Managing Symptoms and Improving Quality of Life in EDMD Patients - Rare Disease

Dr. Chen Shunsheng reply Rare Disease

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The diagnostic criteria for Emery-Dreifuss muscular dystrophy (EDMD) require the identification of at least two affected males and one asymptomatic female or one female with cardiac conduction defects and cardiomyopathy in the family.
Diagnosis of EDMD in a family can be established by a single case exhibiting the core features or by multiple cases sharing the same characteristics.
This allows for the identification of other affected males.
Females may sometimes provide sufficient evidence of being carriers, but the status of most at-risk females remains undetermined.

In the diagnostic criteria, inclusive criteria are denoted by "I," exclusive criteria by "E," and "C" represents commentary.

1.
For definitive linkage analysis in familial EDMD diagnosis, the following characteristics must be present in the family:
1.
Early contractures of the Achilles tendon, elbows, and spine.

2.
Progressive chronic muscle weakness and atrophy, particularly in the humeral and peroneal distributions, affecting both proximal sides.

3.
Cardiac conduction defects and other myocardial abnormalities.

4.
Muscle biopsy showing myopathic changes or atrophy.

5.
Family history consistent with non-Mendelian inheritance.

Age of onset C: Often in childhood, with rare onset after age 20.
Early contractures I: Contractures often appear before significant weakness.
This may affect the elbows, causing the upper arms to adopt a flexed position.
Achilles tendon contractures may lead patients to walk on their toes, while spinal contractures may make neck flexion difficult.
C: There may be wrist extension and flexion contractures.

Muscle atrophy and weakness I: Muscle weakness and atrophy are particularly noted in the humeral and peroneal regions.
I: Bilateral symmetry, followed by weakness in the shoulders and pelvic girdle.
C: Some patients may also exhibit facial involvement, potentially leading to atrophy of the sternocleidomastoid muscle.

Muscle hypertrophy C: Often presents as calf muscle atrophy E: Significant calf muscle hypertrophy.

Disease progression C: Slow progression with cardiac involvement I: Cardiac conduction defects (bradycardia, ectopic beats, atrioventricular block, right bundle branch block) and other myocardial abnormalities (cardiomegaly, left ventricular dysfunction).
Some defects may only be detectable via 24-hour Holter monitoring.

Evidence of X-linked inheritance I: Family history consistent with non-Mendelian inheritance, specifically at least two affected males and inheritance through females (who may be asymptomatic or have cardiac conduction defects or cardiomyopathy).
C: Two affected males and one mother may not provide sufficient representation for linkage analysis, as mosaicism may indicate that if the mother exhibits EDMD features, the inheritance could be autosomal dominant.

Intellectual disability E: Significant intellectual disability excludes this diagnosis.

Blood CPK: Often moderately elevated, but may also be normal.

EMG (electromyography) C: Muscle or neuropathic changes do not meet diagnostic criteria.

Muscle biopsy I: Myopathic changes or atrophy to some degree; some changes may show localized atrophic fibers resembling neuropathic changes.
C: Dystrophin is normal.

DNA analysis C: In typical cases, exclusion of BMD/DMD gene deletions is necessary.

2.
To confirm a male in an affected family with definitive linkage EDMD, the following are required:
I: Any features described in section 1.

C: Only elevated CPK may raise suspicion but is not definitive for affected males.

C: CT or ultrasound may assist in confirming the diagnosis.

C: 24-hour Holter monitoring and echocardiography may aid in diagnosis.

3.
To confirm a non-affected male, the following are needed:
I: Age 20 years or older.

I: Normal CPK.

I: No clinical evidence of cardiomyopathy.

I: Examination by a physician familiar with the condition shows no evidence of EDMD.

4.
For a female in a confirmed X-linked EMD family to be considered a carrier, the following are required:
I: Any features including those in Section 1.

C: Any elevated CPK may raise suspicion but does not definitively indicate carrier status.

Molecular genetic testing focuses on X-linked forms of EDMD, with the gene located at Xp28 on the long arm of the X chromosome.
Multipoint analysis has localized the EMD gene near the red-green color blindness pigment gene, mapped as cen-(DXS52, DXS15)-3cM-(RGCP, EMD)-3cM-F8C-qter.
On polymorphic DNA fragments, DXS52 (probe St14) and DXS15 (DX13) are identified as proximal markers.
The factor VIII coagulant gene at F8C may be the distal marker for EMD.

The EMD gene is likely to be Actin-binding protein 280 (ABP 280, filamin), located between PGCP and G6PD, which cross-links actin in phosphoproteins and enhances branching of actin filaments, connecting actin to glycoproteins on the cell membrane, with the N-terminal actin binding closely to dystrophin.
In cardiomyocytes, intercalated discs may facilitate electrical conduction.
ABP 280 shows that deletions can have widespread and embryonically lethal effects, with mutations specific to isoforms in skeletal and cardiac muscle causing EMD still under debate.

Additionally, ABP-280 provides further evidence for the EMD gene from reports showing RT-PCR from skeletal muscle cells producing abnormal products.
However, detailed analyses have led other groups to disagree that ABP280 is the EMD gene.
Nonetheless, several other genes have recently been identified from the EMD interval analysis, some of which show high expression in cardiac and skeletal muscle, and these are now considered potential causative genes for EMD.

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Reply Date: 2012/10/22