Pyruvate dehydrogenase phosphatase deficiency: orphan disease or an under-diagnosed condition?

Pyruvate dehydrogenase phosphatase (PDP) is an enzyme which regulates the activity of the pyruvate dehydrogenase complex (PDHc). In the past, PDHc deficiency has been attributed to mutations in the complex itself and the regulatory enzymes have not been considered. We have recently reported the first mutation in PDP1, one of the two isoforms of PDP, which results in severe exercise intolerance and mild developmental delay in patients. This novel process of aberrant pyruvate metabolism opens up a new avenue for investigation into PDHc deficiency, that has hitherto been underappreciated.