Expanding the phenotypic and genotypic spectrum of patients with HGSNAT-related retinopathy.

BACKGROUND: Variants in HGSNAT have historically been associated with syndromic mucopolysaccharidosis type IIIC (MPSIIIC) but more recent studies demonstrate cases of HGSNAT-related non-syndromic retinitis pigmentosa. We describe and expand the genotypic and phenotypic spectrum of this disease. MATERIALS AND METHODS: This is a retrospective, observational, case series of 11 patients with pericentral retinitis pigmentosa due to variants in HGSNAT gene without a syndromic diagnosis of MPSIIIC. We reviewed ophthalmologic data extracted from medical records, genetic testing, color fundus photos, fundus autofluorescence (FAF), and optical coherence tomography (OCT). RESULTS: Of the 11 patients, the mean age was 52 years (range: 26-78). The mean age of ophthalmologic symptoms onset was 45 years (range: 15-72). The visual acuity varied from 20/20 to 20/80 (mean 20/30 median 20/20). We described five novel variants in HGSNAT: c.715del (p.Arg239Alafs *37), c.118 G>A (p.Asp40Asn), c.1218_1220delinsTAT, c.1297A>G (p.Asn433Asp), and c.1726 G>T (p.Gly576*). CONCLUSIONS: HGSNAT has high phenotypic heterogeneity. Data from our cohort showed that all patients who had at least one variant of c.1843 G>A (p.Ala615Thr) presented with the onset of ocular symptoms after the fourth decade of life. The two patients with onset of ocular symptoms before the fourth decade did not carry this variant. This may suggest that c.1843 G>A variant is associated with a later onset of retinopathy.

Vitelliform maculopathy in MELAS syndrome.

Purpose: We present a unique case of foveomacular vitelliform lesions in a patient with metabolic encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Observations: After performing large panel next generation sequencing genetic testing, there was no likely alternative genetic etiology for vitelliform maculopathy in this patient. Conclusions and Importance: We present a rare case of a visually asymptomatic pediatric patient with MELAS and vitelliform maculopathy, which may be part of the spectrum of retinal manifestations in MELAS. Pediatric-onset vitelliform maculopathy in MELAS may be under-diagnosed due to its asymptomatic nature. Given the known risk of choroidal neovascularization in vitelliform maculopathy, it is important to identify these patients for proper surveillance.

Improved Rod Sensitivity as Assessed by Two-Color Dark-Adapted Perimetry in Patients With RPE65-Related Retinopathy Treated With Voretigene Neparvovec-rzyl.

Purpose: The purpose of this study was to evaluate rod-mediated function with two-color dark-adapted perimetry (2cDAP) in patients with RPE65-related retinopathy treated with voretigene neparvovec-rzyl. Methods: Following dilation and dark adaptation, 2cDAP and FST were performed. The 2cDAP was measured on an Octopus 900 perimeter (Haag-Streit) with cyan (500 nm wavelength) and red (650 nm wavelength) stimuli. Hill of vision (HOV) analysis was performed on 2cDAP perimetry with Visual Field Modeling and Analysis (VFMA). Full field threshold stimulus testing (FST) was also measured as a secondary measure of rod-mediated function, and assessed on a Diagnosys Espion with the ColorDome stimulator (Diagnosys LLC). Results: Eight eyes from 4 patients who were treated with voretigene bilaterally had rod function assessed by 2cDAP testing at least 1 year after treatment. There was statistically significant improvement in 2cDAP following gene augmentation therapy. HOV VFMA analysis showed widespread improvements that extended beyond the treatment bleb and statistically significant improvement in HOV analysis volumetric measurements post-treatment to cyan and red stimuli. FST testing performed in six eyes from three patients demonstrated statistically significant improvement to all chromatic stimuli following treatment. Conclusions: These findings demonstrated statistically significant improvement in 2cDAP and FST following treatment with voretigene. Translational Relevance: These findings provide a sensitive method of assessing rod-mediated function in a topographic manner that may be useful in future clinical trials for inherited retinal dystrophies.

