Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

Intra-arterial chemotherapy as a treatment for intraocular retinoblastoma: alternatives to direct ophthalmic artery catheterization.

BACKGROUND AND PURPOSE: Intra-arterial chemotherapy is a very effective treatment option for intraocular retinoblastoma. However, direct catheterization of the OA is not always possible. The purpose of this work was to report our initial results with intra-arterial chemotherapy for intraocular retinoblastoma when delivery of the drug was not via direct catheterization of the OA. MATERIALS AND METHODS: Retrospective review of 110 eyes (89 patients) undergoing a total of 351 intra-arterial treatments at our institution between 2006 and 2010 identified 18 eyes (14 patients) that received at least 1 infusion via a vascular route other than direct OA catheterization. Alternatives included catheterization of the orbital branch of the MMA and temporary balloon occlusion of the ICA. RESULTS: Tumor control was observed in 17 of 18 eyes at a mean follow-up of 18.9 months (median, 17.5 months; range, 8-36 months). The mean number of intra-arterial infusions was 3.7 per eye (median, 3; range, 2-9). Treatment routes included the following: MMA only, 3 eyes; MMA + OA, 4 eyes; MMA + balloon, 2 eyes; balloon only, 1 eye; balloon + OA, 7 eyes; balloon + OA + MMA, 1 eye. Intra-arterial chemotherapies included melphalan, topotecan, and carboplatin. Complications were all transient. ERG readings were the following: stable, 10 eyes; improved, 3 eyes; reduced, 5 eyes. One patient died from a second malignancy (pinealoblastoma). CONCLUSIONS: This initial experience shows that when direct OA catheterization is not possible, using alternative routes of intra-arterial chemotherapy saves eyes and preserves vision with acceptable side effects.

Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials.

OBJECTIVE: To describe the disease course and natural history of Type A Niemann-Pick disease (NPD). METHODS: Ten patients with NPD-A (six male, four female; age range at entry: 3 to 6 months) were serially evaluated including clinical neurologic, ophthalmologic, and physical examinations, and assessment of development. Laboratory analyses, abdominal and brain ultrasounds, and chest radiographs also were obtained and information on intercurrent illnesses and cause of mortality was collected. RESULTS: All affected infants had a normal neonatal course and early development. The first symptom detected in all patients was hepatosplenomegaly. Developmental age did not progress beyond 10 months for adaptive behavior, 12 months for expressive language, 9 months for gross motor skills, and 10 months for fine motor skills. Non-neurologic symptoms included frequent vomiting, failure to thrive, respiratory infections, irritability, and sleep disturbance. Neurologic examination at the time of presentation was normal in most patients. Later neurologic examinations revealed progressive hypotonia with loss of the deep tendon reflexes. All patients had cherry red spots by 12 months. The median time from diagnosis to death was 21 months. The cause of death was respiratory failure in nine patients and complications from bleeding in the tenth. CONCLUSIONS: The clinical course in Type A Niemann-Pick disease is similar among affected patients and is characterized by a relentless neurodegenerative course that leads to death, usually within 3 years.

Long-term follow-up of corneal graft survival following bone marrow transplantation in the Maroteaux-Lamy syndrome.

PURPOSE: To present a case of Maroteaux-Lamy syndrome (MLS, mucopolysaccharidosis [MPS] type VI) who underwent bone marrow transplantation (BMT) for gene transfer at the age of 13, and penetrating keratoplasty at the age of 17, and maintained clear corneal grafts bilaterally for 13 years. To our knowledge, this is the longest follow-up reported on corneal graft survival in a patient with MLS and BMT. METHODS: In 1982, BMT was successfully performed on a 13-year-old girl with MLS with growth retardation, typical facial features, skeletal and joint deformities, hepatosplenomegaly, cardiopulmonary dysfunction, and corneal clouding. Corneal transplantation was done on the left eye in 1986, and on the right eye in 1987 (6 months later) without difficulty or complication. RESULTS: Thirteen years postoperatively, the patient was systemically well, and both eyes retained clear corneal grafts. CONCLUSION: BMT retarded further dysfunction from MLS, and the corneal transplants retained clarity. Further controlled studies with longer follow-up are required to establish the efficacy of BMT in ocular manifestations of MPS or MLS.

Evaluation of different recording parameters to establish a standard for flash electroretinography in rodents.

