Macular corneal dystrophy (MCD) is a progressive, bilateral stromal dystrophic disease that arises from mutations in carbohydrate sulfotransferase 6 (CHST6). Corneal transplantation is the ultimate therapeutic solution for MCD patients. Unfortunately, postoperative recurrence remains a significant challenge. We conducted a retrospective review of a clinical cohort comprising 102 MCD patients with 124 eyes that underwent either penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK). Our results revealed that the recurrence rate was nearly three times higher in the DALK group (39.13%, 9/23 eyes) compared with the PKP group (10.89%, 11/101 eyes), suggesting that surgical replacement of the corneal endothelium for treating MCD is advisable to prevent postoperative recurrence. Our experimental data confirmed the robust mRNA and protein expression of CHST6 in human corneal endothelium and the rodent homolog CHST5 in mouse endothelium. Selective knockdown of wild-type Chst5 in mouse corneal endothelium (ACsiChst5), but not in the corneal stroma, induced experimental MCD with similar extracellular matrix synthesis impairments and corneal thinning as observed in MCD patients. Mice carrying Chst5 point mutation also recapitulated clinical phenotypes of MCD, along with corneal endothelial abnormalities. Intracameral injection of wild-type Chst5 rescued the corneal impairments in ACsiChst5 mice and retarded the disease progression in Chst5 mutant mice. Overall, our study provides new mechanistic insights and therapeutic approaches for MCD treatment by high-lighting the role of corneal endothelium in MCD development.

The aim of the study was to investigate oxidative stress as well as cellular protein accumulation in corneal diseases including keratoconus (KC), macular corneal dystrophy (MCD), and Fuchs endothelial corneal dystrophy (FECD) at their primary affecting sites. Corneal buttons from KC, MCD, and FECD patients, as well as healthy controls, were analyzed immunohistochemically to evaluate the presence of oxidative stress and the function of the proteostasis network. 4-Fydroxynonenal (4-HNE) was used as a marker of oxidative stress, whereas the levels of catalase and heat-shock protein 70 (HSP70) were analyzed to evaluate the response of the antioxidant defense system and molecular chaperones, respectively. Sequestosome 1 (SQSTM1) levels were determined to assess protein aggregation and the functionality of autophagic degradation. Basal epithelial cells of the KC samples showed increased levels of oxidative stress marker 4-HNE and antioxidant enzyme catalase together with elevated levels of HSP70 and accumulation of SQSTM1. Corneal stromal cells and endothelial cells from MCD and FECD samples, respectively, showed similarly increased levels of these markers. All corneal diseases showed the presence of oxidative stress and activation of the molecular chaperone response to sustain protein homeostasis. However, the accumulation of protein aggregates suggests insufficient function of the protective mechanisms to limit the oxidative damage and removal of protein aggregates via autophagy. These results suggest that oxidative stress has a role in KC, MCD, and FECD at the cellular level as a secondary outcome. Thus, antioxidant- and autophagy-targeted therapies could be included as supporting care when treating KC or corneal dystrophies.

BACKGROUND: Macular corneal dystrophy is a rare inherited disease of the cornea leading to deposits mainly in the stroma. Affected patients suffer from progressive loss of visual acuity which should be treated with penetrating keratoplasty. This is the first case report describing the clinical and histopathological findings of corneal tissue after failed phototherapeutic keratectomy (PTK) in a patient with macular corneal dystrophy.
METHODS: A 32-year-old man presented with visual impairment, blurred vision and increasing glare sensitivity in both eyes in 2014. All symptoms had existed for several years and had recently increased sharply. A corneal dystrophy was diagnosed and penetrating keratoplasty was recommended but the patient was hesitant to undergo surgery. In 2018, in contrast to current guidelines, a PTK was performed in both eyes in Turkey for unknown reasons. In May 2019, he presented again in our clinic. Best corrected visual acuity was markedly reduced in both eyes. Slit-lamp examination revealed multiple dense, poorly circumscribed grey-white patchy changes in the stroma accompanied by corneal opacity in both eyes. In February 2020, the patient decided to have penetrating keratoplasty performed at the University Eye Hospital in Tübingen. The explanted cornea was stained for acid mucopolysaccharides (AMP) and periodic acid-Schiff staining (PAS). The histopathological examination revealed destruction of Bowman\'s layer and a subepithelial fibrosis band due to the PTK previously performed. The AMP staining demonstrated blue deposits typical of macular corneal dystrophy, mainly in the stroma but also in the endothelium. Interestingly, the acidic mucopolysaccharides were found increased in the PTK-induced subepithelial fibrosis band. The postoperative course after keratoplasty was favourable with a significant increase in visual acuity and a clear graft.
CONCLUSIONS: This report presents the first case of a histologically evident exacerbation of macular corneal dystrophy after PTK and emphasizes the relevance of thorough pre-interventional diagnosis and patient selection to consider other therapeutic approaches, such as penetrating keratoplasty.

