LMNA
The LMNA gene provide instructions for the production of the lamin A and lamin C proteins. Mutations in this gene can cause one four types of LMNA-related disorders:
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LMNA-Related Congenital Muscular Dystrophy (LMNA-CMD)
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Emery-Dreifuss Muscular Dystrophy Type 2 (EDMD2)
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Emery-Dreifuss Muscular Dystrophy Type 3 (EDMD3)
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Limb-Girdle Muscular Dystrophy type 1B (LGMD1B)
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Characteristics by Phenotype
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LMNA-CMD: muscle weakness, pronounced axial weakness (head drop), joint contractures, scoliosis, cardiac conduction defects, and respiratory insufficiency
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EDMD2: muscle weakness, limb-girdle weakness, joint contractures, scoliosis, cardiomyopathy and cardiac arrhythmias
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EDMD3: muscle weakness and atrophy of the upper and lower limbs, joint contractures, scoliosis, and cardiac arrhythmias
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LGMD1B: distal muscle weakness, cardiomyopathy, bradycardia, conduction defects of the heart and respiratory insufficiency
joint contractures
dropped head
(axial weakness)
scapular winging
Diagnosing LMNA-RD
LMNA-CMD: Creatinine Kinase (CK) levels may be elevated and examination of a muscle biopsy would indicate a dystrophic process. Outside of the clinical features, genetic testing for the LMNA mutation
would provide a more specific diagnosis and is less invasive than a muscle biopsy.
Emery-Dreifuss Muscular Dystrophy 2: CK levels can be moderately elevated. Outside of the clinical features, genetic testing for the LMNA mutation would provide a more specific diagnosis and is less invasive
than a muscle biopsy.
Emery-Dreifuss Muscular Dystrophy 3: Muscle biopsy will show dystrophic changes. Outside of the clinical features, genetic testing for the LMNA mutation would provide a more specific diagnosis and is less
invasive than a muscle biopsy.
LGMD1B: Increased CK, muscle biopsy showing mild dystrophic changes, EMG showing myopathic changes.
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Physiology of LMNA Related Disorders
Lamin A/C is a protein found in the intranuclear intermediate filament that attaches to the inner nuclear membrane of the muscle cell. This intranuclear intermediate filament provide stability and strength to cells. Lamins A and C are scaffolding (supporting) 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, and researchers believe it 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. Mutations of this gene will alter the production of the lamin A and C.
LMNA-CMD is predominately congenital onset and on the severe end of the spectrum. Affected individuals have weak neck and axil muscles, can develop “dropped head” syndrome and may not achieve sitting. Contractures of the, spine, hips, knees and Achilles tendons are involved. Scoliosis and spine rigidity can develop. Some affected individuals can achieve walking but will lose that ability later. Respiratory insufficiencies develop requiring intervention. Cardiac conduction abnormalities can occur. LMNA-CMD is inherited in an autosomal dominant manner.
EDMD2 (formerly LGMD1B) is typically early onset, usually within the first decade of life, with slow progression. Muscle wasting and weakness of the limb-girdle is involved and there are contractures of the neck, elbows and Achilles tendon. Scapular winging, rigid spine, scoliosis may be present. Walking may become difficult. Affected individuals can develop an increased risk of cardiac sudden death due to dilated cardiomyopathy, cardiac arrhythmias and cardiac conduction defects. EDMD2 is inherited in an autosomal dominant manner.
EDMD3 can vary in onset, but most individuals develop symptoms during the first or second decade of life. Muscle wasting and weakness of the limb-girdle develops along with difficulty walking. Loss of reflexes in the lower limbs can also develop. Neck, elbow and heel cord contractures may develop, and some affected individuals develop scoliosis. Cardiac arrhythmias may also be present. EDMD3 is inherited in an autosomal recessive manner.