Case-control association between CCT-associated variants and keratoconus in a Saudi Arabian population.

BACKGROUND: Keratoconus (KC) is the most common primary ectatic disease of the cornea and a major indication for corneal transplant. To date, limited KC-associated-risk loci have been identified. Association has recently been suggested between KC and 8 single nucleotide polymorphisms (SNPs) in the genomic regions of FNDC3B, COL4A3, MPDZ-NF1B, RXRA-COL5A1, LCN12-PTGDS, FOXO1, and BANP-ZNF469. These SNPs are associated with central corneal thickness (CCT), a known risk factor to KC. We are questioning whether these SNPs are significantly associated with KC in a Saudi Arabian population. The study included 108 unrelated KC cases and 300 controls. Patients were diagnosed with KC according to the Schimpff-flow based elevation map of the cornea. DNA genotyping was done using probe-based allelic discrimination TaqMan assays. Allele frequencies were compared between the cases and controls. RESULTS: All SNPs were successfully genotyped with high efficiency (>95 %). The SNPs had no significant deviation in cases or controls from Hardy-Weinberg Equilibrium (HWE, p value > 0.05). None of the selected SNPs were significantly associated with KC in the Saudi Arabian population. However, we replicated the same trend of minor allele frequency (MAF) between cases and controls reported by a recent GWAS regarding the 5 SNPs rs4894535 (FNDC3B, chr3: 171995605), rs1536482 (RXRA-COL5A1, chr9: 137440528), rs7044529 (COL5A1, chr9: 137568051), rs11145951 (LCN12-PTGDS, chr9: 139860264), and rs2721051 (FOXO1, chr13: 41110884). CONCLUSIONS: This is the first study investigating the association of these SNPs with KC in a population from Saudi Arabia. We replicated the same trend of MAF alteration of the association between the SNPs rs4894535 (FNDC3B, chr3: 171995605), rs7044529 (COL5A1, chr9: 137568051), rs11145951 (LCN12-PTGDS, chr9: 139860264) and rs2721051 (FOXO1, chr13: 41110884) and KC-risk as reported by a recently published GWAS. Consistently replicated population-based studies are necessary to identify and/or confirm genetic susceptibility for certain diseases. We acknowledge that the lack of significance in our study is due to our small sample size and insufficient statistical power; however our data still add to the body of evidence of potential KC-candidate SNPs. This report aims at supporting the possible association between CCT-associated SNPs and KC susceptibility.

Keratoconus is associated with increased copy number of mitochondrial DNA.

PURPOSE: To investigate the possible association of oxidative stress with keratoconus (KC), we estimated the changes in relative mitochondrial DNA (mtDNA) content. METHODS: The study included 119 patients with KC and 208 controls matched for gender, ethnicity, and systemic disease status. We selected controls who were older than the patients since the mtDNA copy number tends to increase with age. The age mean (standard deviation) was 26.4(7.6) and 54.5(14.4) years for the patients and controls, respectively. The relative mtDNA copy number was estimated with the real-time quantitative PCR (qPCR) method using ND1 as the mtDNA gene and human globulin (HGB; also known as the cytoglobin gene, CYGB) as the reference single-copy nuclear gene. RESULTS: The mean relative mtDNA content was significantly higher in patients with KC (1.20±0.45) than in the normal control subjects (1.04±0.36; p = 0.0004). Subjects with high mtDNA content (>1.259, i.e., greater than 75(th) percentile) were at an increased risk of the disease (odds ratio = 2.62, 95% confidence interval = 1.40 to 4.89; p =0.0025). CONCLUSIONS: Increased mtDNA content in patients with KC may indicate mitochondrial respiratory chain defects and thus mitochondrial-abnormality involvement.

Successful management of a retained host Descemet's membrane after penetrating keratoplasty (PKP) - A case report.

