscle cells. However, the exact mechanism by which these changes cause joint contractures, muscle weakness and wasting, and heart problems remains unknown.

Other disorders

Several other muscle disorders also result from mutations in the FHL1 gene. These include reducing body myopathy, X-linked scapuloperoneal myopathy, X-linked myopathy with postural muscle atrophy (XMPMA), and rigid spine syndrome. Together with Emery-Dreifuss muscular dystrophy, these conditions are known as FHL1-related myopathies or FHL1opathies. Features common among these disorders include skeletal muscle weakness, particularly in the shoulders and lower legs; contractures involving the joints of the spine (rigid spine); and heart abnormalities. However, the disorders differ in their age of onset, the severity of muscle weakness, and how quickly the signs and symptoms worsen.

More than 50 FHL1 gene mutations have been associated with the FHL1-related myopathies. Each of these mutations affects some or all of the FHL1 isoforms. In general, mutations that affect all three isoforms cause more severe signs and symptoms than mutations that affect only one or two isoforms. Researchers have proposed several possible mechanisms by which FHL1 mutations lead to the FHL1-related myopathies. In some cases, mutations lead to the production of a nonfunctional version of the protein or no protein at all. In others, mutations may result in the production of an abnormal version of the protein that can form clumps (called reducing bodies) within muscle cells. Reducing bodies have been found in people with reducing body myopathy, X-linked scapuloperoneal myopathy, and rigid spine syndrome, but it is unclear how they are related to the major features of these disorders.

Other Names for This Gene

• bA535K18.1
• FHL-1
• FHL1A
• FHL1B
• FLH1A
• four-and-a-half Lin11, Isl-1 and Mec-3 domains 1
• KYO-T
• KYOT
• LIM protein SLIMMER
• MGC111107
• RBMX1A
• RBMX1B
• skeletal muscle LIM-protein 1
• SLIM
• SLIM-1
• SLIM1
• SLIMMER
• XMPMA

Genomic Location

Normal Function

The LMNA gene provides instructions for making several slightly different proteins called lamins. The two major proteins produced from this gene, lamin A and lamin C, are made in most of the body's cells. These proteins are made up of a nearly identical sequence of protein building blocks (amino acids). The small difference in the sequence makes lamin A longer than lamin C.

Lamins A and C are structural proteins called intermediate filament proteins. Intermediate filaments provide stability and strength to cells. Lamins A and C are supporting (scaffolding) components of the nuclear envelope, which is a structure that surrounds the nucleus in cells. Specifically, these proteins are located in the nuclear lamina, a mesh-like layer of intermediate filaments and other proteins that is attached to the inner membrane of the nuclear envelope. The nuclear envelope regulates the movement of molecules into and out of the nucleus. Lamins A and C are also found inside the nucleus, and researchers believe the proteins may play a role in regulating the activity (expression) of certain genes.

The lamin A protein must be processed within the cell before becoming part of the lamina. Its initial form, called prelamin A, undergoes a complex series of steps that are necessary for the protein to be inserted into the lamina. Lamin C does not have to undergo this processing before becoming part of the lamina.

Health Conditions Related to Genetic Changes

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Emery-Dreifuss muscular dystrophy

More than 130 mutations in the LMNA gene have been identified in people with Emery-Dreifuss muscular dystrophy, a condition that affects muscles used for movement (skeletal muscles) and the heart (cardiac muscle). This condition is characterized by joint deformities called contractures, which restrict the movement of certain joints; muscle weakness and wasting that worsen over time; and heart problems, including an increased risk of sudden death.

Most of the LMNA gene mutations that cause Emery-Dreifuss muscular dystrophy change single protein building blocks (amino acids) in lamins A and C, which alters the structure of these proteins. The effect of LMNA gene mutations within cells is unclear. Abnormal versions of lamins A and C may alter the activity of certain genes or weaken the structure of the nucleus, making cells more fragile. Researchers continue to investigate how LMNA mutations affect skeletal muscles and cardiac muscle, leading to the characteristic features of Emery-Dreifuss muscular dystrophy.

