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

Distrofia muscular congênita: estudo da variabilidade fenotípica e análise da correlação clínico - imuno-histoquímica

THESES

CONGENITAL MUSCULAR DYSTROPHY: A STUDY OF PHENOTYPICAL VARIABILITY AND CLINICAL-IMMUNOHISTOCHEMICAL CORRELATION (ABSTRACT)^*.THESIS. SÃO PAULO, 1999.

UMBERTINA CONTI REED^**

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 merosin-positive 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 clinical heterogeneity in the merosin-positive group (30 cases), that included 5 cases with associated central nervous system involvement (brain cortical atrophy in one and mental retardation in 4, two of them also with cataracts), two possible cases of rigid spine syndrome and one possible case of hypotonic-sclerotic type of CMD.

Statistical analysis between the two groups was done and there was a significant difference regarding many different parameters. In relation to clinical phenotype - age of onset, poor sucking and respiratory distress at birth, degree of congenital hypotonia, maximal motor capacity, muscular weakness, facial involvement, facial dysmorphism, creatine kinase level, and type of clinical course - showed statistical significance and pointed to a prognosis much more severe in merosin-deficient patients. In relation to muscle biopsy - lipomatosis, endo-perimysial fibrosis, and variation in fiber size - were significantly higher in the merosin deficien group. Finally, also the results of the immunohistochemical analysis showed that both - the overexpression of alpha-1 chain, and the slight reduction of beta-1, beta-2 and gamma-1 chains expression - were significantly more marked in the merosin-deficient type of CMD.

We conclude that the overexpression of the alpha-1 chain associated with a slight reduction of beta-1 and beta-2 laminin chains is characteristic of the merosin-deficient group that is better defined by the utilization for the alpha-2 300 kDa and even in a few merosin-positive cases who had a greater clinical severity (30%) there are heterogenous manifestations and it is not possible to demonstrate clinical overlap between the two subgroups.

KEY WORDS: congenital muscular dystrophy, phenotypical variability, clinical-immunohistochemical correlation.

**Address: Rua Marechal Hastinphilo de Moura 338/B-19A, 05641-900 São Paulo SP, Brasil.

*

Distrofia muscular congênita: estudo da variabilidade fenotípica e análise da correlação clínico - imuno-histoquímica (Resumo) Tese de Livre-Docência, Faculdade de Medicina da Universidade de São Paulo (Disciplina de Neurologia Infantil).

Publication Dates

• Publication in this collection
  06 Dec 2000
• Date of issue
  June 2000