INTRODUCTION AND IMPORTANCE: To report the 21st case showing the rare occurrence of retained Descemet's membrane (DM) following penetrating keratoplasty (PKP). We intend to investigate possible etiologies, expected sequelae, and outcome of neodymium-dpoed yttrium alumnium garnet (Nd: YAG) laser membranectomy. CASE PRESENTATION: Our case is a 74-year-old male who underwent PKP surgery in the right eye secondary to corneal decompensation following cataract surgery in addition to corneal thinning secondary to superficial keratectomy related to the pre-existing climatic droplet keratopathy (CDK). Postoperative assessment revealed a retro-corneal membrane within the anterior chamber, which was affecting his vision. CLINICAL DISCUSSION: Based on the post-operative course and the decreased vision as an indication for intervention, it was decided to excise the retained DM. Membranectomy with Nd: YAG laser was performed, and the patient's visual acuity measurement improved from 20/400 to 20/25. However, the endothelial cell count decreased from 1479 to 520 cells/mm2 (35 % loss) at 15 months post YAG membranectomy with clear graft. Histopathological examination confirmed the clinical suspicion of a retained DM, since it was absent in the submitted host corneal tissue in addition to the pre-existing CDK. CONCLUSION: Retention of DM following PKP is a rare but possible complication and high index of suspicion is required for proper diagnosis and management to obtain better visual outcome. Nd: YAG laser membranectomy was effective in excising the retained DM and improving vision. Endothelial cell loss following Nd: YAG laser membranectomy as a complication was observed and should be addressed during the treatment plan.

Association between Polymorphism rs61876744 in PNPLA2 Gene and Keratoconus in a Saudi Cohort.

The genetic etiology of Keratoconus (KC) in Middle Eastern Arabs of Saudi origin is still unclear. A recent genome-wide study identified two significant loci in the region of PNPLA2 (rs61876744) and CSNK1E (rs138380) for KC that may be associated with KC in the Saudi population. In addition, polymorphisms in the apolipoprotein E (APOE) gene, namely, rs429358 and rs7412, responsible for APOE allelic variants ε2, ε3, and ε4, may influence KC via oxidative stress mechanism(s). Thus, we investigated the possible association of polymorphisms rs61876744, rs138380, rs429358, rs7412, and APOE genotypes in KC patients of the Saudi population. This study included 98 KC cases and 167 controls. Polymorphisms rs6187644 and rs138380 were genotyped using TaqMan assays, and rs429358 and rs7412 were genotyped via Sanger sequencing. Although the allele frequency of rs61876744(T) in PNPLA2 was a protective effect against KC (odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.44-0.93), the p-value (p = 0.020) was not significant for multiple testing correction (p = 0.05/4 = 0.015). However, rs6187644 genotype showed a modestly significant protective effect in the dominant model (OR = 0.53, 95% CI = 0.32-0.88, p = 0.013). Polymorphisms rs138380, rs429358, and rs7412 showed no significant allelic or genotype association with KC. However, the ε2-carriers (ε2/ε2 and ε2/ε3 genotypes) exhibited a greater than 5-fold increased risk of KC, albeit non-significantly (p = 0.055). Regression analysis showed no significant effect of age, gender, and the four polymorphisms on KC. Our results suggest that polymorphism rs6187644 in PNPLA2 might be associated with KC in the Middle Eastern Arabs of Saudi origin but warrant a large-scale association analysis at this locus.

Analysis of the VSX1 gene in keratoconus patients from Saudi Arabia.

PURPOSE: To screen the visual system homebox 1 (VSX1) gene in Saudi Arabian keratoconus patients. METHODS: We sequenced the entire coding region, exon-intron boundaries in clinically confirmed keratoconus patients (n=55) and 50 ethnically matched healthy controls. All cases and controls were unrelated. RESULTS: Sequencing VSX1 revealed the presence of five nucleotide changes, 3 of which were non-coding (g.8326 G>A, g.10945 G>T, and g.11059 A>C) and 2 were synonymous-coding sequence changes (g.5053 G>T and g.8222 A>G). All five sequence changes were benign polymorphisms with no apparent clinical significance. CONCLUSIONS: In our keratoconus cohort, no pathogenic VSX1 mutation(s) were identified.

High-resolution analysis of DNA copy number alterations in patients with isolated sporadic keratoconus.

PURPOSE: To determine whether patients with sporadic, non-familial keratoconus and no pathogenic mutations in the visual system homeobox 1 (VSX1) gene have evidence of chromosomal copy number alterations. METHODS: Twenty Saudi Arabian patients with isolated keratoconus, no family history of the disease and no mutations in VSX1 were recruited. Additionally, 10 ethnically-matched healthy controls were also recruited for this study. We screened patients for chromosomal copy number aberrations using the Agilent Human Genome CGH 244A Oligo Microarray Chip. RESULTS: None of the keratoconus patients screened had evidence of chromosomal copy number alterations when compared to normal ethnically matched controls. CONCLUSIONS: Chromosomal deletions and/or duplications were not detected in any of the patients tested here. Other chromosomal imbalances such as translocations, inversions, and some ploidies cannot be detected by current array CGH technology and other nuclear genetic or epigenetic factors cannot be excluded as a possible contributing factor to keratoconus pathogenesis.