Different electrodes and stimulus protocols commonly used for electroretinography in rodent eyes were compared for convenience of use, degree of damage to corneal epithelium, and for magnitude of amplitude, reproducibility, left versus right eye accuracy, and reliability of recorded parameters of the flash electroretinogram (ERG). Adult C57BL/6 pigmented mice and albino Wistar rats were used to determine scotopic ERGs in response to Ganzfeld or strobe-light stimulation and light-adapted (photopic) ERGs recorded from both eyes at the same time. Test-retest data were used for statistical analyses to compare a monopolar gold-wire contact lens electrode (CLE), a cotton-wick silver-silver chloride electrode (CSCE), a DTL fiber electrode (DTLE), and a circular stainless steel wire electrode (SSE). Corneas were evaluated for abrasion after ERG recordings using fluorescein staining and also for the time taken, ease of insertion, and re-insertions required for the different electrodes. Compared to CSCE, DTLE, and SSE, the ERG potentials recorded by CLE had significantly larger scotopic amplitudes and oscillatory potentials under strobe or Ganzfeld stimulation and for light-adapted ERG b-wave amplitudes in both mice and rats. In analyzing test-retest data of scotopic ERG a-wave and b-wave amplitudes, the intraclass correlation coefficient showed the best agreement for the CLE (range 0.61-0.94) compared to the SSE (0.13-0.77), DTLE (0.02-0.69), and CSCE (0.12-0.51). In mice and rats, logistic regression analyses revealed significant correlations for amplitudes of most scotopic ERG parameters between contralateral eyes obtained with CLE and for some ERG components recorded by SSE. When comparing ERG amplitudes for stimulation by strobe or Ganzfeld, the difference was least with the CLE compared to DTLE, CSCE, or SSE. The time taken to insert the four different electrodes was greatest for the CLE in both mice and rats. The extent of corneal abrasion resulting from electrode use in mice was largest for the SSE followed by the CLE. However, in rats there was almost no corneal damage after ERG recordings with the CLE. Because of the stability of eye contact, the CLE allows ERGs to be determined over a longer recording session. Recording of scotopic and photopic (light-adapted) ERGs in rodents with monopolar gold-wire contact lens electrodes provides greater amplitudes and higher reproducibility when compared to other commonly used corneal electrodes. These electrodes are significantly better overall than others that were evaluated and should be considered for a standard protocol to monitor retinal function in rodent eyes.

[Pilot study of pattern-electroretinographic changes in the DBA/2NNia mouse. Animal model of congenital angle-closure glaucoma]. / Pilotstudie zu musterelektroretinographischen Veränderungen bei der DBA/2NNia-Maus. Tiermodell eines angeborenen Engwinkelglaukoms.

PURPOSE: The aim of this study was to document the time-course of retinal dysfunction by pattern-electroretinography (PERG) in eyes of the DBA/2NNia substrain of mouse that develop an inherited angle-closure glaucoma. METHODS: Twelve DBA/2NNia mice and 12 control C57BL/6 J mice were studied by PERG recordings from 2 to 10 months of age. PERGs were recorded using different spatial and temporal frequencies. RESULTS: PERGs recorded with a temporal frequency of 7.5 Hz and a spatial frequency of 0.4 cycles/degree performed best to discriminate between DBA/2NNia mice and C57BL/6 J mice. When compared with normal C57BL/6 J mice, significant amplitude reductions of the PERG (Student's t-test; p < 0.01) were found in DBA/2NNia mice by 5 months of age and continued to decline as the animals aged. At beginning of follow-up, the mean PERG amplitude in DBA/2NNia mice was 2.3 +/- 0.5 microV. At 5 months of age, the mean PERG amplitude was reduced by 0.9 +/- 0.45 microV (paired t-test; p < 0.0001). CONCLUSION: Previously, a significant loss of retinal ganglion cells was found in the DBA/2NNia mouse substrain at 6-7 months of age. In the present study, we found decreases in PERG amplitudes, occurring from the age of 5 months onward. Similarities with the findings in human glaucoma indicate the relevance of this animal model for further glaucoma research.

Is intraoperative topography predictive of postoperative topographical changes following refractive surgery?

