Research Article: Trinucleotide repeat expansion length as a predictor of the clinical progression of Fuchs’ Endothelial Corneal Dystrophy

Date Published: January 25, 2019

Publisher: Public Library of Science

Author(s): Yu Qiang Soh, Gary Peh Swee Lim, Hla Myint Htoon, Xin Gong, V. Vinod Mootha, Eranga Nishanthie Vithana, Viridiana Kocaba, Jodhbir Singh Mehta, Alfred S. Lewin.


To determine if CTG18.1 TNR expansion length prognosticates the clinical progression of Fuchs’ Endothelial Corneal Dystrophy (FECD).

This was a prospective cohort study. A total of 51 patients with newly diagnosed FECD were recruited and followed-up over a period of 12 years, from November 2004 to April 2016. Baseline clinical measurements included central corneal thickness (CCT), endothelial cell density (ECD) and CTG18.1 TNR expansion length from peripheral leukocytes, with yearly repeat measurements of CCT and ECD. A patient was defined to have experienced significant clinical progression and to have developed Threshold Disease if any of these criteria were fulfilled in either eye: a) CCT increased to >700μm, b) ECD decreased to <700 cells/mm2, or c) underwent keratoplasty for treatment of FECD. Patients were categorized as having at least one allele whose maximum allele length was equal to or greater than 40 repeats (L≥40, n = 22, 43.1%), or having both alleles shorter than 40 repeats (L<40). Threshold Disease rates at the 5-year time point were 87.5% for the L≥40 group and 47.8% for the L<40 group (p = 0.012). This difference narrowed and was no longer statistically significant at the 8-years (92.9% vs 78.9%, p = 0.278) and 10-years (92.9% vs 84.2%, p = 0.426) time points. L≥40 patients are at greater risk of FECD progression and development of Threshold Disease within the first 5 years following diagnosis.

Partial Text

Fuchs’ endothelial corneal dystrophy (FECD) is one of the leading indications for endothelial keratoplasties (EK) in developed nations. In 2015, FECD accounted for 47.1% of all endothelial keratoplasty procedures performed in the United States of America.[1] FECD is characterized by guttate excrescences on the Descemet’s membrane (DM) located mostly within the central inter-palpebral zone, with relative sparing of the peripheries.[2] DM guttata are associated with dysfunctional corneal endothelial cells exhibiting morphological features such as pleomorphism and polymegathism, and derangements in the endothelial cell pump function.[3]

In this prospective cohort study, all newly diagnosed FECD patients presenting to the corneal department in the Singapore National Eye Centre (SNEC) for the first time were evaluated. FECD was diagnosed based on the classic clinical features of DM guttae and corneal edema, and evidence of endothelial dysfunction on specular microscopy, such as the presence of a reduced corneal endothelial cell density, pleomorphism and polymegathism.[25] Inclusion criteria was that of FECD with disease severity of at least Grade 4 on the Krachmer clinical grading scale.[7] Patients who had previously undergone any form of ocular surgery, including cataract extraction surgery, were excluded. All patients were recruited following informed consent, with explanation of the nature and possible consequences of the study. Baseline measurements of CTG18.1 repeat expansion length, central corneal thickness and endothelial cell density were obtained. This study was performed in accordance to the tenets of the Declaration of Helsinki, with ethical approval granted by the Singapore Health Services (Singhealth) Institutional Review Board (IRB).

Patients with early FECD who do not yet require keratoplasty are often managed conservatively with regular yearly follow-up evaluations. While the initial diagnosis and severity of FECD can be easily determined by a clinician during each visit, it may not be possible currently to accurately advise the patient on his or her risk of experiencing significant clinical progression potentially requiring keratoplasty in future. In this study, we found CTG repeat length to be a useful adjunct indicator which may be used to counsel an FECD patient regarding his or her risk of significant clinical progression and keratoplasty over the next 10 years. There was more rapid clinical progression of FECD amongst patients who harbor an expanded CTG18.1 allele (i.e. L≥40 group), during the first 5 years. This difference was subsequently reduced and eventually became statistically insignificant from 8 years onwards, due to clinical progression which also eventually occurred, albeit at a slower rate, amongst patients in the L<40 group. The observed phenomenon of a large majority of L<40 patients eventually progressing to develop threshold disease by the 8th year is probably also reflective of the fact that FECD progression is dependent on genetic factors (i.e. CTG repeat expansion length) as well as epigenetics influences such as environmental exposure to oxidative stresses, which have not been characterized in this study.   Source:


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