X-Linked Retinoschisis.

X-linked retinoschisis (XLRS) is an inherited vitreoretinal dystrophy causing visual impairment in males starting at a young age with an estimated prevalence of 1:5000 to 1:25,000. The condition was first observed in two affected brothers by Josef Haas in 1898 and is clinically diagnosed by characteristic intraretinal cysts arranged in a petaloid "spoke-wheel" pattern centered in the macula. When clinical electroretinogram (ERG) testing began in the 1960s, XLRS was noted to have a characteristic reduction of the dark-adapted b-wave amplitude despite normal or usually nearly normal a-wave amplitudes, which became known as the "electronegative ERG response" of XLRS disease. The causative gene, RS1, was identified on the X-chromosome in 1997 and led to understanding the molecular and cellular basis of the condition, discerning the structure and function of the retinoschisin protein, and generating XLRS murine models. Along with parallel development of gene delivery vectors suitable for targeting retinal diseases, successful gene augmentation therapy was demonstrated by rescuing the XLRS phenotype in mouse. Two human phase I/II therapeutic XLRS gene augmentation studies were initiated; and although these did not yield definitive improvement in visual function, they gave significant new knowledge and experience, which positions the field for further near-term clinical testing with enhanced, next-generation gene therapy for XLRS patients.

A possible ocular biomarker for response to hyperornithinemia in gyrate atrophy: the effect of pyridoxine, lysine, and arginine-restricted diet in a patient with advanced disease.

BACKGROUND: Loss of function variants in the ornithine aminotransferase (OAT) gene cause accumulation of ornithine levels, leading to gyrate atrophy. The benefit of ornithine-lowering therapies has been documented in a mouse model and young patients, however, the effect in adults with advanced disease has not been well described. MATERIALS AND METHODS: Case report of an adult patient with advanced gyrate atrophy, who underwent treatment with pyridoxine and an arginine-restricted diet for four years. RESULTS: A 51-year-old female with advanced chorioretinal degeneration presented with hyperornithinemia (961 vs. normal 18-135 µmol/L) and compound heterozygous pathogenic variants in OAT (p.Tyr299* and p.Ala270Pro). Treatment with pyridoxine and arginine-diet restriction yielded a maximal reduction in ornithine levels by 71% (275 µmol/L). Optical coherence tomography (OCT) showed a reduction in ellipsoid zone (EZ) thickness that correlated with lower ornithine levels and reversed with higher ornithine levels. While her best-corrected visual acuity remained unchanged, the progressive decline in her visual fields appeared to stabilize during a one-year period when ornithine levels were below 500 µmol/L. CONCLUSIONS: In this report, we demonstrate that chorioretinal degeneration appears to stabilize in an adult patient with gyrate atrophy in association with a partial reduction in ornithine levels. We also observed a correlation with reduced EZ thickness on OCT and propose this may be a novel biomarker for ornithine reduction therapies. Our case study characterizes the potential retinal structure-function benefits of ornithine-lowering treatments even in cases of advanced chorioretinal degeneration. Thus, we recommend a low threshold for treating all patients with gyrate atrophy.

Three-Year Safety Results of SAR422459 (EIAV-ABCA4) Gene Therapy in Patients With ABCA4-Associated Stargardt Disease: An Open-Label Dose-Escalation Phase I/IIa Clinical Trial, Cohorts 1-5.

