HyperCKemic, proximal muscular dystrophies and the dystrophin membrane cytoskeleton, including dystrophinopathies, sarcoglycanopathies, and merosinopathies.

Of the various muscular dystrophies, the dystrophinopathies are the most common, accounting for the majority of male muscle disease patients and for about 10% of female patients referred for the evaluation of muscular dystrophy or persistent high serum creatine kinase values (hyperCKemia). The approach to diagnosis and family genetic counseling for the dystrophinopathies is now well established, and implementation of carrier detection and prenatal diagnosis has dramatically decreased the incidence of familial cases. With the decreasing observation of a positive family history in newly ascertained cases, molecular genetic and protein studies become imperative for accurate diagnosis. Genetic counseling in families of isolated cases can still be problematic. There is a wide range of opinions regarding the management of Duchenne muscular dystrophy, with surgical interventions (eg, tendon lengthenings and spinal fusion), steroid use, and extent of respiratory support actively debated. There has been progress in defining the underlying cause of disease for some patients of muscular dystrophy who have normal dystrophin findings. Nearly all patients with proximal, hyperCKemic muscular dystrophy who have normal dystrophin show no family history of the disorder, consistent with autosomal recessive disease. Approximately 5% of both boys and girls with childhood-onset dystrophy and normal dystrophin have been found to have mutations in one of the four sarcoglycan proteins identified to date. Also, approximately half of the patients with congenital muscular dystrophy show deficiency of a component of the muscular extracellular matrix. (merosin/laminin-alpha 2). In this review, we give a short primer on relevant muscle structure and function, followed by a series of case reports on patients referred for molecular testing that illustrate the diagnostic protocols, range of clinical presentations, and genetic counseling options in the work-up of proximal muscular dystrophy and hyperCKemia.