PURPOSE: To evaluate the usefulness of measuring corneal topography intraoperatively by Intraoperative PAR Corneal Topography System (IOPAR CTS) to predict the postoperative topographical changes in patients undergoing refractive surgery. METHODS: Topographical measurements of 9 eyes of 9 patients were taken by IOPAR CTS: 6 immediately after Intrastromal Corneal Ring Segments (ICRS) placement surgery and 3 immediately after Photorefractive Keratectomy (PRK) surgery. The topographical images taken by IOPAR CTS were analyzed to determine the quality of the image produced and the correlation of the keratometric data from the central 3 mm of cornea with measurements taken from an autokeratometer (Auto-Km) and the EyeSys Corneal Analysis System (CAS) for the same eyes taken three months following the procedure. RESULTS: At the 3-month postoperative exam, the correlation coefficients for flat (K1), steep (K2), and average keratometry (AK) readings produced by the Auto-Km and the EyeSys CAS were quite high. However, the correlation coefficients for K1, K2, AK, As or steep meridian axis (Ax) readings taken intraoperatively by IOPAR CTS were quite low when compared to the readings taken by either the Auto-Km or EyeSys CAS three months postoperatively. CONCLUSION: We found IOPAR CTS, relatively difficult to perform in the operating room during refractive surgical procedures and not useful clinically in predicting the postoperative topographical changes induced by ICRS or PRK procedure. Further studies are required to establish the efficacy and reproducibility of the instrument.

Characteristics of the myopic patient population applying for refractive surgery.

PURPOSE: Assessment of the characteristics of the myopic patient population applying for refractive surgery in order to determine the potential market for myopic refractive surgery. METHODS: Records of consecutive patients who responded to an advertisement for refractive surgery to correct myopia were evaluated retrospectively with regards to patient demographics and the amount and distribution of the refractive error. Data were compared to that available from population-based statistics for distribution of myopia in the general population. For statistical analysis, one sample Student's t-test and two tailed Student's t-test were utilized. RESULTS: Two hundred fifty seven patients (140 women and 117 men) responded to an advertisement for refractive surgery during the six month period between January and June 1998. Mean spherical equivalent (SEQ) of the patient population was -4.59+/-2.54 D (min;-0.25 D, max;-15.75 D) right eye (OD) and -4.62+/-2.82 D (min;-0.25 D, max;-15.25 D) left eye (OS). Among the patients who had myopia with an astigmatism of at most 1.00 D (n=165), the distribution of refractive error was statistically significantly different from that obtained from population-based statistics, such that, although most of the myopic population (40%) had an SEQ of -1.00 to -2.25 D, the majority of our patients (54.8%) who applied for myopic refractive surgery had an SEQ of -2.50 to -5.00 D. Another striking difference was that, although patients with an SEQ more than -6.00 D were a minority(2%) in the population study, in our study group, they comprised 16.7% of the patients seeking refractive correction. The difference between the SEQ of the right and left eyes ranged from 0.00 D to 13.0 D (mean, 0.89+/-1.5 D), 47.1 % having a difference of at most +/-0.5 D between the two eyes. The mean cylindrical error in the patient population was 0.69+/-0.93 D (min: 0, max: -4.5) OD and 0.69+/-0.96 D (min: 0, max: -4.5) OS. There were no statistically significant differences between the distribution of SEQ or cylindrical refractive error between males and females. CONCLUSION: Although a population-based study reported that most of the myopic population (40%) had an SEQ of -1.00 to -2.25 D, the majority of our patients (54.8%) who applied for myopic refractive surgery had an SEQ of -2.50 to -5.00 D. On the other hand, while patients with an SEQ of -6.00 D and more constituted only about 2% of the general population, they accounted for 16.7% of our study population. Therefore, the refractive characteristics of the patient population applying for myopic refractive surgery may not necessarily parallel that of general population-based statistics. In order to establish a more effective refractive surgery practice, it is feasible to perform local studies and reevaluate the requirements of your practice accordingly.

CNS myelin and sertoli cell tight junction strands are absent in Osp/claudin-11 null mice.

Oligodendrocyte-specific protein (OSP)/claudin-11 is a recently identified transmembrane protein found in CNS myelin and testis with unknown function. Herein we demonstrate that Osp null mice exhibit both neurological and reproductive deficits: CNS nerve conduction is slowed, hindlimb weakness is conspicuous, and males are sterile. Freeze fracture reveals that tight junction intramembranous strands are absent in CNS myelin and between Sertoli cells of mutant mice. Our results demonstrate that OSP is the mediator of parallel-array tight junction strands and distinguishes this protein from other intrinsic membrane proteins in tight junctions. These novel results provide direct evidence of the pivotal role of the claudin family in generating the paracellular physical barrier of tight junctions necessary for spermatogenesis and normal CNS function.

