Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration.

BACKGROUND: Characterization of retinal degeneration (RD) using high-resolution retinal imaging and exome sequencing may identify phenotypic features that correspond with specific genetic defects. MATERIALS AND METHODS: Six members from a non-consanguineous Indian family (three affected siblings, their asymptomatic parents and an asymptomatic child) were characterized clinically, using visual acuity, perimetry, full-field electroretinography (ERG), optical coherence tomography and cone structure as outcome measures. Cone photoreceptors were imaged in the proband using adaptive optics scanning laser ophthalmoscopy. The exome was captured using Nimblegen SeqCap EZ V3.0 probes and sequenced using lllumina HiSeq. Reads were mapped to reference hg19. Confirmation of variants and segregation analysis was performed using dideoxy sequencing. RESULTS: Analysis of exome variants using exomeSuite identified five homozygous variants in four genes known to be associated with RD. Further analysis revealed a homozygous nonsense mutation, c.1105 C > T, p.Arg335Ter, in the FAM161A gene segregating with RD. Three additional variants were found to occur at high frequency. Affected members showed a range of disease severity beginning at different ages, but all developed severe visual field and outer retinal loss. CONCLUSIONS: Exome analysis revealed a nonsense homozygous mutation in FAM161A segregating with RD with severe vision loss and a range of disease onset and progression. Loss of outer retinal structures demonstrated with high-resolution retinal imaging suggests FAM161A is important for normal photoreceptor structure and survival. Exome sequencing may identify causative genetic variants in autosomal recessive RD families when other genetic test strategies fail to identify a mutation.

The effects of gender and age on the range of the normal human electro-oculogram.

PURPOSE: To define the normal ranges for the slow oscillations (SO) and fast oscillations (FO) of the electro-oculogram (EOG) recorded to International Society for Clinical Electrophysiology of Vision (ISCEV) standards. The effects of age and gender on the EOG ranges were examined. METHODS: ISCEV standard SOs and FOs were recorded from 121 subjects (51 % male) aged from 7 to 72 years. Study variables for the SO were dark trough (DT) and light peak (LP) amplitudes (µV), times to DT and LP (min), and the Arden ratio (LP/DT amplitude). The FO was fit by a sine wave and peak-to-peak amplitude (µV), phase (°), and peak-to-trough (PT) ratios derived. The effects of age, gender and pupil size on EOG parameters were examined by multiple regression analysis. RESULTS: The average Arden ratio was 2.5. Arden ratio decreased with age at a rate of 0.13 per decade of age (R (2) = 0.14, P < 0.0001). The 5th percentile of the Arden ratio decreased from 2.0 to 1.7 between 10 and 60 years of age. Median time to LP was 9 min (interquartile range 8-9 min). Time to LP was age-dependent and increased by 2 min for subjects over 55 years of age compared with those less than 25 years. EOG amplitudes were greater in women than in men (P < 0.005). The average PT ratio was 1.18, which was not affected by age or gender. Time to reach the light trough of the FO was 40 s, which increased with age (1.1 s/decade). No correlation was observed between Arden ratio and PT ratio. CONCLUSIONS: The major strength of this study is the definition of the normal range and associated lower limits of ISCEV standard EOGs based on recordings from 121 subjects balanced by gender and spanning the 1st through 8th decades of life. Decreased Arden ratio and increased time to LP are associated with aging, which is likely due to the intricate mechanisms involved in generation of the light rise. Differences between the FO and SO with respect to the effects of aging are consistent with separate generation of these two EOG signals.

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study.

BACKGROUND: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene (CLN1 or PPT1) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate ceroid depletion in cultured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal ceroid lipofuscinosis. METHODS: Children between 6 months and 3 years of age with infantile neuronal ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6-12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal ceroid lipofuscinosis and that of affected older siblings. This trial is registered with ClinicalTrials.gov, number NCT00028262. FINDINGS: Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. INTERPRETATION: Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. FUNDING: National Institutes of Health.

Patients with Bardet-Biedl syndrome have hyperleptinemia suggestive of leptin resistance.

