Background Histopathology & Immunohistochemistry Differential Diagnosis Reference

BACKGROUND AND CLINICAL INFORMATION: Head

Summary Genetics Biochemistry Clinical Features

Summary: Emery-Dreifuss muscular dystrophy is a relatively mild muscular dystrophy. Typically, there is adolescent or early adulthood onset. The clinical triad includes conduction problem of the heart, contractures at the elbows, ankles and neck and muscle weakness or wasting. The muscle weakness follows a scapulohumeroperoneal distribution and muscle wasting is most prominent in the upper arms. Most cases are X-linked recessive, some are autosomal dominant and a small number of them are autosomal recessive. The gene involved in the X-linked cases is the STA gene on chromosome Xq28 that encodes emerin; pathologically, this type is best regarded as a laminopathy. The histopathologic picture of muscle is non-specific but emerin is absent or dramatically reduced in muscle biopsy.

Age: Onset in adolesence or early adults; early childhood onset has also been reported.

Laminopathies or nuclear envelopathies: This is a group of diseases linked to defects in genes encoding nuclear envelope specific proteins, most notably A-type lamins and emerin. This family includes Emery-Dreifuss muscular dystrophy and Dunnigan-type familial partial lipodystrophy and cardiomyopathy 1A (CMD1A). [Burke B. et al., Traffic 2001 Oct;2(10):675-83]

Genetics:
Pattern of transmission is heterogeneous. The X-linked form and autosomal dominant form involved mutations on completely different genes.

· X-linked form: Most cases are X-linked recessive. Some cases are transmitted in an autosomal dominant pattern and still less common is the autosomal recessive pattern. Affected girls have been recognized. The gene involved in the X-linked cases is the STA gene (2.1 kb) on chromosome Xq28 that encodes emerin. Mutations scattered in the gene without hot spots.

· Autosomal dominant form: The autosomal dominant form is cuased by missense mutations in LMNA gene for lamins A and C on chromosome 1q21.3. Lamins A and C interact directly with enmerin.

Biochemistry:

· Emerin is a type II integral membrane protein and has a molecular weight of 34 kDa. It is a member of a group of integral membrane proteins that include lamina-associated proteins, MAN1 and the lamin B receptors which interact with lamins in the nuclear and/or with chromatin. Emerin is normally found in the nuclear membrane and its function is unknown but may be associated with stability of the inner nuclear membrane. Emerin is totally absent or dramatically reduced in Emery-Dreifuss syndrome. [Morris GE., Trends Mol Med 2001 Dec;7(12):572-7]

· Nuclear lamins: The nuclear lamins polymerize to form the nuclear lamina, a fibrous structure found on the inner face of the nuclear membrane. The lamins also appear to form structures within the nucleoplasm. These various lamin structures help to establish and maintain the shape and strength of the interphase nucleus, but recent work also suggests that the lamins have a role in nuclear processes such as DNA replication. [Moir RD, Spann TP. Cell Mol Life Sci 2001 Nov;58(12-13):1748-57] Two types of nuclear lamins are present. All four proteins involved are very closely related in sequence and structures.

· A type nuclear lamins: There are at least 4 type A nuclear lamins. Nuclear lamins A and C are two alternatively-spliced products of a single gene. The other minor ones are Ad10 and C2.

· B-type nuclear lamins: Nuclear lamins B1 and B2 are products of two different gens.

Clinical:

· Diagnostic Triad: heart conduction problem, contractures at elbows, ankles and neck and muscle weakness or wasting.

· Clinical manifestations: Expression of the phenotype is variable. Penetration in autosomal Emery-Dreifuss myscular dystrophy is incomplete. Creatine kinase is moderately elevated (5-10 tims of normal).

· Correlation with genetic changes is not reproductible. Mutations in emerin or lamin A/C can cause different clinical features in different individuals even within the same family. Clinical manifestation can vary from full phenotypic expression to asymptomatic.

· Diagnosis by biopsy: Skin biopsy and immunohistochemical demonstration of the absence of emerin in smooth muscle.

· Contracture: Initial presenting feature is usually tightness of tightness of various muscle groups resulting from contracture. The ankle is most often affected and the spinal extensor muscle can also be affected. Limitation of full elbow extension due to contracture of flexor muscle is also frequent.

· Muscle weakness: It is usually mild and selectively affects the scapulohumeroperoneal muscles. Wasting of muscle of upper arm is often very striking, wasting of calf muscle may also be seen.

· Cardiac involvement: In general, arrhythmia is common in younger patients and dilated cardiomyopathy with heart block is seen in older patients with prolonged survival. Many patients died eventually because of cardiac problem. The arrhythmia is probably resulted from conduction problem. Carriers usually do not have muscular manifestation but often have arrthymia and need pace makers.

· Sudden cardiac death is seen in as many as 40% of patients. Prophylactic placement of pacemaker is necessary.

· Respiratory involvement can be seen in some patients and is mild and not life threatening.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Nonspecific myopathic picture: Histologic and histochemical studies are basically non-diagnostic.

Immunostaining: Absense of emerin in nuclear membrane in skeletal muscle and other cell types including smooth muscle, a useful feature for diagnosis by using skin biopsy.

DIFFERENTIAL DIAGNOSIS: Head

Rigid spine syndrome: This entity shares several features with Emery-Dreifuss muscular dystrophy. It predominantly affects boys. Muscle weakness is noticed at between a few months to 13 years of age. Flexion of the spine, contracture at the elbow and ankles may be present. In contrast to Emery-Dreifuss muscular dystrophy, there is no cardiac involvement.

LGMD 1B (Bethlem myopathy) vs. Emery-Dreifuss muscular dystrophy: In Emery-Dreifuss muscular dystrophy, there is a clinical triad of heart conduction problem, contractures at elbows, ankles and neck and muscle weakness or wasting; skin biopsy and immunohistochemical demonstration of the absence of emerin in smooth muscle.

In contrast, LGMD 1B has early-childhood onset with slow progression. The most constant feature is contracture of the interphalangeal joints of the fingers; there are also early flexion contractures of elbow and ankles. CK is not usually elevated. Muscle biopsy findings are uniform but nonspecific; there is very marked increase in adipose tissue in the muscle.

REFERENCES: Head