Pearson?s Syndrome (PS) is a mostly sporadic systemic disorder of oxidative phosphorylation. The disease shows considerable heterogeneity, as patients present in infancy with severe, transfusion dependent macrocytic anemia, lactic acidosis, and many other possible symptoms. All previously reported PS cases have been associated with mitochondrial DNA (mtDNA) rearrangements. We have identified the first example of a non-deletion case of PS. I will test the hypothesis that the breadth of phenotypes seen in patients with PS is a result of the type of mutation, which may include missense mutations, and the degree of heteroplasmy present in the affected organ. This will involve the following specific aims:
Aim 1 : Establish the clinical relevance of a unique mitochondrial missense mutation affecting cytochrome b in a non-deletion case of PS.
Aim II : Develop a valid, fast-throughput laboratory-based system for diagnosis of PS.
Aim III Determine the breadth of genetic heterogeneity of patients with PS by screening patients for missense mutations and classifying the associated biochemical defect.
Aim I V: Improve the outcome of PS patients by hormonally stimulating bone marrow cell division and differentiation.
