Congenital muscular dystrophy: a study of phenotypical variability and clinical-immunohistochemical correlation

Abstract

We studied 57 patients with congenital muscular dystrophy (CMD) and among them 40 were assessed for 5-laminin chains (alfpha-1, alpha-2, beta-1, beta-2, and gamma-1) by immunohistochemistry on the muscular biopsy, and 7 only for alpha-2 laminin (merosin). Of the 47 patients assessed for merosin, 22 were merosin-deficient and 25 merosin-positive, including two typical cases of Walker-Warburg syndrome with "cobblestone" lissencephaly, hydrocephalus, severe mental retardation, microphthalmia and other ocular abnormalities. A subgroup of 7 patients with merosin deficiency showed only a partial reduction that was detected by both antibodies for alpha-2 80 kDa and alpha-2 300 kDa in 6 and only by the antibody for alpha-2 300 kDa in one, thus demonstrating that the antibody for alpha-2 300 kDa offers a more precise immunohistochemical detection of the partially deficient type of CMD. Twenty-one merosin-deficient patients had abnormal T2 sequence signal of white matter on magnetic resonance imaging (MRI) and one had hypodensity of brain white matter on computerized tomography (CT) scanning; no patient in this group achieved independent walking except one with partial deficiency who after a period of independent walking lost it at the end of the first decade of life. Among the remaining patients with partial deficiency of merosin we observed that three patients with complete absence of one merosin fragment and reduction of the other showed a more severe clinical phenotype than other three who had a partial expression of both fragments. The immunohistochemical pattern of the remaining merosin chains in 19 merosin-deficient patients who had complete immunohistochemical analysis of laminin chains on muscle biopsy was characterized by overexpression of alpha-1 chain in 100% and weakly reduced expression of beta-1, beta-2 and gamma-1 chains in 89.5%, 73.7% and 57.9%, respectively. Excluding the two cases with Walker-Warburg syndrome, in addition to the remaining 23 merosinpositive patients we included 5 familiar cases without biopsy whose phenotype was identical to the respective siblings. Of the last 5 patients without any immunohistochemical analysis, three had abnormal white matter on brain MRI and severe muscle involvement and were included within the merosin-deficient group and two had respectively mild and moderate clinical phenotype, one of them with no abnormalities of brain white matter on CT scanning, while the other did not perform neuroimaging examination. Both patients were included among merosin-positive group. In the total group of 30 merosin-positive patients, 70% achieved independent walking and among 19 who had a complete immunohistochemical analysis of laminin chains, 31.6% showed alpha-1 overexpression, and 26.3%, 21.1% and 21.1% showed a slight reduction of expression of beta-1, beta-2 and gamma-1 laminin chains, respectively. Considering the total amount of patients with and without immunohistochemical study, we observed homogeneous clinical severity in the merosin-deficient group (25 cases) and strong cl...