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Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndrome
D W Hollister1, M Godfrey, L Y Sakai
1Portland Unit, Shriners Hospitals for Crippled Children.
Background:
Indirect-immunofluorescence studies of skin and cultured dermal fibroblasts from patients with the Marfan syndrome demonstrate apparent deficiency of one element of connective tissue--the microfibrillar-fiber system--in assays using specific antibodies against fibrillin, a major microfibrillar protein. This study was designed to test whether these immunostaining abnormalities are consistent and diagnostic features of the disease.
Methods:
We studied patients with either the Marfan syndrome or various other inherited connective-tissue disorders and normal subjects according to a single-blind protocol in which coded samples of skin, fibroblast cultures, or both were analyzed without knowledge of the clinical diagnosis and classified as "Marfan" or "non-Marfan" before the sample codes were broken.
Results:
Of the 27 patients with the Marfan syndrome, 24 were correctly identified by the decreased content of microfibrillar fibers in their skin, cultured fibroblasts, or both; in contrast, 19 of 25 patients with other heritable disorders of connective tissue and all 13 normal subjects were correctly classified as "non-Marfan" by these assays (P less than 0.001).
Conclusions:
These results document consistent, relatively specific abnormalities of microfibrillar fibers in the Marfan syndrome. The biomechanical incompetence of these structural elements, due to quantitative or qualitative abnormalities, may account for the pleiotropic clinical manifestations of the disease. Therefore, various defects in the expression, structure, assembly, or degradation of the constituent structural glycoprotein (or glycoproteins) of microfibrils may be implicated in the causation of the Marfan syndrome.
Insights
Immunostaining for fibrillin, a key microfibrillar protein, reveals consistent abnormalities in Marfan syndrome patients. This diagnostic test accurately distinguishes Marfan syndrome from other connective tissue disorders.
Area of Science:
- Connective tissue disorders
- Molecular biology of extracellular matrix
- Genetic disease diagnostics
Background:
- Marfan syndrome is characterized by connective tissue abnormalities.
- Previous studies showed apparent microfibrillar system deficiency in Marfan syndrome patients using fibrillin antibodies.
- The consistency and diagnostic utility of these findings were unconfirmed.
Purpose of the Study:
- To determine if immunostaining abnormalities for fibrillin are consistent and diagnostic for Marfan syndrome.
- To assess the specificity of these abnormalities in differentiating Marfan syndrome from other connective tissue disorders.
Main Methods:
- A single-blind study analyzed skin and cultured dermal fibroblasts from Marfan syndrome patients, other connective tissue disorder patients, and normal subjects.
- Samples were coded and analyzed for microfibrillar fiber content using fibrillin-specific antibodies before clinical diagnoses were revealed.
Main Results:
- The assays correctly identified 24 out of 27 Marfan syndrome patients based on decreased microfibrillar fiber content.
- In contrast, 19 out of 25 patients with other connective tissue disorders and all 13 normal subjects were correctly classified as non-Marfan.
- These classification differences were statistically significant (P < 0.001).
Conclusions:
- Abnormalities in microfibrillar fibers are consistent and relatively specific features of Marfan syndrome.
- Biomechanical incompetence of these fibers, due to quantitative or qualitative defects, likely underlies the diverse clinical manifestations.
- Defects in the expression, structure, assembly, or degradation of microfibril glycoproteins may cause Marfan syndrome.