Comparisons of the amplitude size and the reproducibility of three different electrodes to record the corneal flash electroretinogram in rodents.

To compare corneal electrodes commonly used in rodent eyes for repeat and left versus right eye accuracy and variability to record the flash electroretinogram (ERG). Animals studied were eight C57BL/6 mice and eight rats of the Wistar strain. Scotopic ERGs were recorded from eyes of dark-adapted anesthetized rodents to compare a custom-made gold-wire contact lens electrode (CLE), a cotton-wick silver-silver chloride electrode (SCLE), and a coiled stainless steel wire electrode (SSE). Compared to SCLE and SSE. the potentials recorded by CLE are characterized by significantly larger ERG amplitudes and oscillatory potentials in both rats and mice (p <0.0001). In analyzing test-retest data comparing the three different electrodes the coefficient of variation was smaller (range, 10.3-15.5%) and the interclass correlation coefficient (0.77-0.93) showed a better agreement for the CLE. Recording scotopic ERGs with custom-made gold-wire contact lens electrodes records large amplitudes and shows a good reproducibility and reliability to monitor retinal function in rodent eyes.

Diagnostic yield of the routine dilated fundus examination.

OBJECTIVE: This study aimed to estimate the risk of errors of omission inherent in the elimination of the routine dilated fundus examination in asymptomatic patients presenting for routine eye checkups, or in patients with purely refractive complaints. DESIGN: The study design was a retrospective chart review. PARTICIPANTS: The authors reviewed the records of initial visits of more than 3800 patients drawn from the practices of 3 board-certified ophthalmologists with substantial general ophthalmology components. Patients with best-corrected visual acuity in either eye of poorer than 20/25, myopia greater than -3.00 diopters, or other risk factors for disease of the fundus or optic nerve (such as ocular hypertension, glaucoma, previous ocular surgery, diabetes mellitus, and history of retinal detachment) were excluded. The authors identified 1094 such records that documented the findings of dilated fundus examination, including indirect ophthalmoscopy. MAIN OUTCOME MEASURES: The authors recorded the prevalence of all fundus abnormalities, of those deemed clinically significant, and those beyond the view of routine examination with the direct ophthalmoscope. Findings were stratified by patient age. RESULTS: Of the 1094 eligible records, 53 (4.84%) had recorded fundus abnormalities. Of these, 23 were of no adverse ophthalmologic consequences and were considered clinically insignificant. Of the 30 (2.74%) potentially significant findings, only 3 were located beyond the view of routine examination with the direct ophthalmoscope (0.274%; 95% confidence limits: 0.56%-0.80%). The prevalence of fundus findings increased strongly with increasing patient age, from 2.4% younger than age 20 to 14.8% older than age 60. Clinically significant findings increased from 0.8% younger than age 20 to 8.9% older than age 60. CONCLUSIONS: The authors estimate the rate of detection through routine dilated fundus examination of clinically significant fundus lesions in asymptomatic patients at 2.73% (95% confidence limits, 1.86%-3.80%). One tenth of these are beyond the view of the direct ophthalmoscope. The prevalence of fundus abnormalities increases tenfold with increasing patient age.

Mastocytosis-induced nyctalopia.

Systemic mastocytosis is characterized by an increased number of mast cells in multiple organs particularly skin. A 55-year-old man with mastocytosis presented with nyctalopia caused by malabsorption of vitamin A. Diagnosis was made by documenting a low vitamin A level and an ERG that showed rod-cone deficiency with rods affected more than cones. Vitamin A therapy led to return of good visual function. To our knowledge, this is the first reported case of mastocytosis induced nyctalopia. Vitamin A deficiency should be considered as a potential cause of visual loss in patients with sudden onset of night blindness.

An indication for "granny glasses".

A young woman with a large astigmatic refractive error obtained no visual improvement with glasses. Repeated manifest refractions revealed persistent variations in the apparent cylinder axis. A suitable choice of spectacle frames facilitated a satisfactory outcome. The pitfalls inherent in the clinical specification of cylinder axis, and the potential visual consequences, are discussed.

