LAMININ ALPHA-2 CHAIN-DEFICIENT CONGENITAL MUSCULAR-DYSTROPHY - VARIABLE EPITOPE EXPRESSION IN SEVERE AND MILD CASES

Objective: To characterize the expression of distinct fragments of lam inin alpha 2 chain in patients with partial laminin alpha 2 chain defi ciency and variable clinical severity. Background: Deficiency of lamin in alpha 2 chain caused by mutations of the LAMA2 gene on chromosome 6 q2 account for approximately 50% of cases of congenital muscular dystr ophy (CMD) in white patients. The complete absence of laminin alpha 2 is usually associated with a severe phenotype affecting skeletal muscl e and the peripheral and central nervous systems. Methods: Quantitativ e assessment of immunofluorescence to study the expression of C- and N -terminal portions of laminin alpha 2 chain in five patients with part ial laminin alpha 2 chain deficiency and variable phenotype. All five patients showed abnormal T2 signal on brain MRI, Results: Immunohistoc hemistry of muscle specimens showed preserved or minimally reduced exp ression of the C-terminal region of the laminin alpha 2 chain (67 to 7 4%), but a marked reduction of the N-terminal region in four patients (13 to 19%). One patient with a mild phenotype had a partial reduction (45%) of the C-terminal and the N-terminal (51%) portions of the lami nin alpha 2 chain. Two patients were unable to walk or sit, although t he C-terminal portion of the laminin alpha 2 chain was expressed at si gnificant levels (67 to 74%). In contrast, two patients with a similar expression of the C-terminus (67 to 70%) had a milder phenotype and b ecame ambulatory. It was impossible to predict the phenotypes in these four patients with a strong expression of the C-terminus and with low levels of the N-terminus based on the amount of protein expressed. In addition, the laminin beta 2 chain was moderately reduced (54 to 75%) in all patients with laminin alpha 2 chain deficiency. A strong corre lation between the amount of the C-terminus but not for the N-terminus and laminin beta 2 reduction could be observed. Conclusions: N-termin al antibodies to the laminin alpha 2 chain provide a more precise immu nohistochemical detection of partially laminin alpha 2 chain-deficient CMD, The secondary reduction of laminin beta 2 chain may better defin e laminin alpha 2 chain-deficient CMD. More data are needed to predict which portions of C-terminus and midrod region of the laminin alpha 2 chain result in a semifunctional protein and a milder phenotype.