Severe Phenotypes of Granular Corneal Dystrophy Type 2

and Genetic Analysis Results Yong Woo Ji, MD, Eung Kweon Kim, MD, PhD, Seung-Il Choi, PhD,

Bong-Yoon Kim, PhD, Tae-im Kim, MD, PhD, and Hyung Keun Lee, MD, PhD

Corneal Dystrophy Research Institute, Department of Ophthalmology, Severance Hospital,

Yonsei University College of Medicine, Seoul, Korea

The authors have no financial or proprietary interest in any of the products or techniques mentioned in this presentation.

Granular corneal dystrophy Type 2 (GCD2)

• Also called Avellino Corneal Dystrophy

• GCD2 is an autosomal dominant disorder caused by an Arg124His (R124H) mutation in the transforming growth factor-β-induced (TGFBI) gene on chromosome 5q31.

• GCD2 have prevalence of about 11.5 affected patients per 10,000 individuals in Korea. Among corneal dystrophies related to TGFBI gene mutation, GCD2 shows the highest prevalence.

• Progressive accumulation and aggregation of hyaline and amyloid in the corneal stroma with aging is a characteristic clinical feature of GCD2.

Heterozygous GCD2

• In the early stage of expression in GCD2 heterozygotes, granular deposits are detected in the superficial stromal layer, while lattice deposits are in the deeper stroma later, resulting in diffuse stromal haze with visual impairment.

• Corneal opacities worsen slowly and most patients maintain vision and may experience severe visual impairment only late in life time.

Each PatientIn one’s Teens

In Twenties

In Sixties

Heterozygous GCD2

• However, distinctive heterozygous GCD2 can express diverse phenotypes and unpredictable rapid progression threatening vision even within family or young age.

Molecular Vision 2012;18:1755-1762Cornea 2013;32:296–300

Fig 1. Minimal phenotype of heterozygous GCD2 in 34 year-old male patient

Fig 2. Severe phenotype of heterozygous GCD2 in 35 year-old female patient

Purpose

• GCD2 heterozygotes showed extremely varied phenotypes between individual patients.

• However, the genetic etiology of this variation has not been discussed previously.

• We investigated second TGFBI factors related to more severe expressivity of heterozygous GCD2 for patient’s age.

Methods

(This study was performed in accordance with the Declaration of Helsinki and was approved by the Severance Hospital Institutional Review Board)

Results

Clinical evaluation

A 35 year-old woman visited our clinic for extensive severe multiple discoid granular corneal deposits on both eyes resembling homozygous GCD2. She had best corrected visual acuity (BCVA) 20/50 on both eyes and no other ocular history.

Molecular genetic analysis

A heterozygous C→T transition at nucleotide 535 of exon 5 at the first position of codon 179 (Arg179Stop, R179X) with was detected on the TGFBI gene in GCD2 patient.

Results

Pedigree of family members with genetic analysesAnd clinical evaluation R179X mutation of TGFBI gene is silent by itself. However, when it accompanied with heterozygous R124H, compound heterozygous patient had severe phenotype even in younger age (35 year-old).

Clinical evaluation

A 25 year-old man was referred with severe diffuse corneal haze with multiple granular and lattice deposits causing visual disturbance, even after phototherapeutic keratectomy (PTK) for both eyes at other clinic. His BCVA was 20/50 on right and 20/60 on left eye. Additional PTK for each eye was performed separately 5 years ago at our clinic. Therefore he had still favorable vision, BCVA 20/25 on both eyes.

Molecular genetic analysis

A heterozygous T→A transition at nucleotide 740 of exon 6 at the second position of codon 247 (Ile247Asn, I247N) with was detected on the TGFBI gene in GCD2 patient.

Results

adfasPedigree of family members with genetic analysesAnd clinical evaluation I247N mutation of TGFBI gene is silent by itself. However, when it accompanied with heterozygous R124H, compound GCD2 phenotypes become severe and recur fast after PTK ablation, even with heterozygote.

Results

Conclusions

Arg179Stop and Ile247Asn mutation, etc….