Combined amplitude and phase criteria for evaluation of macular electroretinograms.

Focal electroretinograms (ERGs) were obtained from 35 normal eyes and 48 eyes with known macular disease using the MaculoScope stimulator-ophthalmoscope instrument. Response amplitude and phase were combined to permit interpretation of the ERG responses as two-dimensional vectors. This vector interpretation avoids statistical anomalies and distortions inherent in the use of amplitude and phase response parameters. Furthermore, the vector interpretation permits the use of the Hotelling T2 statistic for the assessment of the significance of the differences between ERG responses, providing greater statistical power than simultaneous comparison of amplitude and phase data separately. The distribution of normal responses yielded limiting normal values of 135 nV for the amplitude and -95 degrees for the phase lag of the focal ERG as recorded by the MaculoScope instrument. Significant abnormalities of the focal ERG are illustrated for cases of cilioretinal artery occlusion, Stargardt's disease, idiopathic macular hole, diabetic macular edema, and idiopathic macular dysfunction with normal fundus. This study demonstrates the potential value of the focal ERG in the demonstration of macular disease undetectable by conventional electroretinography.

Electrophysiological findings in paraneoplastic retinopathy.

Paraneoplastic retinopathy is a cancer-related non-metastatic retinopathy mainly associated with lung cancer. We examined two patients with presumed paraneoplastic retinopathy, both ophthalmologically and electrophysiologically. Both patients presented with initial visual complaints of moderate reduction of visual acuity. No specific fundus anomaly was found in the fundus except for a mild attenuation of the retinal arteries. The electroretinogram and pattern reversal visual evoked responses were either markedly reduced in amplitude or non-recordable. The electrooculogram recorded in one patient demonstrated a markedly reduced light peak/dark trough ratio. These results indicate the presence of a severe and diffuse bilateral retinal dysfunction, despite the relatively good visual acuities and mild fundus changes. Electrophysiological evaluations play an important role in the diagnosis of paraneoplastic retinopathy.

Corneal topography and the hirschberg test.

A simple trigonometric analysis of the Hirschberg test with the assumption that the corneal surface is spherical predicts a sinusoidal dependence of the corneal reflex displacement on the angle of ocular rotation. A comparison with corneal reflex photographs demonstrates that at angles larger than 50 prism diopters (26 deg) the reflex displacements are larger than predicted by the spherical model. This discrepancy may be accounted for by incorporating a more general description of the corneal topography into the geometric analysis. The linear Hirschberg relation that is seen in typical data is accounted for by a relative flattening of the peripheral cornea by ~ 20% of the apical curvature. This geometric analysis of the functional dependence of the Hirschberg relation on the corneal topography can be expressed as an integral equation. Differentiation yields a second-order differential equation for the corneal topography in terms of the Hirschberg data. If the Hirschberg relation is assumed to be linear, a quadratic dependence is found for the corneal curvature. A similar differential approach can be formulated for the Placido disk. In this sense the corneal topography problem given in terms of Placido disk data is shown to be wellformulated. The relative simplicity of the Hirschberg geometry is seen to stem from the alignment of the light source with the eye of the observer.

Retinal dysfunction as an initial ophthalmic sign in AIDS.

Three cases of patients with AIDS in whom severe retinal dysfunction preceded the development of widespread funduscopic abnormalities are presented. The disparity between the minimal extent of visible retinal lesions and the severe loss of retinal function was confirmed by visual field and electroretinographic studies. This pattern of early visual loss in AIDS patients may represent infection of the retina by the HIV virus.

Calibration of Hirschberg test photographs under clinical conditions.

The feasibility of determining the angle of ocular deviation from clinical photographs was assessed. Corneal reflex photographs were obtained from 30 strabismic patients and 5 orthophoric control subjects, using a centered electronic flash, with a millimeter ruler placed across the forehead for calibration. Measurements of corneal reflex displacement were obtained from the photographs and compared with standard prism-cover results. The value of 20.89 prism diopters (PD) per millimeter of corneal reflex displacement was obtained for the factor of conversion from reflex displacement to strabismic angle. This value of the Hirschberg coefficient is valid only for measurements of reflex displacement along a true frontal plane, as provided in a photograph. Detailed algorithms for the calculation of strabismic angle from photographic data are provided in an appendix.