Vogt-Koyanagi-Harada disease occurring during interferon-alpha and ribavirin therapy for chronic hepatitis C virus infection.

We report a case of Vogt-Koyanagi-Harada (VKH) disease in a 30-year-old patient who was receiving interferon-alpha and ribavirin therapy for chronic hepatitis C virus infection. The intraocular inflammation responded to systemic corticosteroid and mycophenolate mofetil treatment. Physicians should be aware of the association between interferon-alpha and ribavirin therapy for hepatitis C virus infection and the development of VKH disease.

Corneal elevation indices and pachymetry values of Saudi myopes using scheimpflug imaging.

OBJECTIVES: To report the corneal elevation and thickness values for Saudi myopes and to evaluate the differences between these parameters in subgroups of this target population. Methods: Pentacam corneal topographic maps of the right eyes of patients visiting Al-Hokama Eye Clinic, Riyadh, Saudi Arabia, a tertiary eye center between January 2009 and December 2015 were retrospectively analyzed in this cross-sectional study. The patients were grouped into 3 categories based on their spherical readings: mild (-0.25 to -2.75D), moderate (-3.00 to -5.75D), and severe (≥-6.00D). Furthermore, patients with cylindrical readings of ≥-1.00 diopter were categorized as having myopic astigmatism, whereas those with less than -1.00 cylindrical diopter were categorized as having simple myopia. Results: Our sample was comprised of 1,276 patients; 838 (65.7%) had simple myopia and 438 (34.3%) had myopic astigmatism. The values for the whole myopic group were as follows:  anterior corneal elevation (AE) at the apex= 2.60±1.48 (standard deviation), thinnest AE= 2.56±1.68, posterior elevation (PE) at the apex= 3.67±3.58, thinnest PE= 4.92±3.81, central pachymetry= 550.09±34.29, apical pachymetry=550.73±34.64, and thinnest pachymetry= 546.30±34.61. All of the measurements, except the apical PE and thinnest PE, were statistically significant across the simple and myopic astigmatism groups (p less than 0.05). Comparing the mild to moderate myopia groups revealed a significant difference in the apical AE (p=0.037). Moreover, the comparison between the mild and severe myopia groups revealed that the apical PE and the thinnest PE, as well as the central, apical, and thinnest pachymetry values were statistically significantly different (p less than 0.05). Conclusion: The corneal elevation indices and thicknesses specific to the Saudi myopes were found to be comparable to the international databases in terms of the elevation and thickness in some of the parameters.

Successful surgical management of post-penetrating or deep lamellar keratoplasty Acquired Corneal Sub-Epithelial Hypertrophy (ACSH): A case series.

INTRODUCTION: Acquired Corneal Sub-Epithelial Hypertrophy (ACSH) has been described in patients with peripheral superficial corneal opacities following penetrating keratoplasty and might present similar to Salzmann's nodular degeneration (SND) or peripheral hypertrophic sub-epithelial corneal degeneration (PHSCD). We describe the clinical presentation, topographic findings and the surgical outcome of three cases, which fit the appearance and characteristics of ACSH. PRESENTATION OF CASES: Three patients (3 eyes) with paracentral or peripheral corneal opacification were reviewed to describe their clinical examination (SL), morphology of the opacity (depth, diameter and density) and document their topographic changes before and after surgical intervention by peeling of the epithelium with or without superficial keratectomy under the microscope in addition to brief description of their histopathological examination. DISCUSSION: All 3 cases were secondary to corneal procedures [Penetrating keratoplasty (PKP) in 1 for pseudophakic bullous keratopathy and deep anterior lamellar keratoplasty (DLK) in 2 for advanced keratoconus]. All cases presented with reduced vision, astigmatic changes in topography or manifest refraction. The visual acuity, symptoms, and topographical findings all improved after treatment. Histopathologically, all cases fit the newly described entity of ACSH. CONCLUSION: Careful clinical judgement guided by corneal topography are needed for proper the diagnosis of acquired corneal opacification that results in reduction of vision to identify ACSH from other similar conditions (PHSCD and SND). Peeling of the thickened epithelial and sub-epithelial tissue is curative avoiding the need for corneal re-grafting.

