Efficacy and Safety of Anti-Tumor Necrosis Factor Alpha in Very Early Onset Inflammatory Bowel Disease.

BACKGROUND: Very early onset inflammatory bowel disease (VEOIBD) is defined as disease onset in patients younger than 6 years. Challenges in treatment of VEOIBD include lack of approved therapies and increased incidence of monogenic immunodeficiencies. We report on patterns of anti-TNF use, efficacy, and safety in a large cohort of patients with VEOIBD. METHODS: Very early onset inflammatory bowel disease patients receiving care at a single center were prospectively enrolled in a data registry and biorepository starting in 2012. Whole exome sequencing was available to all patients. Clinical data including IBD medication use and response were extracted from the medical record. We examined antitumor necrosis factor (anti-TNF) cumulative exposure and time to failure and evaluated the effect of covariates on anti-TNF failure using Cox proportional hazard regression. RESULTS: In this cohort of 216 VEOIBD patients with median 5.8-year follow-up, 116 (53.7%) were TNF-exposed. Sixty-two TNF-exposed patients (53.4%) received their first dose at younger than 6 years. Cumulative exposure to anti-TNF was 23.6% at 1 year, 38.4% at 3 years, and 43.4% at 5 years after diagnosis. Cumulative exposure was greater in patients with Crohn's disease (P = .0004) and in those diagnosed in 2012 or later (P < .0001). Tumor necrosis factor failure occurred in 50.9% of those exposed. Features predictive of anti-TNF failure included ulcerative colitis/IBD-unclassified (hazard ratio, 1.94; P = .03), stricturing (hazard ratio, 2.20; P = .04), and younger age at diagnosis (hazard ratio, 1.25; P = .01). Adverse events occurred in 22.6% of infliximab-exposed and 14.3% of adalimumab-exposed. CONCLUSIONS: Efficacy and safety of anti-TNFs in VEOIBD is comparable to what has previously been reported in older patients.

Half of VEOIBD patients followed for a median 5.8 years used anti-TNF. Anti-TNF failure occurred in half of those exposed. Stricturing, UC/IBD-U, and younger age at diagnosis were predictors of failure. Adverse events were similar to those reported in older patients.

Robotic-assisted completion cholecystectomy with repair of cholecystoduodenal fistula.

Post-cholecystectomy syndrome (PCS) is a well-documented complication of incomplete cholecystectomy. The etiology is often post-surgical chronic inflammation from unresolved cholelithiasis, which is secondary to anatomical abnormalities, including a retained gallbladder or a large cystic duct remnant (CDR). An exceedingly rare consequence is retained gallstone fistulization into the gastrointestinal tract. We present a case of a 70-year-old female with multiple comorbidities 4 years status-post incomplete cholecystectomy, who developed PCS with cholecystoduodenal fistula secondary to retained gallstone in the remnant gallbladder, with CDR involvement, treated via robotic-assisted surgery. Reoperation in PCS has been traditionally performed via laparoscopic approach with recent advances made in robotic-assisted surgery. However, we report the first documented case of PCS complicated by bilioenteric fistula repaired with robotic-assisted surgery. This highlights the value of robotic-assisted surgery in complicated cases, where one must contend with post-surgical anatomic abnormalities and visualization difficulties. Subsequent investigation is necessary to objectively quantify the safety and reproducibility of our approach.

Clinical Phenotypes and Outcomes in Monogenic Versus Non-monogenic Very Early Onset Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Over 80 monogenic causes of very early onset inflammatory bowel disease [VEOIBD] have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-centre cohort of patients with VEOIBD and universal access to whole exome sequencing [WES]. METHODS: Patients receiving IBD care at a single centre were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise a VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function, or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns. RESULTS: This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients [7.9%] had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn's disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of intensive care unit [ICU] hospitalisation, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, haematopoietic stem cell transplant, and death. A total of 41 patients [19.0%] had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes. CONCLUSIONS: Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.

Epithelial Claudin Proteins and Their Role in Gastrointestinal Diseases.

