LAMA2-RD is the result of two genetic mutations that cause complete or partial deficiency in the production of the laminin 211 (merosin) protein. Affected individuals are characterized by muscle weakness, joint contractures, facial weakness, white matter changes, and sometimes seizures.
Characteristics of LAMA2-Related Dystrophy
Brain abnormalities, including white matter changes as noted on MRI
Along with observation of clinical characteristics of 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. Genetic testing to identify mutations in LAMA2, along with muscle imaging and brain MRI with white matter changes, may confirm diagnosis. A muscle or skin biopsy may also reveal whether there is a partial or complete absence of laminin, but this is an invasive procedure not necessarily recommended in light of other testing modalities now available .
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White matter changes
Prof. Umbertina Conti Reed, Arq. Neuro-Psiquiatr.
vol.67 no.1 São Paulo Mar. 2009
Physiology of LAMA2-RD
LAMA2-RD is caused by two mutations in the LAMA2 (laminin alpha 2) gene which codes for the production of the protein, merosin. This protein is part of the extracellular matrix (ECM) of the muscle cell membrane. Merosin supports muscle cell stability and regeneration while allowing the muscle cell to adhere to the ECM. Laminins plays a major role in binding other proteins together, not only in the ECM but also to the muscle cell membrane. Laminins help maintain muscle fiber stability.
Affected individuals with complete deficiency are most likely to experience symptom onset at birth or soon after. Symptoms may include hypotonia, joint contractures, breathing and feeding difficulties, and facial weakness causing an open-mouth appearance. Scoliosis may develop within the first decade of life.
Those with partial merosin deficiency may develop milder symptoms later in life, with some affected individuals retaining ambulation into adulthood.
White matter abnormalities on brain MRI is typically present across the LAMA2-RD spectrum, and approximately 30% of affected individuals will develop seizures.
Mutations in LAMA2 can also cause Limb Girdle Muscular Dystrophy (LGMD23), which is also autosomal recessive.
Inheritance and Genetic Testing
LAMA2-RD is inherited in an autosomal recessive fashion, meaning there must be two pathogenic mutations present to cause symptoms. Mutations may be inherited from each parent, or may be denovo (spontaneous). Because the LAMA2 gene is quite large, it is not uncommon for only one of the two mutations to be identified with standard genetic testing. One pathogenic mutation, along with clinical characeristics, elevated CK, white matter changes, and partial or complete absence of merosin on muscle or skin biopsy can confirm a diagnosis of LAMA2-RD.