Macular corneal dystrophy (MCD) is a rare form of hereditary corneal dystrophy caused by CHST6 mutations. Owing to the genetic heterogeneity and population differences among patients with MCD, the genetic cause of MCD has not been fully elucidated, and the pathogenesis underlying the genetic mutation is still unclear. In this study, Chinese families and sporadic patients were included as subjects, and clinical and genetic analyses were performed to detect novel CHST6 mutations. In addition, the underlying pathogenic mechanisms of MCD were investigated by in vitro cell experiments. Two consanguineously married families and 10 sporadic patients with MCD were enrolled. Direct sequencing of the CHST6 gene was performed in all the patients to identify novel mutations. Wild-type and mutant overexpression cell lines were constructed to study the effects of the mutation in vitro. The expressions of endoplasmic reticulum (ER) stress markers and apoptotic factors, cell senescence, and migration levels tests were performed in different overexpression cell lines. As a result, four novel mutations (R155Afs*66, S84Cfs*17, E71G, and E71Q) and 10 previously reported mutations in the CHST6 gene were identified. Among the reported mutations, the most frequent mutations detected in the patients were L21Rfs*88 (4/14) and L21H (4/14). All the novel mutations were absent in the 50 healthy controls and were predicted to alter highly conserved amino acids across the different species and considered to be \"disease causing\" by function prediction. The results of the in vitro cell experiment further demonstrated that the novel homozygous frameshift mutations (S84Cfs*17 and R155Afs*66) of CHST6 detected in the consanguineously married families could lead to truncated proteins with defect functions, higher ER stress and apoptotic levels, decreased cell migration, and excessive cell senescence in corneal stromal cells, thereby affecting the normal functions of corneal stromal cells. These changes might play important roles in corneal opacity, which is characteristic of corneas with MCD. Our study extended the existing spectrum of disease-causing mutations and further elucidated the underlying pathogenic mechanisms of MCD.

Macular corneal dystrophy (MCD) is a rare corneal stromal dystrophy with bilateral progressive vision loss. The pathogenic gene of MCD is carbohydrate sulfotransferase 6 (CHST6). Herein, we report a novel missense mutation and a rare exon deletion mutation in the CHST6 gene in a Chinese family with MCD.
Genomic DNA was extracted from the peripheral blood, and next generation sequencing was used to analyse the gene sequence. The pathogenic mutations were identified in all affected family members. The proband successively received binocular penetrating keratoplasty (PKP), and the corneas were examined by histopathology and colloidal iron staining to prove the diagnosis. A long-term follow-up was made to observe the changes after PKP.
Genetic analysis demonstrated hemizygous mutations in the proband, including a novel c.520A>C (p.K174Q) missense mutation and a rarely reported exon 3 deletion mutation, which were co-segregated with the MCD phenotypes in the pedigree. The positive colloidal iron staining confirmed the diagnosis of MCD in the proband. However, the clinical phenotype and pathological manifestation of both eyes were different from each other because of complicated keratitis in the left eye. During the nine years of follow-up, visual acuity was improved significantly, and the cornea was transparent without rejection and postoperative recurrence in both eyes.
The novel hemizygous mutations were thought to contribute to the loss of CHST6 function, which induced typical clinical and pathological features of MCD. PKP was an effective treatment for MCD.

UNASSIGNED: To compare the postoperative outcomes of deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PKP) for macular corneal dystrophy (MCD).
UNASSIGNED: Single-center, retrospective, interventional case series.
UNASSIGNED: A chart review was performed of 100 patients (157 eyes) who underwent primary DALK (DALK group) and PKP (PKP group) for histopathologically confirmed MCD for whom at least 12 months of follow-up were available. Between-group comparisons were performed of visual acuity (VA), graft survival, and postoperative complications.
UNASSIGNED: There were 22 eyes in the DALK group and 135 in the PKP group. Postoperative best-corrected visual acuity (BCVA) of 20/40 or better was achieved in 90.9% of the DALK group and 76.3% of the PKP group (P=0.12). At last visit, graft survival was 95.5% (21 eyes) and 91.1% (123 eyes) in DALK and PKP groups, respectively (P=0.69, Log rank test). Corneal graft rejection episodes occurred in 1 (4.5%) DALK graft and 19 (14.1%) PKP grafts. Five of the 19 graft rejections in the PKP group were irreversible. Microbial keratitis and cataract occurred in 6 (4.5%) and 15 (11.1%) PKP eyes. One (4.5%) eye in the DALK group had cataract and none of the DALK cases developed microbial keratitis. Clinically significant recurrence was observed in 4 (2.9%) PKP eyes and 1 (4.5%) DALK eye (P=0.69), respectively.
UNASSIGNED: DALK is a viable option for MCD without Descemet membrane involvement. DALK had comparable medium-term visual and survival outcomes to PKP. DALK has the advantage of lower open sky intraoperative complications and lower graft rejection episodes.

