Macular Corneal Dystrophy
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Disease Entity
Macular corneal dystrophy (MCD, Fehr corneal dystrophy, Corneal dystrophy Groenouw type II) [ICD-10: H18.551, H18.552, H18.553, H18.559]
Disease
Macular corneal dystrophy (MCD) is a stromal corneal dystrophy characterized by ill-defined gray-white opacities located within a hazy stroma. These opacities can progress to involve the entire corneal and cause corneal thinning. The corneal opacities and stroma hazy seen in MCD are visually significant and can progress to vision loss. Despite MCD classification as a stromal dystrophy, the Descemet’s membrane and the endothelium can be involved. This condition was first differentiated from the other corneal stroma dystrophies by German ophthalmologist Oskar Fehr.[1]
Etiology
MCD has an autosomal recessive inheritance pattern. This inheritance sets this corneal dystrophy apart from most corneal stromal dystrophies, which usually have an autosomal dominant inheritance pattern. Locus was identified on chromosome 16q22 with a mutation of the CHST6 gene which codes for carbohydrate sulfotransferase 6, an enzyme responsible for the sulfation of the keratan molecules.[2] This results in the accumulation of intracytoplasmic glycosaminoglycans leading to clinical manifestations such as stromal hazy and corneal opacities.
The three immunophenotypes of MCD are determined by the amount of keratan sulfate in the cornea and serum.[2] MCD type I is characterized by no detectable keratan sulfate in the cornea or serum. MCD type II is characterized by normal amounts of keratan sulfate in the cornea and serum. MCD Type IA lacks detectable antigenic keratan sulfate in the serum but has stainable keratan sulfate in the keratocytes. MCD type I and IA are more common given most patients do not have detectable keratan sulfate in the serum. However, the differences between these three immunophenotypes are clinically insignificant and cannot be clinically distinguished on examination. [3]
Risk Factors
Like most corneal dystrophies, a positive family history increases the risk of developing MCD. Epidemiologic studies have demonstrated a higher prevalence in Southern India, Saudi Arabia, and Iceland due to increased rates of mutations in genes attributed to MCD.[1] One study demonstrated an MCD prevalence of 19 per 250,000 individuals in Iceland when compared to a prevalence of 0.3 per 250,000 individuals in the United States.[4] This condition is rare in the US and studies have shown that there tends to be increased incidence in families with consanguinity. [3]
General Pathology
Pathophysiology
MCD is caused by the irregular accumulation of glycosaminoglycans in stromal keratocytes due to abnormal carbohydrate sulfotransferase 6. The buildup for these glycosaminoglycans can also infiltrate adjacent layers including Bowman’s, Descemet’s, and the endothelium with sparing of the epithelium. The underlying defect is due to decreased synthesis of keratan sulfate. Without keratan sulfate, proteoglycans such as lumican and keratocan are not produced sufficiently. Lumican and keratocan are vital in corneal collagen fibril organization and insufficient amounts of the proteoglycans result in difficulty maintaining corneal transparency. Furthermore, non-sulfonated keratan can precipitate in the extracellular matrix resulting in smaller collagen fibrils with less interfibrillar spacing, leading to loss of corneal transparency.[5]
Studies have revealed that MCD may be likely secondary to a systemic disorder of keratan sulfate metabolism, supported by a reduced concentration of ear cartilage in a set of patients. [3] Disruption of autophagy due to the mutations associated with this disease has been implicated in causing pyroptosis, contributing to the development of this disorder. [6]
Primary prevention
No preventive strategies have been studied to date. Gene-targeted therapies have been proposed as a possible permanent strategy. However, creating such therapies and implementing them in clinical practice has been faced with multiple challenges.[1]
Diagnosis
History
Patients will start to exhibit corneal stromal opacities and hazy typically in the first or second decade of life but even as late as the sixth decade.[2] Vision becomes significantly impaired usually before the fifth decade as the stromal opacities continue to spread throughout the corneal stroma. This contrasts with most endothelial dystrophies which manifest at a slower rate and become more noticeable once endothelial cells are lost from aging2,5.
