chondroitin-sulfates and Developmental-Disabilities

In the past several years, a great deal has been learnt about the molecular basis through which specific neural pathways in the visual system are established during embryonic development. This review provides a framework for understanding the principles of retinal ganglion cell axon guidance, and introduces some of the families of axon guidance molecules involved. In addition, the potential relevance of retinal axon guidance to human visual developmental disorders, and to retinal axon regeneration, is discussed.

Topics: Axons; Child; Chondroitin Sulfates; Developmental Disabilities; Drosophila Proteins; Ephrins; Eye; Fibronectins; Humans; Nerve Growth Factors; Nerve Regeneration; Nerve Tissue Proteins; Netrin-1; Neural Pathways; Nucleotides, Cyclic; Optic Disk; Receptors, Drug; Retinal Ganglion Cells; Semaphorins; Superior Colliculi; Tumor Suppressor Proteins; Visual Cortex

Costello syndrome is a distinctive multiple congenital anomaly syndrome, characterized by loose soft skin with deep palmar and plantar creases, loose joints, distinctive coarse facial features, skeletal abnormalities, cardiac abnormalities (cardiovascular malformation (CVM), hypertrophic cardiomyopathy, tachycardia), predisposition to malignancy, developmental delays, and mental retardation. Previous studies with cultured fibroblasts from individuals with Costello syndrome demonstrate excessive accumulation of chondroitin sulfate-bearing proteoglycans, associated with both impaired formation of elastic fibers and an unusually high rate of cellular proliferation. Despite multiple clinical reports of cardiac abnormalities, there has been only one previously published report describing post-mortem findings in hearts from Costello syndrome patients. Here we provide a detailed description of the post-mortem findings of the hearts of three children with Costello syndrome. Routine histological examination and results of targeted histochemical and immunohistochemical studies revealed that in addition to cardiomyocyte hypertrophy, these hearts also demonstrated massive pericellular and intracellular accumulation of chondroitin sulfate-bearing proteoglycans and a marked reduction of elastic fibers. Normal stroma was replaced by multifocal collagenous fibrosis. Most peculiar was the finding that the bulk of the chondroitin sulfate accumulated in these Costello syndrome hearts is a chondroitin-6-sulfate. In contrast, deposition of chondroitin-4 sulfate was below the level detected in normal hearts. We propose that an imbalance in sulfation of chondroitin sulfate molecules and subsequent accumulation of chondroitin-6-sulfate in cardiomyocytes contribute to the development of the hypertrophic cardiomyopathy of Costello syndrome.

Topics: Abnormalities, Multiple; Cardiomyopathy, Hypertrophic; Child; Child, Preschool; Chondroitin Sulfates; Developmental Disabilities; Face; Fatal Outcome; Humans; Infant; Intellectual Disability; Male; Myocardium; Skin Abnormalities; Syndrome