BACKGROUND: Corneal dystrophies are a group of rare, inherited disorders that are usually bilateral, symmetric, slowly progressive, and not related to environmental or systemic factors. The majority of publications present the advanced form of the disease with a typical clinical demonstration. The initial signs and symptoms of different epithelial and stromal corneal dystrophies are not specific; therefore, it is very important to establish the early characteristic corneal features of these disorders that could guide the diagnostic process.
METHODS: The main purpose of this study was to report the differential diagnosis of a pediatric patient with bilateral anterior corneal involvement suspected of corneal dystrophy. An 8-year-old male patient presented with asymptomatic, persistent, superficial, bilateral, diffuse, anterior corneal opacities. Slit lamp examination results were not specific. Despite the lack of visible stromal involvement on the slit lamp examination, corneal analysis based on confocal microscopy and optical coherence tomography revealed characteristic features of macular corneal dystrophy (MCD). The diagnosis of MCD was confirmed by CHST6 gene sequencing. The early corneal characteristic features of MCD, established based on the findings of this case report, include corneal astigmatism (not specific), diffuse corneal thinning without a pattern of corneal ectasia (specific), and characteristic features on confocal microscopy (specific), including multiple, dark, oriented striae at different corneal depths.
CONCLUSIONS: The clinical examination should be complemented with corneal imaging techniques, such as confocal microscopy and optical coherence tomography. In patients suspected of corneal dystrophy, genetic testing plays an important role in establishing the final diagnosis.

Macular Corneal Dystrophy is an autosomal recessive form of corneal dystrophy due to a mutation in CHST6 gene, which results in abnormal proteoglycan synthesis. There is accumulation of abnormal glycosaminoglycans in the corneal stroma and endothelium. The deposition results in progressive loss of corneal transparency and visual acuity. The histopathology shows characteristic alcian blue positive deposits. Management in the cases with visual loss requires keratoplasty either full thickness or lamellar. The decision about the ideal type of keratoplasty depends on age and pre-operative clinical features. Although prognosis after keratoplasty is good, recurrences can occur. Future research should be targeted towards gene therapy in this condition.

Purpose: To report the recurrence of a macular corneal stromal dystrophy 50 years after penetrating keratoplasty (PKP). Methods: Observational case report Case description: A 76-year-old male patient presented with visual impairment in the right eye (OD) 50 years after PKP in 1962 (44 years after PKP also in the left eye (OS) in 1968) following explosion injury. His visual acuity had already been impaired before the trauma because of bilateral corneal opacities. The central corneal thickness of the graft measured 584 µm (OD) and 544 µm (OS), whilst the peripheral host thickness (8 mm zone), however, was 1233 µm (OD, cranial) and 1131 µm (OS, nasal). The original graft diameter measured 6 mm in both eyes and the recipient cornea was cloudy and gray. The endothelial cell count was measured centrally (OD 1162 c/mm2, OS 1320 c/mm2). The visual acuity was 20/100 (OD) and 20/40 (OS). After excimerlaser-assisted repeated PKP (8.0/8.1 mm, OD), the histological analysis of the former graft revealed deposits of acid mucopolysaccharides (AMP) subepithelially, within the interface, in the donor stroma, and in the endothelium, which proved the peripheral recurrence of a macular corneal stromal dystrophy on the graft. Conclusion: Recurrence of macular corneal stromal dystrophy is seldom, but it may occur many decades after PKP. In this patient, the host\'s stroma was twice as thick as that of the graft. This may be caused by the active production of acid mucopolysaccharides in the host endothelium with secondary endothelial decompensation. Thus, PKP remains the gold standard in the cure of macular corneal dystrophy for long-term visual rehabilitation.

Phototherapeutic keratectomy (PTK) with 193-nm excimer laser is a safe and effective procedure for the treatment of superficial corneal pathology. We aimed to review the use of PTK for the treatment of corneal macular dystrophy (MCD).
Case report and literature review.
A 16-year-old boy presented to an ophthalmologist with a 4-year history of reduced vision, glare and photophobia in his left eye. He was diagnosed with corneal macular dystrophy and underwent sequencing of the CHST6 gene. Left excimer PTK with mitomycin C was performed. He remained relapse free until 18 months post procedure when his visual acuity declined and the stroma appeared more \"milky\". He underwent a penetrating keratoplasty in his left eye 24 month following the initial PTK.
Phototherapeutic keratectomy is an effective means of visual restoration in patients with macular corneal dystrophy and may delay penetrating keratoplasty. Patients should be counselled regarding the high risk of recurrence. This is the first reported case of a CHST6 gene positive patient with MCD that was treated with phototherapeutic keratoplasty.