Physical examination
It is important to obtain a thorough and complete eye exam for any patient where there is a concern for MCD. In addition to general health evaluation, there should be an assessment of the corneal curvature, astigmatism, and thickness. Best potential vision needs to be evaluated and monitored over time. Tracking the visual acuity will help track the patient’s disease course and guide when it is best to consider surgical intervention. On the slit lamp exam, you can expect to see stromal haze early in the disease course which will be followed by irregular white deposits. [1][2]
Signs and Symptoms
The most common presenting symptom of MCD is decreased visual acuity. Depending on the location of the corneal opacities, visual acuity can range dramatically. One study of MCD reported average visual acuity of 1.1-1.3 LogMar which converts to 20/250 to 20/400 Snellen equivalent. [7] Along with progressive visual impairment, patients can present with eye irritation, eye pain, and photophobia. MCD can also cause reduced corneal sensitivity that is thought to be attributed to recurrent corneal erosions. [8]
Early in the disease process, ill-defined corneal opacities are seen within a diffusely hazy stroma in both eyes. These opacities will continue to expand and eventually merge over time. Anterior stroma depositions are linked with the development of irregular astigmatism. As the condition continues to progress, thinning of the central corneal can develop and deposition in Descemet’s membrane and endothelium can be seen.
Clinical diagnosis
MCD can be diagnosed via slit-lamp biomicroscopy and family history. Additional testing and imaging can aid in the diagnosis. It is important to note that the mean age of diagnosis for this corneal dystrophy tends to be earlier than most others, likely due to the earlier onset of symptoms and progression. [1][3]
Diagnostic procedures
Anterior Segment OCT allows for visualization of anterior and deeper layers of the cornea. Studies utilizing OCT have revealed that there can be a very wide spectrum of presentation and location of deposits in the cornea depending on the patient. [9]
Confocal microscopy will demonstrate hyperreflective material with ill-defined borders and loss of normal keratocytes. [10]
Corneal Topography may demonstrate a higher density of corneal density at the corneal apex with central corneal thinning.
Ultrasound Biomicroscopy may be used to demonstrate deep opacities and focal protrusions of the posterior cornea. [11]
Laboratory test
On histopathological testing, MCD stains positive with periodic acid-Schiff, Alcain blue, and metachromatic dyes, and has an affinity for colloidal iron.[12] The glycosaminoglycans are located intracellularly within the keratocytes and corneal endothelium. Similar compounds are found in the extracellular matrix of the corneal stroma and Descemet’s membrane. Guttae are commonly seen on Descemet’s membrane.
Additional blood testing for serum levels of keratan sulfate can aid in differentiating the types of MCD but may not always be present. [13]
Differential diagnosis
Schnyder Corneal Dystrophy (SCD)
Autosomal dominant corneal stromal dystrophy characterized by the annular deposition of birefringent cholesterol crystals in Bowman’s layer and the adjacent stroma. SCD is associated with a mutation in the UBIAD1 gene on chromosome 1p34.1-p36. Characteristics findings include the development of arcus lipoides due to cholesterol accumulation at the limbus. Patients with SCD will endorse glare and exhibit progressive photopic vision loss. Patients may also present with dyslipidemia with elevated cholesterol levels. [2][14]
Congenital Stromal Corneal Dystrophy (CSCD)
Autosomal dominant corneal stromal dystrophy characterized by diffuse limbus-to-limbus stroma haze that is present at birth. CSCD is associated with a mutation in the DCN gene on chromosome 12q13.2. Although CSCD is visually significant like MCD, it is present at birth and associated with a pronounced thickening of the corneal stroma. [15]
Fleck Corneal Dystrophy (FCD)
Autosomal dominant corneal stromal dystrophy characterized by numerous dandruff-like opacities distributed throughout the corneal stroma. The opacities are caused by the intracytoplasmic accumulation of glycosaminoglycans and complex lipids in keratocytes. FCD is associated with a mutation in the PIP5K3 gene on chromosome 2q35. Areas of stroma between these opacities are grossly normal and opacities are confined only to the stroma. [2][16]
Posterior Amorphous Corneal Dystrophy (PACD)
Autosomal dominant corneal stromal dystrophy characterized by irregular laminar opacities predominantly in the posterior corneal stroma and Descemet’s membrane. The key defining feature of PACD from MCD is the manifestations of non-corneal findings such as scleral changes, iris coloboma, iridocorneal adhesion, iris atrophy, and corectropia. [17]
Pre-Descemet Corneal Dystrophy (PDCD)
Autosomal dominant corneal stromal dystrophy is characterized by small, pleomorphic stroma opacities that are located in the posterior stroma and endothelium. This condition rarely manifests in childhood and is not visually significant.