OBJECTIVE: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder of the primary cilium associated with obesity. In BBS mouse models, ciliary dysfunction leads to impaired leptin signaling and hyperleptinemia before obesity onset. To study the pathophysiology of obesity in BBS, we compared patients with BBS and body mass index Z-score (BMI-Z)-matched controls. DESIGN AND METHODS: Fifty patients with BBS were matched 2:1 by age, sex, race, and BMI-Z with 100 controls. Patients with BBS and controls were compared for differences in body composition (dual-energy x-ray absorptiometry, abdominal magnetic resonance imaging), blood pressure Z-score (BP-Z; standardized for age, sex, and height), and fasting concentrations of leptin, lipids, insulin, and glucose. Patients with BBS were also compared by genotype. RESULTS: Leptin, triglycerides, intraabdominal fat mass, and diastolic BP-Z were significantly greater in patients with BBS than in the controls. BBS1 (27%) and BBS10 (30%) mutations were the most prevalent. Patients with BBS10 mutations had significantly higher BMI-Z, greater visceral adiposity, and greater insulin resistance than those with BBS1 mutations. CONCLUSIONS: Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. The preferential deposition of fat intraabdominally in patients with BBS may indicate a predisposition for metabolic complications, including hypertension and hypertriglyceridemia. The observation of disparate results in the BBS10 vs. BBS1 mutation groups is the first demonstration of physiological differences among patients with BBS caused by mutations in distinct genes. These results suggest that the obesity of BBS is distinct from nonsyndromic obesity.

Molecular mechanisms leading to null-protein product from retinoschisin (RS1) signal-sequence mutants in X-linked retinoschisis (XLRS) disease.

Retinoschisin (RS1) is a cell-surface adhesion molecule expressed by photoreceptor and bipolar cells of the retina. The 24-kDa protein encodes two conserved sequence motifs: the initial signal sequence targets the protein for secretion while the larger discoidin domain is implicated in cell adhesion. RS1 helps to maintain the structural organization of the retinal cell layers and promotes visual signal transduction. RS1 gene mutations cause X-linked retinoschisis disease (XLRS) in males, characterized by early-onset central vision loss. We analyzed the biochemical consequences of several RS1 signal-sequence mutants (c.1A>T, c.35T>A, c.38T>C, and c.52G>A) found in our subjects. Expression analysis in COS-7 cells demonstrates that these mutations affect RS1 biosynthesis and result in an RS1 null phenotype by several different mechanisms. By comparison, discoidin-domain mutations generally lead to nonfunctional conformational variants that remain trapped inside the cell. XLRS disease has a broad heterogeneity in general, but subjects with the RS1 null-protein signal-sequence mutations are on the more severe end of the clinical phenotype. Results from the signal-sequence mutants are discussed in the context of the discoidin-domain mutations, clinical phenotypes, genotype-phenotype correlations, and implications for RS1 gene replacement therapy.

Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL.

Leber congenital amaurosis (LCA) is a congenital retinal dystrophy characterized by severe visual loss in infancy and nystagmus. Although most often inherited in an autosomal recessive fashion, rare individuals with mutations in the cone-rod homeobox gene, CRX, have dominant disease. CRX is critical for photoreceptor development and acts synergistically with the leucine-zipper transcription factor, NRL. We report on the phenotype of two individuals with LCA due to novel, de novo CRX mutations, c.G264T(p.K74N) and c.413delT(p.I138fs48), that reduce transactivation in vitro to 10% and 30% of control values, respectively. Whereas the c.413delT(p.I138fs48) mutant allows co-expressed NRL to transactivate independently at its normal, baseline level, the c.G264T(p.K74N) mutant reduces co-expressed NRL transactivation and reduces steady state levels of both proteins. Although both mutant proteins predominantly localize normally to the nucleus, they also both show variable cytoplasmic localization. These observations suggest that some CRX-mediated LCA may result from effects beyond haploinsufficiency, such as the mutant protein interefering with other transcription factors' function. Such patients would therefore not likely benefit from a simple, gene-replacement strategy for their disease.

Absent optic chiasm presenting with horizontal nystagmus.

A female infant with horizontal nystagmus and normal ophthalmic examination had isolated absence of the optic chiasm on magnetic resonance imaging. Eye movements were recorded on video and reviewed. Horizontal nystagmus without see-saw nystagmus was observed. Visual evoked potential showed inter-hemispheric asymmetry compatible with the absence of crossing chiasmal fibers. Systemic abnormalities in this patient included cleft lip, preauricular skin tags, broad thumbs, and an anteriorly positioned anus, suggestive of Townes-Brock syndrome.

