In this podcast from Nationwide Children’s Hospital, pediatric neurologist Francesco Muntoni describes how current understanding of CMD is creating opportunities for therapy development
|Editor's note (Oct. 19, 2012): This story was updated to reflect the fact that Kevin Flanigan co-directs the MDA Clinic at Nationwide Children's Hospital in Columbus, Ohio.|
In a September 2012 podcast from Nationwide Children's Hospital in Columbus, Ohio, pediatric neurologist and MDA grantee Francesco Muntoni discusses recent advances in the understanding of congenital muscular dystrophies (CMD).
The 25-minute podcast is based on a paper by Muntoni and Eugenio Mercuri, published online July 23, 2012, in Annals of Neurology. (See The ever-expanding spectrum of congenital muscular dystrophies for a summary.) A transcript is provided along with the podcast on the Nationwide site in the section called "This Month in Muscular Dystrophy."
Muntoni is Chair of Paediatric Neurology at University College London and is an MDA research grantee.
He's interviewed by Kevin Flanigan, a specialist in neuromuscular disorders and a principal investigator in the Center for Gene Therapy at Nationwide Children's Hospital. Flanigan also co-directs the MDA neuromuscular disease clinic at Nationwide.
Muntoni makes several points in the podcast.
The term "congenital" muscular dystrophies implies onset of weakness at birth or within the first weeks to months of life. Muscle damage in CMDs probably occurs while a baby is developing before it is born, and may reflect an abnormality in the way muscle forms and how muscle stem cells known as satellite cells proliferate and expand.
Until about 20 years ago, CMDs were divided into only two subtypes — those with major brain involvement and those without major brain involvement. Since then, the field has "exploded" in terms of understanding subtypes of CMD with and without brain involvement.
Most of the proteins that, when deficient, give rise to CMDs, generally fall into two categories. One category consists of proteins that anchor muscle fibers to surrounding tissue. These are located just outside the fibers.
Another category includes enzymes involved in the modification of dystroglycan, one of the anchoring proteins. A large number of these enzymes are involved in glycosylation — "sugar coating" — of dystroglycan.
Until the beginning of 2012, seven types of enzyme deficiencies were in this dystroglycan modification group; they're now known as dystroglycanopathies. Four additional types have been identified in the last few months. There may be more than 20 dystroglycanopathies in all.
This shared mechanism — inadequate coating of dystroglycan with sugar molecules — provides an opportunity for therapeutic development. Some work suggests that it is possible, at least theoretically, to increase this glycosylation process by various methods. Some of these methods may work across several different CMDs.
In the meantime, we know more about predicting and managing the cardiac and respiratory aspects of CMDs and can "keep a step ahead" of these conditions, Muntoni said. The result has been that care for children with CMD has improved to the point where many who previously did not reach adulthood have now transitioned to adult care.
Muntoni also said there are plans to perform clinical trials in CMD, using drugs that intervene at some of the biochemical steps that have now been identified.