While it is imperative to consider other corneal stromal dystrophies on the differential, it is also important to consider Systemic Mucopolysaccharidoses as a possible underlying cause given consistent with MCD.[3]
Management
General treatment
Treatment will be necessary for patients with MCD as this disease is expected to become visually significant and interfere with daily activities prior to the fifth decade of life. Treatment is directed at addressing symptomatic relief and corneal transplantation once vision has deteriorated.
Medical therapy
Common initial medications and strategies for symptomatic management include artificial tears, nighttime lubricants, and NSAIDs for pain. For recurrent corneal erosions, patients will likely require periodic bandage contact lenses and antibiotic drops. Currently, no medical treatment has been developed to directly address the progression of MCD. Current research is investigating enzyme replacement therapy to help clear keratan sulfate in the cornea.[1][3] Another avenue of treatment may be gene replacement therapy. Studies have shown the possibility of gene editing in Meesmann’s Epithelial Corneal Dystrophy, suggesting another possible avenue of treatment for MCD.[18]
Surgery
Corneal transplantation is the historical treatment option once MCD is visually significant.
Penetrating keratoplasty (PKP) involves a full-thickness corneal transplantation and has been the most common surgical treatment to improve visual acuity.2 One study reported the mean age for the first PKP for MCD was 41 ± 4 years.[19] While PKP confers good visual outcomes, disease recurrence can lead to graft failure and the need for repeat PKP. For patients that undergone PKP for MCD, about 2.5% will require a repeat keratoplasty. [20]
Deep Anterior Lamellar Keratoplasty (DALK) is a partial thickness corneal transplant that has recently been implemented in the treatment of MCD. However, only MCD without endothelium involvement will benefit from DALK given the native Descemet’s membrane and endothelium are not removed.[21] Some studies have shown comparable efficacy in MCD with less endothelial damage and rejection when compared to PKP12. Although there may be a lesser chance of graft rejection with the retained native corneal endothelium, this procedure may not be useful since MCD can affect deep stroma and Descemet’s membrane. Therefore, surgeons tend to choose PKP if there is deep involvement.
Other surgical procedures have been implemented to manage MCD. Phototherapeutic keratectomy (PTK) can help improve vision, especially for patients with recurrent erosions.[3] This is a repeatable and precise procedure, but it can induce hyperopic shifts and stromal haze. Femtosecond laser-assisted lamellar keratectomy can be used to remove corneal opacities and delay keratoplasties.[3] However, these procedures have limited benefits in addressing vision loss associated with MCD.
Prognosis
There is an overall good prognosis following corneal transplantation for MCD. Recurrence of MCD necessitating repeat transplantation is an undesirable outcome. One retrospective study demonstrated graft survival rate of 98.1% at 1 year, 89.8% at 5 years, 82.1% at 10 years, and 74.1% at 15 years.[22] Furthermore, the size of the transplant graft has an inverse relationship with the rate of rejection.[19] Regardless, corneal transplantation remains the first-line treatment in the treatment of visually significant MCD.
Additional Resources
https://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/macular-corneal-dystrophy.htm
https://disorders.eyes.arizona.edu/disorders/corneal-dystrophy-macular
https://www.aao.org/Assets/7619b2b8-dabc-4896-8219-8aea47b334cc/637151444255430000/k43-pdf?inline=1
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Aggarwal, Shruti, et al. "Macular corneal dystrophy: A review." Survey of ophthalmology 63.5 (2018): 609-617.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Klintworth, Gordon K. "Corneal dystrophies." Orphanet journal of rare diseases 4.1 (2009): 1-38.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Singh, Shalini, et al. "Macular corneal dystrophy: an updated review." Current Eye Research 46.6 (2021): 765-770.