Retinal disease in Rpe65-deficient mice: comparison to human leber congenital amaurosis due to RPE65 mutations.

PURPOSE: To quantify the retinal disease in Rpe65-deficient mice across a wide age span and compare the results to those in humans with Leber congenital amaurosis (LCA) caused by RPE65 mutations. METHODS: Full-field electroretinograms (ERGs) were recorded from wild-type (C57BL/6; Rpe65(+/+)) and Rpe65(-/-) mice at ages ranging from ∼1 month to 2 years. A physiologically based model of rod phototransduction activation was used to determine photoreceptor (P3) cell components of ERG photoresponses. A bipolar (P2) cell component was also derived. Photoreceptor and inner retinal thickness measurements were made by using optical coherence tomography in human RPE65-LCA. RESULTS: Age-related declines in ERG photoreceptor and bipolar amplitudes were present in the Rpe65(-/-) mouse. The loss of photoresponse amplitude with age in the mutant mice paralleled reported losses of photoreceptor nuclear layer thickness over the same age range. Unexpectedly, the early activation phase of photoresponses in Rpe65(-/-) mice accelerated with age as amplitude decreased; this was not a feature of Rpe65(+/+) mice. Inner retinal dysfunction increased with age in the mutant mice. Human RPE65-LCA patients had retinal degeneration and loss of photoreceptors in the first decade of life. Unlike the mouse model, there were no examples of a normal photoreceptor complement. Abnormal thickening of the inner retina occurred with increasing loss of photoreceptors. CONCLUSIONS: The differences in time course of murine and human RPE65-deficiency diseases suggests that preclinical efficacy testing of therapeutic modalities would be most informative when the murine disease becomes comparable to early human disease, toward the end of the first year of life in Rpe65(-/-) mice.

Rapid vision loss associated with fludarabine administration.

PURPOSE: The purpose of this study was to report the clinical and pathologic findings of three cases of rapid vision loss associated with fludarabine toxicity. METHODS: A retrospective, single-center case series was conducted. Autopsies of the eyes from three cases were performed. RESULTS: A 23-year-old man (Case 1) with systemic lupus erythematosus developed rapid and severe vision loss, generalized neurologic decline, and eventual death after administration of fludarabine before stem cell transplantation. A 48-year-old woman (Case 2) and a 60-year-old man (Case 3), both with metastatic melanoma, had similar courses after receiving fludarabine as part of a preparatory regimen before adoptive cell therapy. Fundus examination showed punctuate yellow flecks in the macula after visual decline in two cases. In all three cases, serum antiretinal antibodies were negative before and after treatment; electrophysiological testing showed markedly decreased B-waves; and pathologic analysis showed loss of retinal bipolar and ganglion cells, gliosis within the retina and optic nerve, and optic nerve atrophy. CONCLUSION: Fludarabine toxicity can result in severe vision loss attributable to damage to retinal bipolar and ganglion cells. Although effective treatments are not known, care should be taken to consider fludarabine toxicity in patients who present with vision loss approximately 1 month after treatment.

Children with infantile neuronal ceroid lipofuscinosis have an increased risk of hypothermia and bradycardia during anesthesia.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative diseases characterized by lysosomal accumulation of autofluorescent material in neurons and other cell types. The infantile NCL (INCL) subtype is rare (1 in >100,000 births), the most devastating of childhood subtypes, and is caused by mutations in the gene CLN1, which encodes palmitoyl-protein thioesterase-1. METHODS: To investigate the incidence of hypothermia and bradycardia during general anesthesia in patients with INCL, we conducted a case-control study to examine the perianesthetic course of patients with INCL and of controls receiving anesthesia for diagnostic studies. RESULTS: Eight children with INCL (mean age 25 mo [range, 10-32] at first anesthetic) and 25 controls (mean age 44 mo [range, 18-92]) underwent 62 anesthetics for nonsurgical procedures. Patients with INCL had neurologic deficits including developmental delay, myoclonus, and visual impairment. Patients with INCL had lower baseline temperature (36.4 +/- 0.1 vs 36.8 +/- 0.1, INCL versus controls, P < 0.007), and during anesthesia, despite active warming techniques, had significantly more hypothermia (18 vs 0 episodes, P < 0.001) and sinus bradycardia (10 vs 1, P < 0.001) compared with controls. INCL diagnosis was significantly associated with temperature decreases during anesthesia (P < 0.001), whereas age, sex, and duration of anesthesia were not (P = NS). CONCLUSIONS: We report that patients with INCL have lower baseline body temperature and during general anesthesia, despite rewarming interventions, are at increased risk for hypothermia and bradycardia. This suggests a previously unknown INCL phenotype, impaired thermoregulation. Therefore, when anesthetizing these children, careful monitoring and routine use of warming interventions are warranted.