PURPOSE: To report on the safety of the first 5 cohorts of a gene therapy trial using recombinant equine infectious anemia virus expressing ABCA4 (EIAV-ABCA4) in adults with Stargardt dystrophy due to mutations in ABCA4. DESIGN: Nonrandomized multicenter phase I/IIa clinical trial. METHODS: Patients received a subretinal injection of EIAVABCA4 in the worse-seeing eye at 3 dose levels and were followed for 3 years after treatment. MAIN OUTCOME MEASURES: The primary end point was ocular and systemic adverse events. The secondary end points were best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, multifocal ERG, color fundus photography, short-wavelength fundus autofluorescence, and spectral domain optical coherence tomography. RESULTS: The subretinal injections were well tolerated by all 22 patients across 3 dose levels. There was 1 case of a treatment-related ophthalmic serious adverse event in the form of chronic ocular hypertension. The most common adverse events were associated with the surgical procedure. In 1 patient treated with the highest dose, there was a significant decline in the number of macular flecks as compared with the untreated eye. However, in 6 patients, hypoautofluorescent changes were worse in the treated eye than in the untreated eye. Of these, 1 patient had retinal pigment epithelium atrophy that was characteristic of tissue damage likely associated with bleb induction. No patients had any clinically significant changes in best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, or multifocal ERG attributable to the treatment. CONCLUSIONS: Subretinal treatment with EIAV-ABCA4 was well tolerated with only 1 case of ocular hypertension. No clinically significant changes in visual function tests were found to be attributable to the treatment. However, 27% of treated eyes showed exacerbation of retinal pigment epithelium atrophy on fundus autofluorescence. There was a significant reduction in macular flecks in 1 treated eye from the highest dose cohort. Additional follow-up and continued investigation in more patients will be required to fully characterize the safety and efficacy of EIAV-ABCA4.

Effect of Pharmacological Pupil Dilation on Dark-Adapted Perimetric Sensitivity in Healthy Subjects Using an Octopus 900 Perimeter.

Purpose: To determine whether dilation status has a clinically meaningful effect on sensitivity in normal subjects undergoing two-color dark-adapted perimetry, which can be useful to assess rod function. Methods: A perimeter measured naturally and pharmacologically dilated scotopic sensitivities using a test grid consisting of 16 points across the horizontal meridian ranging from 60° temporal to 45° nasal using cyan (500 nm wavelength) or red (650 nm wavelength) stimuli. The primary outcome was average overall sensitivity based on dilation status, which was compared using a linear mixed effect model for each color stimuli. A difference of 2 dB or more was considered clinically significant. Results: Twenty-nine eyes from 15 subjects (nine female) ages 23 to 63 with no known retinal pathology were included. Pharmacologically dilated eyes were 0.54 dB (95% confidence interval [CI], 0.05 dB to 1.03 dB; P = 0.032) more sensitive to a red stimulus than naturally dilated eyes, but this was not statistically significant after correction for multiple comparisons. Pharmacologically dilated eyes were 0.03 dB (95% CI, -0.20 dB to 0.14 dB; P = 0.734) less sensitive to a cyan stimulus compared to naturally dilated eyes. Conclusions: These findings show no clinically significant differences in sensitivity of scotopic perimetry in eyes without retinal pathology based on dilation status for both cyan and red stimuli. Translational Relevance: In this study, pharmacological dilation did not have a clinically meaningful effect on sensitivity, suggesting that this is not necessary when using two-color dark-adapted perimetry to assess for rod function.

Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.

Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here, we characterize the clinical phenotype of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12.Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease-causing variants in CEP78, CEP250, ARSG, or ABHD12.CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12-related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe.This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients who have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.

Characterization of the Spectrum of Ophthalmic Changes in Patients With Alagille Syndrome.

Purpose: The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome. Methods: We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fundus photography, fundus autofluorescence, optical coherence tomography, visual fields, electrophysiological assessments, and molecular genetic findings. Results: Cardiovascular abnormalities were found in 83% of all cases (of those, 74% had cardiac murmur), whereas 61% had a positive history of hepatobiliary issues, and musculoskeletal anomalies were present in 61% of all patients. Dysmorphic facies were present in 16 patients, with a broad forehead being the most frequent feature. Ocular symptoms were found in 91%, with peripheral vision loss being the most frequent complaint. Median (range) Snellen visual acuity of all eyes was 20/25 (20/20 to hand motion [HM]). Anterior segment abnormalities were present in 74% of the patients; of those, posterior embryotoxon was the most frequent finding. Abnormalities of the optic disc were found in 52%, and peripheral retinal abnormalities were the most frequent ocular finding in this series, found in 96% of all patients. Fifteen JAG1 mutations were identified in 16 individuals; of those, 6 were novel. Conclusions: This study reports a cohort of patients with Alagille syndrome in which peripheral chorioretinal changes were more frequent than posterior embryotoxon, the most frequent ocular finding according to a number of previous studies. We propose that these peripheral chorioretinal changes are a new hallmark to help diagnose this syndrome.