Efficacy and safety of deep sclerectomy in uveitic glaucoma.

PURPOSE: To evaluate the safety and efficacy of deep sclerectomy with implant and mitomycin C in uveitic glaucoma. Design Prospective, noncomparative case study. PATIENTS AND METHODS: Nine patients (13 eyes) with uncontrolled uveitic glaucoma underwent deep sclerectomy with implant from 2002 to 2006. All patients had their uveitis controlled before and after surgery with anti-inflammatory therapy. Main outcome measures Control of intraocular pressure. A secondary outcome measure was the number of antiglaucoma medications required to achieve the desired intraocular pressure. Visual acuity and complication associated with the surgery were monitored. RESULTS: Mean follow-up was 21 months (range 12-54 months). Intraocular pressure (IOP) was reduced from a mean preoperative value of 28.7 mmHg to a mean postoperative value of 13.85 mmHg (Wilcoxon signed rank test P = 0.005). At the most recent visit, complete success was obtained in 84.6%, qualified success was obtained in 7.7%, and complete failure in 7.7%. Mean number of antiglaucoma medications was reduced from 3.07 to 0.2 (Wilcoxon signed rank test P = 0.001). Neodymium:YAG goniopuncture was performed in two eyes. Postoperative complications included transient hypotony with maculopathy in one eye, shallow choroidal effusions in two eyes, and progression of cataract in four eyes. CONCLUSION: Deep sclerectomy with implant in uveitic glaucoma appeared to be effective in controlling the IOP at short-term follow-up with no serious postoperative side-effects.

PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus.

Keratoconus (KC) is the most common corneal ectatic disorder affecting >300,000 people in the US. KC normally has its onset in adolescence, progressively worsening through the third to fourth decades of life. KC patients report significant impaired vision-related quality of life. Genetic factors play an important role in KC pathogenesis. To identify novel genes in familial KC patients, we performed whole exome and genome sequencing in a four-generation family. We identified potential variants in the PPIP5K2 and PCSK1 genes. Using in vitro cellular model and in vivo gene-trap mouse model, we found critical evidence to support the role of PPIP5K2 in normal corneal function and KC pathogenesis. The gene-trap mouse showed irregular corneal surfaces and pathological corneal thinning resembling KC. For the first time, we have integrated corneal tomography and pachymetry mapping into characterization of mouse corneal phenotypes which could be widely implemented in basic and translational research for KC diagnosis and therapy in the future.

Mycophenolate mofetil combined with systemic corticosteroids prevents progression to chronic recurrent inflammation and development of 'sunset glow fundus' in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada disease.

PURPOSE: To evaluate the effectiveness and safety of mycophenolate mofetil (MMF) as first-line therapy combined with systemic corticosteroids in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease. METHODS: This prospective study included 38 patients (76 eyes). The main outcome measures were final visual acuity, corticosteroid-sparing effect, progression to chronic recurrent granulomatous uveitis and development of complications, particularly 'sunset glow fundus'. RESULTS: The mean follow-up period was 37.0 ± 29.3 (range 9-120 months). Visual acuity of 20/20 was achieved by 93.4% of the eyes. Corticosteroid-sparing effect was achieved in all patients. The mean interval between starting treatment and tapering to 10 mg or less daily was 3.8 ± 1.3 months (range 3-7 months). Twenty-two patients (57.9%) discontinued treatment without relapse of inflammation. The mean time observed off of treatment was 28.1 ± 19.6 months (range 1-60 months). None of the eyes progressed to chronic recurrent granulomatous uveitis. The ocular complications encountered were glaucoma in two eyes (2.6%) and cataract in five eyes (6.6%). None of the eyes developed 'sunset glow fundus', and none of the patients developed any systemic adverse events associated with the treatment. CONCLUSIONS: Use of MMF as first-line therapy combined with systemic corticosteroids in patients with initial-onset acute VKH disease prevents progression to chronic recurrent granulomatous inflammation and development of 'sunset glow fundus'.

Chronic Recurrent Vogt-Koyanagi-Harada Disease and Development of 'Sunset Glow Fundus' Predict Worse Retinal Sensitivity.