Null retinoschisin-protein expression from an RS1 c354del1-ins18 mutation causing progressive and severe XLRS in a cross-sectional family study.

PURPOSE: To explore the retinoschisin (RS1) protein biochemical phenotype from an RS1 exon-5 deletion/insertion frame-shift mutation in a family with X-linked retinoschisis (XLRS) and describe the clinical and electrophysiological features. METHODS: Six XLRS males underwent ophthalmic examination and electroretinogram (ERG) recording. The RS1 gene was sequenced. Mutant RS1-RNA and protein expression were assessed by transfecting COS-7 cells with minigene constructs. RESULTS: All six males carried the RS1 c354del1-ins18 mutation in which an 18-bp insertion replaced nucleotide 354, duplicating the adjacent upstream intron 4-to-exon 5 junction and creating a premature termination codon downstream. Analysis indicated normal pre-mRNA splicing producing mRNA transcripts. Truncated RS1 protein was expressed transiently but was degraded rapidly by a proteasomal pathway rather than by nonsense-mediated mRNA decay. Two boys, 1.5 and 5 years of age, had foveal cysts and minimal peripheral schisis, and retained near-normal scotopic b-wave amplitude and normal ERG waveforms. The 5-year-old's ERG was diminished when repeated 3 years later. Four older XLRS relatives 32 to 45 years old had substantial b-wave loss and strongly electronegative ERGs; three had overt macular atrophy. Cross-sectional family analysis showed the b-/a-wave amplitude ratio as inversely related to age in the six males. CONCLUSIONS: The c354del1-ins18 mutation caused an RS1-null biochemical phenotype and a progressive clinical phenotype in a 5-year-old boy, whereas the older XLRS relatives had macular atrophy and marked ERG changes. The phenotypic heterogeneity with age by cross-sectional study of this family mutation argues that XLRS disease is not stationary and raises questions regarding factors involved in progression.

Isolated ocular disease is associated with decreased mucolipin-1 channel conductance.

PURPOSE: To evaluate a 15-year-old boy with MLIV (mucolipidosis type IV) and clinical abnormalities restricted to the eye who also had achlorhydria with elevated blood gastrin levels. METHODS: In addition to a detailed neuro-ophthalmic and electrophysiological assessment, his mutant mucolipin-1 was experimentally expressed in liposomes and its channel properties studied in vitro. RESULTS: The patient was a compound heterzygote for c.920delT and c.1615delG. Detailed neuro-ophthalmic examination including electroretinography showed him to have a typical retinal dystrophy predominantly affecting rod and bipolar cell function. In vitro expression of MCOLN1 in liposomes showed that the c.1615delG mutated channel had significantly reduced conductance compared with wild-type mucolipin-1, whereas the inhibitory effect of low pH and amiloride remained intact. CONCLUSIONS: These findings suggest that reduced channel conductance is relatively well tolerated by the brain during development, whereas retinal cells and stomach parietal cells require normal protein function. MLIV should be considered in patients with retinal dystrophy of unknown cause and screened for using blood gastrin levels.

Mutations in NYX of individuals with high myopia, but without night blindness.

PURPOSE: High myopia is a common genetic variant that severely affects vision. Genes responsible for myopia without linked additional functional defects have not been identified. Mutations in the nyctalopin gene (NYX) located at Xp11.4 are responsible for a complete form of congenital stationary night blindness (CSNB1). High myopia is usually observed in patients with CSNB1. This study was designed to test the possibility that mutations in the NYX gene might cause high myopia without congenital stationary night blindness (CSNB). METHODS: The genomic sequence of NYX in 52 male probands with high myopia but without CSNB was analyzed through direct DNA sequencing. Variations in the NYX were verified by analyzing available family members and 232 controls. RESULTS: Two unrelated male individuals with high myopia but without night blindness were found to have novel Cys48Trp and Arg191Gln mutations in NYX. The mutations were found to be located in distinct regions, different from the locations of mutations known to cause congenital stationary night blindness with myopia (CSNB1). CONCLUSIONS: Mutations in NYX may cause high myopia without CSNB. The observations suggest that NYX may have independent effects on myopia and night blindness.