The new landscape of retinal gene therapy.

Novel therapeutics for inherited retinal dystrophies (IRDs) have rapidly evolved since groundbreaking clinical trials for LCA due to RPE65 mutations led to the first FDA-approved in vivo gene therapy. Since then, advancements in viral vectors have led to more efficient AAV transduction and developed other viral vectors for gene augmentation therapy of large gene targets. Furthermore, significant developments in gene editing and RNA modulation technologies have introduced novel capabilities for treatment of autosomal dominant diseases, intronic mutations, and/or large genes otherwise unable to be treated with current viral vectors. We highlight strategies currently being evaluated in gene therapy clinical trials and promising preclinical developments for IRDs.

The Role of ERK1/2 Activation in Sarpogrelate-Mediated Neuroprotection.

Purpose: To characterize the mediators of 5-HT2A serotonin receptor-driven retinal neuroprotection. Methods: Albino mice were treated intraperitoneally with saline or sarpogrelate, a 5-HT2A antagonist, immediately before light exposure (LE). Following LE, retinas were harvested for a high-throughput phosphorylation microarray to quantify activated phosphorylated proteins in G protein-coupled receptor (GPCR) signaling. To confirm microarray results and define temporal changes, Western blots of select GPCR signaling proteins were performed. Since both methodologies implicated MAPK/ERK activation, the functional significance of sarpogrelate-mediated ERK1/2 activation was examined by inhibition of ERK1/2 phosphorylation via pretreatment with the MEK inhibitor (MEKi) PD0325901. The degree of neuroprotection was evaluated with spectral-domain optical coherence tomography (SD-OCT) and electroretinography (ERG). To determine the effects of sarpogrelate on gene expression, a qPCR array measuring the expression of 84 genes involved in oxidative stress and cell death was performed 48 hours post LE. Results: Sarpogrelate led to an activation of the MAPK/ERK pathway. Temporal analysis further demonstrated a transient activation of ERK1/2, starting with an early inhibition 20 minutes into LE, a maximum activation at 3 hours post LE, and a return to baseline at 7 hours post LE. Inhibition of ERK1/2 with MEKi pretreatment led to attenuation of sarpogrelate-mediated neuroprotection. LE caused significant changes in the expression of genes involved in iron metabolism, oxidative stress, and apoptosis. These changes were prevented by sarpogrelate treatment. Conclusions: Sarpogrelate-mediated retinal protection involves a transient activation of the MAPK/ERK pathway, although this pathway alone does not account for the full effect of neuroprotection.

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy.

Purpose: Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. Methods: Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. Results: Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. Conclusions: This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration.

Importance: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. Objective: To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. Design, Setting, and Participants: A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. Main Outcomes and Measures: Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. Results: There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses. Conclusions and Relevance: This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist.

PURPOSE: To assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model. METHODS: Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections. RESULTS: A five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice. CONCLUSIONS: Intraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation.

Molecular and Clinical Findings in Patients With Knobloch Syndrome.