Familial partial lipodystrophy

Several mutations in the LMNA gene have been found to cause familial partial lipodystrophy type 2 (also known as familial partial lipodystrophy, Dunnigan type), a rare condition characterized by an abnormal distribution of fatty (adipose) tissue in the body. Adipose tissue is lost from the arms, legs, and hips, and excess fat is deposited in the face, neck, and abdomen. The abnormal fat storage is related to changes in the development and function of adipocytes, which are the fat-storing cells in adipose tissue. The effects of LMNA gene mutations on adipocytes are not well understood. Studies suggest that these mutations may weaken the nuclear envelope, ultimately leading to the premature death of these cells and leaving the body unable to store and use fats properly. These abnormalities of adipose tissue alter hormone production and affect many of the body's organs. However, it is unclear why the changes cause fat to be lost in some parts of the body and stored abnormally in others.

Hutchinson-Gilford progeria syndrome

A specific mutation in the LMNA gene has been found in most patients with Hutchinson-Gilford progeria syndrome, which is a condition that causes the dramatic, rapid appearance of aging beginning in childhood. This mutation changes a single DNA building block (nucleotide) in the gene. Specifically, the mutation replaces the nucleotide cytosine with the nucleotide thymine at position 1824 (written as C1824T). This mutation is also sometimes noted as Gly608Gly or G608G, which refers to the position in the lamin A protein affected by the mutation. Although the C1824T mutation is not predicted to change an amino acid, it alters the way the gene's instructions are used to make a protein. The C1824T mutation leads to an abnormal version of the lamin A protein called progerin, which is missing 50 amino acids near one end. The location of this mutation does not affect the production of lamin C. Other mutations in the LMNA gene have been identified in a small number of people with the features of Hutchinson-Gilford progeria syndrome.

The mutations responsible for this disorder result in an abnormal version of prelamin A that cannot be processed correctly within the cell. When the altered protein is incorporated into the lamina, it disrupts the shape of the nuclear envelope. Over time, a buildup of this altered protein appears to damage the structure and function of the nucleus, making cells more likely to die prematurely. Researchers are working to determine how these changes lead to the signs and symptoms of Hutchinson-Gilford progeria syndrome.

LMNA-related congenital muscular dystrophy

At least 15 mutations in the LMNA gene have been reported to cause LMNA-related congenital muscular dystrophy (L-CMD), a rare condition characterized by skeletal muscle weakness and atrophy beginning very early in life. Most of the mutations associated with this disorder change single amino acids in lamin A and lamin C, while a few add or remove a small number of amino acids from these proteins.

The mutations that cause L-CMD lead to the production of abnormal lamins. These malfunctioning proteins alter the structure of the nuclear envelope in ways that are not well understood. Researchers are working to determine how these changes affect muscle cells and lead to muscle weakness and atrophy in people with L-CMD.

Some of the mutations identified in people with L-CMD seem to be unique to this disorder, while others have also been reported in people with other LMNA-related conditions, such as Emery-Dreifuss muscular dystrophy (described above). It is unclear why certain mutations can cause different disorders in different people.

Mandibuloacral dysplasia

At least four mutations in the LMNA gene cause mandibuloacral dysplasia type A (MADA). This condition is characterized by a variety of signs and symptoms, which can include bone abnormalities; mottled or patchy skin coloring; and loss of fatty tissue under the skin, particularly affecting the limbs (type A lipodystrophy). The LMNA gene mutations that cause this condition change single amino acids in the lamin A and lamin C proteins. The most common mutation replaces the amino acid arginine at position 527 with the amino acid histidine (written as Arg527His or R527H).

The effects of LMNA gene mutations in this condition are not well understood. The amino acid changes may affect the structure of the lamin A or lamin C protein, or both, and alter how they interact with other proteins in the nuclear lamina. Some researchers speculate that these changes disrupt the nuclear envelope, making cells more fragile; however, it is unclear how the altered lamin proteins contribute to the signs and symptoms of MADA.

Arrhythmogenic right ventricular cardiomyopathy

MedlinePlus Genetics provides information about Arrhythmogenic right ventricular cardiomyopathy

Familial atrial fibrillation

MedlinePlus Genetics provides information about Familial atrial fibrillation

Familial dilated cardiomyopathy

MedlinePlus Genetics provides information about Familial dilated cardiomyopathy

Left ventricular noncompaction

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Limb-girdle muscular dystrophy

MedlinePlus Genetics provides information about Limb-girdle muscular dystrophy

Other disorders

Mutations in the LMNA gene have been found to cause several other conditions. Health conditions that result from mutations in lamin proteins are known as laminopathies. These disorders often have overlapping signs and symptoms, and in some cases different conditions can result from the same LMNA mutation. Researchers suspect that some laminopathies represent variants of a single condition instead of separate disorders.