Clinical and genetic heterogeneity of crystalline retinopathies: report of two families without bietti crystalline dystrophy.

PURPOSE: To report variations in the inheritance pattern and clinical presentation of crystalline retinopathies. METHODS: Two different families with crystalline retinopathy were studied with a complete family history and ophthalmologic examination including Goldmann kinetic perimetry and electroretinography. Genetic studies were performed in one of the families. RESULTS: One of the families had a clearly autosomal dominant mode of inheritance while the other family most likely follows an autosomal recessive pattern. Several members in each family had significant retinal pigment epithelial atrophy, intraretinal crystals, relatively pink optic nerves, and paracentral visual field defects, all of which are clinical features resembling those of Bietti crystalline retinopathy. Examination of peripheral leukocytes using transmission electron microscopy in selected affected members showed no evidence of classical lysosomal crystals that are characteristics for Bietti crystalline retinopathy. No pathogenic mutations were identified in the CYP4V2 gene. CONCLUSIONS: Not all crystalline retinopathies are Bietti's. Further genetic, biochemical, and pathologic studies are required to better differentiate between these retinopathies.

Autoantibodies to p75/LEDGF, a cell survival factor, found in patients with atypical retinal degeneration.

We have identified a group of patients with an atypical retinal degeneration having anti-retinal autoantibodies in their sera. This select population is characterized by a progressively severe loss of vision associated with a decrease in photoreceptor function, abnormal pigmentation of the retinal pigment epithelium and a negative family history of retinal dystrophy. Immunohistochemical analysis on mouse retinal tissues with sera from this group of patients demonstrated high titers of anti-retinal antibodies (320 to 1,280). Anti-retinal reactivity at these levels was not detected in sera from normal individuals, or from patients with uveitis or known genetic retinal degenerations. One antigen that was identified from a retina cDNA library with sera from a patient with atypical retinal degeneration was lens epithelium-derived growth factor (LEDGF). Western blot analysis revealed that sera from all three patients demonstrated reactivity to p75/LEDGF, a survival factor that protects cells from oxidative, thermal and UV damage. In conclusion, we have found a novel group of patients with a retinal degeneration of non-paraneoplastic, non-familial origin demonstrating immunoreactivity to an autoantigen, p75/LEDGF, heretofore not associated with this disease. Finally, identification of specific anti-retinal antibodies may have applications in the diagnosis and management of retinal degeneration.

Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy.

PURPOSE: Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by the intracellular accumulation of cystine. Treatment involves intracellular cystine depletion with oral cysteamine. A wide spectrum of ocular pathologic features has been associated with nephropathic cystinosis. We used the largest documented cohort of patients in the world to study the posterior segment manifestations associated with infantile nephropathic cystinosis and to determine retrospectively the effect of chronic oral cysteamine therapy on the frequency of these abnormalities. DESIGN: Cross-sectional study of a series of patients. PARTICIPANTS: Two hundred eight patients with infantile nephropathic cystinosis were studied at the National Institutes of Health between 1976 and 2004. METHODS: All patients underwent an ophthalmic evaluation. Patients older than 11 years also underwent Humphrey static perimetry, and electrophysiological testing was performed when possible. MAIN OUTCOME MEASURES: Visual acuity, retina findings, visual fields, and electroretinographic (ERG) findings. RESULTS: Pigmentary changes with retinal pigment epithelial mottling, seen as early as infancy, were the most common posterior segment manifestations. Moderate to severe constriction of the visual fields, as well as moderate to severe reduction of rod- and cone-mediated ERG responses, was seen in older patients. The frequency of retinopathy correlated directly with time not receiving oral cysteamine therapy and inversely with time receiving oral cysteamine therapy. CONCLUSIONS: Infantile nephropathic cystinosis has posterior segment complications that can contribute to significant visual handicap. Early initiation of oral cysteamine therapy can reduce the frequency of posterior segment complications in cystinosis patients.

Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants.

Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by cells transfected with the human CNTF gene and sequestered within capsules that were surgically implanted into the vitreous of the eye. The outer membrane of the encapsulated cell implant is semipermeable to allow CNTF to reach the retina. Ten participants received CNTF implants in one eye. When the implants were removed after 6 months, they contained viable cells with minimal cell loss and gave CNTF output at levels previously shown to be therapeutic for retinal degeneration in rcd1 dogs. Although the trial was not powered to form a judgment as to clinical efficacy, of seven eyes for which visual acuity could be tracked by conventional reading charts, three eyes reached and maintained improved acuities of 10-15 letters, equivalent to two- to three-line improvement on standard Snellen acuity charts. A surgically related choroidal detachment in one eye resulted in a transient acuity decrease that resolved with conservative management. This Phase I trial indicated that CNTF is safe for the human retina even with severely compromised photoreceptors. The approach to delivering therapeutic proteins to degenerating retinas using encapsulated cell implants may have application beyond disease caused by genetic mutations.

Late-onset macular degeneration and long anterior lens zonules result from a CTRP5 gene mutation.

PURPOSE: To identify the gene responsible for a complex ocular phenotype of late-onset macular degeneration, long anterior zonules (LAZ), and elevated intraocular pressure (IOP) and to study its expression. METHODS: Ocular examination, visual field, fluorescein angiography, and electrophysiology testing were performed. One affected individual was treated with vitamin A. DNA from 55 family members (UM:H389) was used for linkage, mapping, and mutation analysis. Linkage analysis of macular degeneration and LAZ phenotypes was performed independently. Mutations in candidate genes were screened by sequencing. mRNA expression of CTRP5 and MFRP, which are bicistronic genes, was studied by semiquantitative RT-PCR (qRT-PCR) in various human tissues. CTRP5 expression was also evaluated by in situ hybridization. RESULTS: Affected members had LAZ detectable by the third decade and/or macular degeneration by the fourth to fifth decade. A six-month treatment with vitamin A shortened dark adaptation considerably in one affected member. Both conditions mapped independently with zero recombination to 11q23, with maximum lod scores of 3.31 for macular degeneration and 5.41 for LAZ. The same CTRP5 missense mutation was identified in all affected individuals. Retinal pigment epithelium (RPE) and ciliary epithelium (CE) showed highest CTRP5 transcript expression, which was also true for MFRP. CTRP5 tissue expression was confirmed by in situ hybridization. CONCLUSIONS: A single locus at 11q23 is implicated in a complex ocular phenotype involving RPE and CE, tissues of neuroectodermal origin. All individuals with either LAZ and/or macular degeneration carry the same CTRP5 S163R mutation, which is transmitted in autosomal dominant manner.

Central visual function and the NEI-VFQ-25 near and distance activities subscale scores in people with type 1 and 2 diabetes.

PURPOSE: To investigate relationships between clinical measures of central visual function and NEI-VFQ-25 Near and Distance Activities subscales in patients with diabetic retinopathy. DESIGN: Clinic-based, cross-sectional, observational study. METHODS: The NEI-VFQ-25 was administered to 170 people with type 1 or 2 diabetes before an ocular examination that included visual acuity, contrast sensitivity, and central visual fields. Multiple linear regression and exact multiple logistic regression were used to assess the relationship between poor acuity (<69 letters), poor contrast sensitivity (<1.5 log units), and abnormal visual fields (mean deviation < or = -5dB) and NEI-VFQ-25 subscale scores. RESULTS: Final multivariable linear models explained a beta = 4.7 letter difference (P < or = .001) for each 25-point Near Activities subscale score difference. Similar effects were observed for the Distance Activities subscale, although the magnitudes of regression and partial correlation coefficients were lower (beta = 3.3 letters, P < or = .01). Final logistic regression models on abnormal clinical categories of central visual function demonstrated relationships only with the Near Activities subscale. For a 1-point change in Near Activities subscale score, the odds of obtaining a poor score for visual acuity, central visual fields, and contrast sensitivity changed by 0.08 (P < or = .001), 0.07 (P < or = .05), and 0.12 (P < or = .001), respectively. CONCLUSIONS: NEI-VFQ-25 Near and Distance Activities subscales demonstrate utility as measures of central visual function in persons with type 1 or 2 diabetes. Low scores on the NEI-VFQ-25 may reflect poor central visual fields and contrast sensitivity in addition to poor visual acuity.