IMPORTANCE: Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, retinal detachment, and occipital encephalocele, but it is now known to have an increasingly variable phenotype. There is a lack of reported electrophysiologic data, and some key clinical features have yet to be described. OBJECTIVE: To expand on current clinical, electrophysiologic, and molecular genetic findings in Knobloch syndrome. DESIGN, SETTING, AND PARTICIPANTS: Twelve patients from 7 families underwent full ophthalmic examination and retinal imaging. Further investigations included electroretinography and neuroradiologic imaging. Bidirectional Sanger sequencing of COL18A1 was performed with segregation on available relatives. The study was conducted from July 4, 2013, to October 5, 2015. Data analysis was performed from May 20, 2014, to November 3, 2015. MAIN OUTCOMES AND MEASURES: Results of ophthalmic and neuroradiologic assessment and sequence analysis of COL18A1. RESULTS: Of the 12 patients (6 males; mean age at last review, 16 years [range, 2-38 years]), all had high myopia in at least 1 eye and severely reduced vision. A sibling pair had unilateral high myopia in their right eyes and near emmetropia in their left eyes from infancy. Anterior segment abnormalities included absent iris crypts, iris transillumination, lens subluxation, and cataract. Two patients with iris transillumination had glaucoma. Fundus characteristics included abnormal collapsed vitreous, macular atrophy, and a tesselated fundus. Five patients had previous retinal detachment. Electroretinography revealed a cone-rod pattern of dysfunction in 8 patients, was severely reduced or undetectable in 2 patients, and demonstrated cone-rod dysfunction in 1 eye with undetectable responses in the other eye in 2 patients. Radiologic imaging demonstrated occipital encephalocele or meningocele in 3 patients, occipital skull defects in 4 patients, minor occipital changes in 2 patients, and no abnormalities in 2 patients. Cutaneous scalp changes were present in 5 patients. Systemic associations were identified in 8 patients, including learning difficulties, epilepsy, and congenital renal abnormalities. Biallelic mutations including 2 likely novel mutations in COL18A1, were identified in 6 families that were consistent with autosomal recessive inheritance with a single mutation identified in a family with 2 affected children. CONCLUSIONS AND RELEVANCE: This report describes new features in patients with Knobloch syndrome, including pigment dispersion syndrome and glaucoma as well as cone-rod dysfunction on electroretinography. Two patients had normal neuroradiologic findings, emphasizing that some affected individuals have isolated ocular disease. Awareness of the ocular phenotype may aid early diagnosis, appropriate genetic counseling, and monitoring for potential complications.

Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonic acidemia.

BACKGROUND: Cobalamin C disease (cblC), which leads to methylmalonic acidemia with homocystinuria, is the most common inherited disorder of vitamin B12 metabolism. Reported ocular findings associated with cblC have been maculopathy, pigmentary retinopathy, and optic nerve atrophy. Cobalamin A disease (cblA) which causes an isolated methylmalonic acidemia without homocystinuria is rarer than cblC. This is the first detailed report of the ocular findings associated with cblA. We also describe the spectrum of ocular findings in our cblC patients. MATERIALS AND METHODS: A case series describing the ophthalmologic clinical course of six patients with a diagnosis of cobalamin C type and one patient with cobalamin A type of methylmalonic acidemia. Patients were diagnosed through biochemical laboratory testing and genetic analysis was conducted on most patients. Longitudinal fundus findings, optical coherence tomography (OCT), autofluorescence, and electrophysiology were followed in the patients. RESULTS: The cblA patient demonstrated a relatively mild ocular phenotype with late-onset and slowly progressing temporal disc pallor and peripapillary atrophy in the second decade of life. The patient maintained good visual acuity and central vision, without evidence of maculopathy. The six cblC patients demonstrated a range of ocular findings from unremarkable and mild phenotypes to significant retinopathy, including bull's eye maculopathy, severe maculopathy with punched out chorioretinal atrophy, peripheral bone spicules, and optic nerve atrophy. CONCLUSIONS: The spectrum of ocular manifestations seen with inherited disorders of cobalamin metabolism is wide, ranging from mild optic nerve atrophy to severe macular or retinal degeneration. This heterogeneity may in part reflect the associated biochemical phenotype, such as that observed between our cblA and cblC patients. We also observed heterogeneity within the cblC type in agreement with previous reports.