In addition to the health conditions listed above, mutations in the LMNA gene cause atypical progeroid syndrome (APS); the features of this condition are similar to those of Hutchinson-Gilford progeria syndrome and mandibuloacral dysplasia. As in Hutchinson-Gilford progeria syndrome, children with APS look as though they are aging prematurely, although the signs and symptoms of APS usually begin slightly later. APS can also cause similar abnormalities in bone development and fat distribution as mandibuloacral dysplasia, although they are typically milder in APS.

Mutations in the LMNA gene have also been identified in newborns with a disorder called lethal restrictive dermopathy. Infants with this disorder have tight, rigid skin; underdeveloped lungs; and other abnormalities. They do not usually survive past the first week of life.

Researchers have not determined how mutations in the LMNA gene result in this diverse group of disorders, but the multiple roles of the nuclear lamina in cells may help explain the wide variety of signs and symptoms.

Other Names for This Gene

• LMN1
• LMNA_HUMAN

Genomic Location

Normal Function

The SYNE1 gene provides instructions for making a protein called Syne-1 that is found in many tissues, but it seems to be especially critical in the brain. The Syne-1 protein plays a role in the maintenance of the part of the brain that coordinates movement (the cerebellum). The Syne-1 protein is active (expressed) in Purkinje cells, which are located in the cerebellum and are involved in chemical signaling between nerve cells (neurons). The protein is thought to attach the membrane of Purkinje cells to the actin cytoskeleton, which is a network of fibers that make up the cell's structural framework. It is not clear what role this attachment plays in Purkinje cell function.

Health Conditions Related to Genetic Changes

Autosomal recessive cerebellar ataxia type 1

At least seven mutations in the SYNE1 gene have been found to cause autosomal recessive cerebellar ataxia type 1 (ARCA1). All the mutations that have been identified create a premature stop signal in the instructions for making the Syne-1 protein, resulting in an abnormally short protein with impaired function. A dysfunctional Syne-1 protein is thought to impair Purkinje cell function and disrupt signaling between neurons in the cerebellum. The loss of brain cells in the cerebellum causes the movement problems characteristic of ARCA1, but it is unclear how this cell loss is related to impaired Purkinje cell function.

Emery-Dreifuss muscular dystrophy

MedlinePlus Genetics provides information about Emery-Dreifuss muscular dystrophy

Other Names for This Gene

• ARCA1
• MYNE1
• myocyte nuclear envelope protein 1
• Nesp1
• nesprin-1
• nuclear envelope spectrin repeat protein 1
• spectrin repeat containing, nuclear envelope 1
• SYNE1_HUMAN

Genomic Location

Emery-Dreifuss muscular dystrophy can have several different patterns of inheritance. When the condition is caused by mutations in the EMD or FHL1 gene, it is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In females (who have two X chromosomes), a mutation typically must be present in both copies of the gene to cause X-linked Emery-Dreifuss muscular dystrophy. Females who carry one altered copy of the gene usually do not experience the muscle weakness and wasting that are characteristic of this condition. However, some of these female mutation carriers develop heart problems or mild muscle weakness.

In most cases of Emery-Dreifuss muscular dystrophy resulting from mutations in the LMNA gene, this condition has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. About 65 percent of autosomal dominant Emery-Dreifuss muscular dystrophy cases are caused by new mutations in the LMNA gene and occur in people with no history of the disorder in their family. In the remaining cases, people with this form of the condition inherit the altered LMNA gene from an affected parent.

Rarely, Emery-Dreifuss muscular dystrophy caused by LMNA gene mutations is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.

The overall prevalence of Emery-Dreifuss muscular dystrophy is unknown. The X-linked type of this disorder affects an estimated 1 in 100,000 people. The prevalence of the autosomal dominant type is unknown, although it appears to be more common than the X-linked type. The autosomal recessive type appears to be very rare; only a few cases have been reported worldwide.