PURPOSE: To investigate prognostic factors for retinal sensitivity assessed by microperimetry in patients with Vogt-Koyanagi-Harada (VKH) disease. METHODS: In total, 34 patients with initial-onset acute disease and 19 patients with chronic recurrent disease were retrospectively evaluated. RESULTS: The mean follow-up period was 40.4 ± 40.5 months. Sensitivity was significantly worse in eyes with more severe anterior segment inflammation at presentation, as indicated by the presence of mutton-fat keratic precipitates, anterior chamber reaction ≥2+, and posterior synechiae. Chronic recurrent presentation, development of complications, and 'sunset glow fundus' were significantly associated with worse sensitivity. Using logistic regression analysis, better sensitivity was significantly associated with initial-onset acute presentation (odds ratio, OR = 6.9; 95% confidence interval, CI = 1.53-9.66). CONCLUSIONS: Chronic recurrent presentation and development of complications and 'sunset glow fundus' are associated with a worse sensitivity outcome.

Conjunctival T-cell lymphoma: a clinicopathologic case report.

OBJECTIVE: To report a patient with conjunctival T-cell lymphoma, an extremely rare entity. DESIGN: Single case report. METHODS: Based on clinical examination, an excisional biopsy and immunostaining were performed on the conjunctival lesion. For management, we excised and performed triple freeze-thaw cryotherapy to the involved area, and we consulted the oncology service. MAIN OUTCOME MEASURES: T-cell and B-cell markers, and clinical examination of the lesion. RESULTS: Both examination and laboratory assessment revealed no evidence of systemic involvement. Conjunctival biopsy showed expansion of the substantia propria with an infiltrate of chronic inflammatory cells (including lymphocytes, plasma cells, and eosinophils), and prominent lymphocyte exocytosis with reactive epithelial changes. The CD-45 RO (T-cell marker) was strongly positive, whereas the CD-20 (B-cell marker) was negative. The T-cell receptor gene rearrangement was positive with beta clonality, confirming the diagnosis of T-cell lymphoma. CONCLUSIONS: T-cell lymphoma is a rare but possible diagnosis of gelatinous conjunctival lesions. The oncology consultants were reluctant to treat the patient with systemic chemotherapy or radiation because extraconjunctival extension could never be documented. The answer to the question of what is the most appropriate treatment for conjunctival T-cell lymphoma remains unknown.

Comparison of visual, refractive and topographic keratometry outcomes of Intacs and Intacs SK in mild to moderate keratoconus eyes.

PURPOSE: The purpose was to evaluate and compare the visual and refractive outcomes, topographic keratometry (K) and complications of Intacs and Intacs SK for mild to moderate keratoconus. METHODS: In this retrospective study, all mild to moderate keratoconus eyes that underwent implantation of Intacs (Intacs group) or Intacs SK (Intacs SK group) with minimum follow-up of 12 months were included. Preoperative and postoperative uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction, manifest cylinder, spherical equivalent (SE), minimum topographic keratometry, maximum topographic keratometry, and average topographic keratometry were compared in both groups. RESULTS: There were 16 eyes in the Intacs group and 18 eyes in the Intacs SK group. Preoperatively, both groups were comparable for most parameters except gender and minimum K and average K. At 6 months postoperatively there were statistically significant improvements in UDVA, CDVA, manifest sphere, SE, minimum K, maximum K, and average K (P < 0.05, all comparisons). Manifest cylinder improved at 6 months, but the improvement was not statistically significant (P > 0.05). The outcomes remained stable with no statistically significant differences between the 6 and 12 months visits. There were no complications in both groups. CONCLUSION: Both models of Intacs significantly improved vision and refractive outcomes, and topographic keratometry in cases of mild to moderate keratoconus. Intacs SK provided better (not statistically significant) results.

Analysis of the SOD1 Gene in Keratoconus Patients from Saudi Arabia.

We investigated Saudi patients with familial and sporadic Keratoconus for mutations in the Superoxide dismutase 1, soluble (SOD1) gene. We sequenced the entire coding region, exon-intron boundaries and intron 2 encompassing a 7-bp deletion in clinically confirmed Keratoconus patients (n = 55) and 100 ethnically matched healthy controls. All cases and controls were unrelated. Sequencing the SOD1 gene revealed the presence of four nucleotide changes and all were non-coding. Those were g.12035 C > A; g.13978 T > A; g.12037 G > A and g.11931 A > C with similar frequencies in patients and controls. All four sequence changes were benign polymorphisms with no apparent clinical significance. Additionally, the 7-bp deletion in intro2 reported previously, were not detected in any of our Keratocnus cohort. In our Keratoconus cohort, no pathogenic SOD1 mutation(s) was identified.

