The childhood muscular dystrophies: making order out of chaos.
New discoveries have dramatically changed the way we approach and think about patients with childhood muscular dystrophies. An aura of order and organization seems to be at hand for a group of diseases which previously seemed endlessly heterogeneous. We have learned that young boys and girls with proximal muscle weakness, large calves and elevated serum CK may have any one of a number of closely connected disorders which affect a complex of interacting proteins of the dystrophin-glycoprotein complex. This complex links the intracellular cytoskeleton to the extracellular matrix. Patients with Duchenne and Becker dystrophies lack dystrophin, while some of the limb girdle muscular dystrophies (an archaic term) are deficient in sarcoglycans and other proteins. The concept of interrelated disorders extends to the previously orphaned distal muscular dystrophies, or distal myopathies, as they are often called. A surprise finding is that the C. elegans protein, dysferlin, is conserved and expressed in man. We know little of the function of this protein in human primates, but its loss in muscle has brought seemingly disparate disorders together, since both a form of LGMD (2B) and distal myopathy (Miyoshi myopathy) are deficient in this same gene product. The congenital muscular dystrophies are also well-entrenched in our expanding concepts of orderliness of disease. The defect in the laminin-alpha2 chain, a direct ligand to the dystrophin-glycoprotein complex, causes a form of muscular dystrophy which affects infants. Another variant of congenital muscular dystrophy is deficient the integrin alpha7, an important laminin receptor. Finally, in Fukuyama congenital muscular dystrophy, the deficient fukutin gene product may also be linked to the basal lamina, permitting overmigration of neuronal cells which lead to micropolygyria in the brain, and at the same time cause basal lamina defects in the extracellular matrix of skeletal muscle, which leads to muscular dystrophy. As we approach the millennium, those of us who have seen the transition from the pre-molecular to the molecular era of myology know that we leave behind a great legacy of chaos (no great loss), replaced by a foundation for conceptual organization which will serve to establish new roots for research as well as for the enriched practice of medicine. The future looks bright for our field and our patients!
Tsao
C Y
CY
Department of Neurology, The Ohio State University, Columbus 43210, USA.
Mendell
J R
JR
D002648:Child; D003402:Creatine Kinase / Q000097:blood; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006801:Humans; D007797:Laminin / Q000172:deficiency / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics*; D008565:Membrane Proteins; D009119:Muscle Contraction; D009136:Muscular Dystrophies / Q000151:congenital / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017474:Receptors, Laminin / Q000235:genetics
D016189:Dystrophin; D016326:Extracellular Matrix Proteins; C113587:FKTN protein, human; D007797:Laminin; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011506:Proteins; D017474:Receptors, Laminin; D003402:Creatine Kinase