Clinical correlations in 16 patients with total or partial laminin alpha2 deficiency characterized using antibodies against 2 fragments of the protein.

Abstract

Many patients with classic congenital muscular dystrophy have been found to have partial or total deficiency of the alpha2 chain of laminin 2 (merosin). This deficiency has mostly been studied using only 1 antibody against a fragment of the protein. To characterize the expression of laminin alpha2 in the skeletal muscle of patients with laminin alpha2 deficiency using antibodies against 2 different portions of the protein and to correlate the immunochemical findings with clinical phenotype. We studied 4 patients with total lack of laminin alpha2 and 12 with partial laminin alpha2 deficiency with immunohistochemical techniques and Western blot analysis. We used antibodies recognizing an 80-kd fragment toward the C-terminus and a 300-kd fragment toward the amino-terminal. Patient characteristics examined were functional compromise, magnetic resonance imaging or computed tomography of the brain, electromyography, evoked potentials, and creatine kinase levels. In 4 patients, immunohistochemical analysis revealed no reactivity to either antibody; in 2 patients, the 300-kd fragment alone was partially expressed; in 2 patients, the 80-kd fragment alone was partially expressed; and in 8 patients, both fragments were partially expressed. Immunoblot analysis revealed bands of reduced intensity and normal molecular weight generally corresponding to the immunohistochemical findings. Absence of both fragments or of one with reduction of the other always produced a severe clinical phenotype, while a milder clinical phenotype was observed when both fragments were partially expressed. Extent of laminin alpha2 deficiency in most cases correlates with clinical phenotype but not with peripheral and central white matter abnormalities. Skin biopsy specimens may reveal laminin alpha2 deficiency in patients who have normal laminin alpha2 levels in muscle biopsy specimens.