Ronald D. Cohn

Consensus statement on standard of care for congenital muscular dystrophies

Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. Advances in many areas of medical technology have not been adopted in clinical practice. The International Standard of Care Committee for Congenital Muscular Dystrophy was established to identify current care issues, review literature for evidence-based practice, and achieve consensus on care recommendations in 7 areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/ nutrition/speech/oral care, cardiology, and palliative care. To achieve consensus on the care recommendations, 2 separate online surveys were conducted to poll opinions from experts in the field and from congenital muscular dystrophy families. The final consensus was achieved in a 3-day workshop conducted in Brussels, Belgium, in November 2009. This consensus statement describes the care recommendations from this committee.

Dystroglycan: important player in skeletal muscle and beyond

Dystroglycan is a transmembrane protein that connects the extracellular matrix to the cytoskeleton. Given the ubiquitous tissue expression of dystroglycan, different functional roles in various organ systems have been characterized during the past decade. More recently, aberrant glycosylation of dystroglycan has been identified as a novel pathogenetic mechanism in several forms of congenital and late onset muscular dystrophy syndromes. The current review summarizes the recent scientific achievements as they relate to the function of dystroglycan under normal and pathophysiological conditions.

Infantile Restrictive Cardiomyopathy Resulting From a Mutation in the Cardiac Troponin T Gene

Here we report the first infantile case of restrictive cardiomyopathy caused by a de novo mutation of the cardiac troponin T gene. The patient presented with an apparent life-threatening event. She developed malignant arrhythmias and hemodynamic instability, requiring initial rescue support with extracorporeal membrane oxygenation, and subsequently underwent insertion of a biventricular assist device (VAD). She successfully received an orthotopic heart transplant 172 days after VAD implantation.

Intracranial Hemorrhage as the Initial Manifestation of a Congenital Disorder of Glycosylation

Intracranial hemorrhage in a term neonate is a rare event in the absence of an identifiable precipitating factor such as severe thrombocytopenia, mechanical trauma, asphyxia, infections, or congenital vascular malformations. Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of multisystem disorders characterized by the abnormal glycosylation of a number of glycoproteins. Although bleeding caused by abnormal glycosylation of various coagulation factors is a well-known clinical complication of several types of congenital disorders of glycosylation, intracranial hemorrhage has not been reported as an initial manifestation of this entity. Here we report the detailed history of a family with 2 consecutive male infants, both born at term with intracranial hemorrhage diagnosed within the first 24 hours of life. The diagnosis of a congenital disorder of glycosylation was established in the second infant by an abnormal glycosylation of serum transferrin detected by electrospray-ionization mass spectrometry. Both infants showed significant neurologic deterioration during the first month of life, and both died at 5 months of age. Intracranial hemorrhage in a term neonate without a potential precipitating factor represents yet another clinical feature that should raise the suspicion for a congenital disorder of glycosylation.

D.I.3 Ethical implications of unexpected results from next generation sequencing studies

Abstract Recent advances in next-generation sequencing technologies have brought a paradigm shift in how medical researchers investigate both rare and common human disorders. The ability cost-effectively to generate genome-wide sequencing data with deep coverage in a short time frame is replacing approaches that focus on specific regions for gene discovery and clinical testing. Exome sequencing, and soon whole genome sequencing, places many advantages of the emerging technologies into clinicians and researchers’ hands. The expectation is that, in the very near future, this technology will enable us to identify all the variants in an individual’s personal genome and, in particular, clinically relevant alleles. Beyond this, whole genome sequencing is also expected to bring a major shift in clinical practice in terms of diagnosis and understanding of diseases, ultimately enabling individualized medicine based on one’s genome. As personal genome research advances, investigators and international research bodies must ensure ethical research conduct. Major ethical considerations that have been implicated in whole-genome research include the return of research results to participants; the obligations, if any, that are owed to participants’ relatives; how to deal with an increased ascertainment of novel sequence variants of uncertain clinical significance, and most importantly unveil unanticipated results and ethical dilemmas; and the future use of samples and data taken for whole-genome sequencing. The current lecture will provide an overview of implications for personal genomics and discuss recommendations for appropriate management in the context of research and clinical management involving individual whole-genome sequencing.

Molecular Pathogenesis of Skeletal Muscle Abnormalities in Marfan Syndrome

MFS is a common autosomal dominant systemic disorder of connective tissue with an estimated prevalence of 1 in 5,000–10,000 individuals. It is caused by mutations in FBN1 , the gene encoding the extracellular matrix protein fibrillin-1. Clinical manifestations of MFS include bone overgrowth, ocular lens dislocation, emphysema, and cardiac complications such as aortic aneurysm. A large subset of patients with MFS exhibits a significant decrease in muscle mass, which is often associated with hypotonia, particularly during early childhood. The majority of patients with MFS experience a life-long inability to increase muscle mass despite adequate nutrition and physical exercise. Evidence suggests that the pathogenesis of Marfan syndrome involves excessive activation of and signaling by transforming growth factor-β. The following chapter will discuss how excessive TGF-β signaling contributes to the pathogenesis of muscular abnormalities in Marfan syndrome and other inherited and acquired forms of myopathy.