Purpose To report four cases of Fuchs endothelial corneal dystrophy (FECD)

Purpose To report four cases of Fuchs endothelial corneal dystrophy (FECD) in patients with an established diagnosis of myotonic dystrophy (DM) and suggest a mechanism for their association based on the known molecular genetics and potential pathophysiological parallels of DM and FECD. The corneal specimens from two of the four patients who had undergone corneal transplant were pathologically confirmed to be consistent with FECD. Conclusion To our knowledge FECD has not been previously reported in association with DM. Because both diseases are somewhat prevalent in the WH 4-023 U.S. it is possible that their coexistence is merely a coincidence in these patients. However recent studies into the pathogenesis of each disease have shown more parallels between FECD and DM suggesting the possibility of WH 4-023 a non-coincidental association. Potential mutual pathogenic mechanisms may involve altered protein expression causing deregulation of ion homeostasis an unstable intronic trinucleotide repeat expansion or activation of the unfolded protein response and oxidative stress pathways. gene and is crucial to proper development of the eye.1 SIX5 is expressed throughout the adult human corneal epithelium and endothelium lens and ciliary body epithelium and the retina and sclera.1 Mice deficient in SIX5 develop cataracts but not abnormalities of skeletal muscle Rabbit Polyclonal to JAK2. function.11 Due to the role of the endothelial Na+/K+ ATPase in maintaining deturgescence of the cornea the fact that SIX5 is a transcription factor influencing the expression of the α1 subunit of the ATPase provides a link between DM and FECD.1 Its altered expression may lead to deregulated ion homeostasis within the WH 4-023 cornea as well as within the lens giving a clinical and pathologic picture consistent with FECD. Similar to WH 4-023 DM1 the unstable TCG repeat recently found in TCF4 is WH 4-023 located in a noncoding region (third intron) of the gene so it may cause the FECD phenotype via a toxic RNA-mediated mechanism as WH 4-023 well.6 TCF4 encodes the E2-2 protein of the class I basic helix-loop-helix (bHLH) transcription factors and expression of adjacent genes and downstream proteins may be affected by altered interactions with normal or abnormal transcripts. Although the full significance of the TCF4 intronic trinucleotide repeat in FECD has yet to be elucidated the relationship between the noncoding repeats in both FECD and DM may hint at an analogous genetic and molecular etiology that justifies a clinical correlation between the two diseases. Of note Patient 3 from Table 1 reported that none of her relatives in the generation above her has either MD or FECD but her three children have MD and two of them have confirmed FECD as well (the third has not had an eye exam to her knowledge). It is therefore possible that this variable expressivity of myotonic dystrophy gives a similar picture in certain patients such as the four reported here. This observation may also be due to the phenomenon of anticipation which has been documented in DM1 pedigrees as well as in many other trinucleotide repeat disorders.12 Further investigation into the number of repeats in DM patients with concurrent FECD may provide some answers regarding whether or not there is a threshold repeat length for disease association. Another potential shared mechanism of disease causation involves the apoptotic pathway possibly resulting from oxidative and endoplasmic reticulum (ER) stress. Recent findings have highlighted a potential central role of the oxidative stress and unfolded protein response (UPR) pathways in the pathogenesis of FECD.13 14 Since upregulation of markers in these same pathways have been demonstrated in DM1 muscle cells these results may be consistent with a joint pathway in the progression towards the FECD and DM phenotypes in various cells.15 16 Though many recent advances possess expanded our knowledge of the pathophysiology and genetic basis for FECD and DM the precise molecular mechanisms stay elusive. This record of four instances of FECD in individuals having a known analysis of DM may recommend a non-coincidental shared pathogenic system that merits extra investigation. Not merely will recognition of any putative interrelated pathways common to both illnesses provide additional insights in to the pathogenesis of every disease individually it could also result in new possibilities for therapeutic advancement. Acknowledgments Financing: This function was generously backed by grants through the J. Alice and willard S. Marriott Basis Edward Colburn Lorraine Collins Richard Dianich Mary Finegan Barbara Freeman Stanley Friedler MD Diane Kemker Jean Mattison Lee Silverman and Norman Tunkel PhD (all to.