LAMA2 Congenital Muscular Dystrophy (LAMA2-CMD)
LAMA2-CMD is the result of genetic mutations of the laminin protein
called merosin found in the muscle cells. Affected individuals with
LAMA2-CMD are characterized by muscle weakness and contractures
and may be born with complete or partial merosin deficiency
depending on the genetic mutations.
Characteristics of LAMA2 Congenital Muscular Dystrophy
Respiratory and feeding complications
White matter changes
Prof. Umbertina Conti Reed, Arq. Neuro-Psiquiatr. vol.67 no.1 São Paulo Mar. 2009
Along with observation of physical characteristics common in LAMA2-CMD, a blood test to measure creatinine kinase levels (CK) may be ordered as part of the diagnostic assessment. CK levels in LAMA2-CMD affected individuals are often significantly elevated, but as this is also the case with other subtypes of CMD, it can only be used to rule out certain neuromuscular disorders. A muscle or skin biopsy might also be ordered to reveal whether there is a partial or complete absence of laminin. Finally, genetic testing may provide a definitive diagnosis and is less invasive than a biopsy. Next generation sequencing is now widely available and many physicians are now opting for this testing method rather than ordering.
The Physiology of LAMA2 Congenital Muscular Dystrophy
LAMA2-CMD is caused by two mutations in the LAMA2 (laminin alpha 2) gene which produces merosin, one of the laminin proteins. Merosin makes up part of the extracellular matrix of the muscle cell membrane. The extracellular matrix forms the outside environment around the muscle cell. It performs critical functions by supporting muscle cell stability and regeneration while allowing the muscle cell to adhere to the matrix. Laminins plays a major role in binding itself and other proteins together not only in the extracellular matrix but also to the muscle cell membrane. Laminins help to maintain muscle fiber stability.
Affected individuals with LAMA2-CMD are born with complete or partial merosin deficiency depending on where the genetic mutations are located.
Those with complete merosin deficiency will have early onset of the disorder (present at birth) with hypotonia (decreased muscle tone or floppiness), progressive joint contractures, and will develop breathing and feeding problems early in life. Scoliosis and rigid spine can develop. Some will have cardiac abnormalities.
Those with partial merosin deficiency may have later or milder onset (late childhood/early adulthood). Symptoms may be milder with some affected individuals able to walk into adulthood.
White matter abnormalities in MRI images of the brain can be present across the LAMA2-CMD spectrum and some affected individuals will develop seizures.
A mutation in the LAMA2 gene can also cause Limb Girdle Muscular Dystrophy Related 23. It is also autosomal recessive.
Inheritance and Genetic Testing
LAMA2-CMD is inherited in an autosomal recessive fashion, meaning there must be two pathogenic mutations present to cause symptoms. These mutations may be inherited from each parent, or may be denovo (spontaneous). Because the LAMA2 gene is quite large and researchers are still working to fully map it, it is not uncommon for affected individuals to only have had one of the two mutations identified through genetic testing. One identified mutation along with identifiable physical characteristics, elevated CK, white matter changes, and partial or absence of merosin on muscle or skin biopsy can lead to a confirmed diagnosis of LAMA2-CMD.