- ↑ Klintworth, Gordon K. "Macular corneal dystrophy-a localized disorder of mucopolysaccharides metabolism?." Progress in Clinical and Biological Research 82 (1982): 69-101.
- ↑ Klintworth, G. K. "Research into the pathogenesis of macular corneal dystrophy." Transactions of the ophthalmological societies of the United Kingdom 100.Pt 1 (1980): 186-194.
- ↑ Zheng, Tao, et al. "Impairment of the autophagy-lysosomal pathway and activation of pyroptosis in macular corneal dystrophy." Cell death discovery 6.1 (2020): 1-13.
- ↑ Reddy, Jagadesh C., et al. "Clinical outcomes and risk factors for graft failure after deep anterior lamellar keratoplasty and penetrating keratoplasty for macular corneal dystrophy." Cornea 34.2 (2015): 171-176.
- ↑ Sultana, Afia, et al. "Novel mutations of the carbohydrate sulfotransferase-6 (CHST6) gene causing macular corneal dystrophy in India." Molecular vision 9 (2003): 730-734.
- ↑ Chaurasia, Sunita, Muralidhar Ramappa, and Dilip Kumar Mishra. "Clinical diversity in macular corneal dystrophy: an optical coherence tomography study." International Ophthalmology 39.12 (2019): 2883-2888.
- ↑ Micali, Antonio, et al. "Macular corneal dystrophy: in vivo confocal and structural data." Ophthalmology 121.6 (2014): 1164-1173.
- ↑ Rubinstein, Yair, et al. "Macular corneal dystrophy and posterior corneal abnormalities." Cornea 35.12 (2016): 1605-1610.
- ↑ Klintworth, Gordon K., and F. Stephen Vogel. "Macular corneal dystrophy: an inherited acid mucopolysaccharide storage disease of the corneal fibroblast." The American Journal of Pathology 45.4 (1964): 565.
- ↑ Klintworth, Gordon K., et al. "Macular corneal dystrophy Lack of keratan sulfate in serum and cornea." Ophthalmic paediatrics and genetics 7.3 (1986): 139-143.
- ↑ Weiss, Jayne S. "Schnyder corneal dystrophy." Current Opinion in Ophthalmology 20.4 (2009): 292-298.
- ↑ Bredrup, Cecilie, et al. "Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene." Investigative ophthalmology & visual science 46.2 (2005): 420-426.
- ↑ Goldberg, M. F., et al. "Variable expression in flecked (speckled) dystrophy of the cornea." Annals of ophthalmology 9.7 (1977): 889-896.
- ↑ Kim, Michelle J., et al. "Posterior amorphous corneal dystrophy is associated with a deletion of small leucine-rich proteoglycans on chromosome 12." PloS one 9.4 (2014): e95037.
- ↑ Courtney, D. G., et al. "CRISPR/Cas9 DNA cleavage at SNP-derived PAM enables both in vitro and in vivo KRT12 mutation-specific targeting." Gene therapy 23.1 (2016): 108-112.
- ↑ 19.0 19.1 Akova, Y. A., et al. "Recurrent macular corneal dystrophy following penetrating keratoplasty." Eye 4.5 (1990): 698-705.
- ↑ Klintworth, Gordon K., et al. "Recurrence of macular corneal dystrophy within grafts." American journal of ophthalmology 95.1 (1983): 60-72.
- ↑ Sari, Esin S., et al. "Deep anterior lamellar keratoplasty versus penetrating keratoplasty for macular corneal dystrophy: a randomized trial." American Journal of Ophthalmology 156.2 (2013): 267-274.
- ↑ Al-Swailem, Samar A., Ali A. Al-Rajhi, and Michael D. Wagoner. "Penetrating keratoplasty for macular corneal dystrophy." Ophthalmology 112.2 (2005): 220-224.