Long-term evaluation of efficacy and safety of deep sclerectomy in uveitic glaucoma.

PURPOSE: To assess long-term efficacy and safety of deep sclerectomy (DS) in uveitic glaucoma. PATIENTS AND METHODS: Thirty-three consecutive eyes (21 patients) with uveitic glaucoma underwent DS with mitomycin C and implant. Goniopuncture (GP) was done for uncontrolled postoperative intraocular pressure (IOP). RESULTS: Mean (± SD) follow-up was 33.2 (± 19.8) months. IOP was reduced from a mean preoperative value of 37.2 to postoperative value of 14.7 mmHg (p < 0.0001). Complete success was achieved in 24/33 eyes (72.7%); qualified success was obtained in 7/33 eyes (21.2%). Neodymium:YAG GP was performed in 12 eyes. Postoperative complications included cataract progression in 9 eyes, transient hypotony in 6 eyes, shallow choroidal effusions in 4 eyes, hypotony with persistent maculopathy in 1 eye, hyphema in 1 eye, and decompression retinopathy in 1 eye. CONCLUSION: DS is safe and effective in patients with uveitic open-angle glaucoma. However, laser goniopuncture is frequently needed to improve the outcome.

Screening of the Seed Region of MIR184 in Keratoconus Patients from Saudi Arabia.

Micro-RNAs (miRNAs) are regulators of gene expression that control various biological processes. The role of many identified miRNAs is not yet resolved. Recent evidence suggests that miRNA mutations and/or misexpression may contribute to genetic disorders. Point mutations in the seed region of MIR184 have been recently identified in Keratoconus (KC) patients with or without other corneal and lens abnormalities. We investigated mutations within MIR184 in KC patients from Saudi Arabia and examined the relative expression of miR-184 and miR-205 in human cornea. Ethnically matched KC cases (n = 134) were recruited and sequencing was performed using PCR-based Sanger sequencing and analyzed using the Sequencher 5.2 software. Expression of miR-184 and miR-205 was profiled in postmortem unaffected ocular tissues obtained from donors with no history of ocular diseases. miR-184 expression was 15-fold higher than that of miR-205 in cornea samples. No mutation(s) within the screened genomic region of MIR184 in KC cases was detected. This suggests that mutation in MIR184 is a rare cause of KC alone and may be more relevant to cases of KC associated with other ocular abnormalities. The increased expression of miR-184 versus miR-205 in normal cornea samples implies a possible role of miR184 in cornea development and/or corneal diseases.

Genetics of keratoconus: where do we stand?

Keratoconus is a progressive thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and reduced vision. Keratoconus has a complex multifactorial etiology, with environmental, behavioral, and multiple genetic components contributing to the disease pathophysiology. Using genome-wide and candidate gene approaches several genomic loci and genes have been identified that highlight the complex molecular etiology of this disease. The review focuses on current knowledge of these genetic risk factors associated with keratoconus.

Mitochondrial sequence changes in keratoconus patients.

PURPOSE: We investigated whether a group of patients with keratoconus (KTCN) harbor mutations in the mitochondrial genome. METHODS: We sequenced the full mitochondrial genome in a group of Saudi patients with KTCN (n = 26) and 100 ethnically matched controls who had no KTCN by examination. RESULTS: A total of 10 KTCN patients (38.5%) had potentially pathogenic nonsynonymous mtDNA mutations. Of the nonsynonymous sequence changes detected, 4 (40%) were in Complex I, one was in the tRNA(Glutamine), one was in tRNA(Tryptophan), one was in tRNA(Asparagine), one was in tRNA(Histidine), and two were in the tRNA(Leucine2). One nonsynonymous sequence change was heteroplasmic, whereas all the remaining 9 were homoplasmic. These sequence changes were not detected in controls of similar ethnicity. Four sequence changes were novel (were not reported previously) and 5 were reported previously. Additionally, we detected 54 synonymous (does not result in an amino acid change) sequence changes with no pathologic significance. CONCLUSIONS: If our results are confirmed in a larger cohort and multiple ethnicities, then mtDNA mutation may be considered as a genetic risk factor contributing indirectly through the oxidative stress mechanism to the development and/or progression of KTCN.