Our bodies are protected from the external environment by mucosal barriers that are lined by epithelial cells. The epithelium plays a critical role as a highly dynamic, selective semipermeable barrier that separates luminal contents and pathogens from the rest of the body and controlling the absorption of nutrients, fluid and solutes. A series of protein complexes including the adherens junction, desmosomes, and tight junctions function as the principal barrier in paracellular diffusion and regulators of intracellular solute, protein, and lipid transport. Tight junctions are composed of a series of proteins called occludins, junctional adhesion molecules, and claudins that reside primarily as the most apical intercellular junction. Here we will review one of these protein families, claudins, and their relevance to gastrointestinal and liver diseases.

Retinal findings and a novel TINF2 mutation in Revesz syndrome: Clinical and molecular correlations with pediatric retinal vasculopathies.

BACKGROUND: Revesz syndrome is a telomere disorder in the dyskeratosis congenita (DKC) spectrum characterized by exudative retinopathy, bone marrow failure, neuroradiographic abnormalities, and integumentary findings. MATERIALS/METHODS: We report the ophthalmologic findings, documented by examinations under anesthesia with clinical photography and fluorescein angiography, as well as the systemic manifestations and genetic and molecular testing, in identical twins with Revesz syndrome, and compare and contrast these features to those of other pediatric retinal vasculopathies. RESULTS: Both twins exhibited widespread avascularity and anomalous vasculature of the retinal periphery, retinal telangiectasias, and exudation. One twin developed a combination exudative/tractional/rhegmatogenous retinal detachment, while the other exhibited a focal collection of buds of retinal neovascularization. Both twins developed bone marrow failure and were found to have cerebellar hypoplasia and widespread cerebral calcifications. Telomere testing in lymphocytes and granulocytes revealed telomere length less than the 1st percentile for age, and gene sequencing revealed a novel mutation in the TINF2 gene, resulting in the T284P TIN2 protein variant. CONCLUSIONS: We report ophthalmic findings in twins with Revesz syndrome due to a previously unreported mutation in TINF2 and propose that phenotypic and molecular overlaps between DKC spectrum disorders and pediatric retinal vasculopathies may reflect a shared pathophysiologic basis.

Tongue fat infiltration in obese versus lean Zucker rats.

STUDY OBJECTIVES: Obesity is the most important risk factor for obstructive sleep apnea (OSA), and the effects of obesity may be mediated by tongue fat. Our objective was to examine the effects of obesity on upper airway structures in obese (OBZ) and non-obese (NBZ) Zucker rats. DESIGN: Animal study. SETTING: Academic Medical Center. PARTICIPANTS: OBZ (638.2 ± 39 g; 14.9 ± 1.1 w) and age-matched NBZ Zucker (442.6 ± 37 g, 15.1 ± 1.5 w) rats. INTERVENTIONS: TONGUE FAT AND VOLUME AND WERE ASSESSED USING: in vivo magnetic resonance spectroscopy (MRS), magnetic resonance imaging including Dixon imaging for tongue fat volume, ex vivo biochemistry (fat quantification; triglyceride (mg)/tissue (g), and histology (Oil Red O stain). MEASUREMENTS AND RESULTS: MRS: overall OBZ tongue fat/water ratio was 2.9 times greater than NBZ (P < 0.002) with the anterior OBZ tongue up to 3.3 times greater than NBZ (P < 0.002). Biochemistry: Triglyceride (TG) in the tongue was 4.4 times greater in OBZ versus NBZ (P < 0.0006). TG was greater in OBZ tongue (3.57 ± 1.7 mg/g) than OBZ masseter muscle (0.28 ± 0.1; P < 0.0001) but tongue and masseter TG were not different in NBZ rats (0.82 ± 0.3 versus 0.28 ± 0.1 mg/g, P = 0.67). Dixon fat volume was significantly increased in OBZ (56 ± 15 mm3) versus NBZ (34 ± 5 mm3, P < 0.004). Histology demonstrated a greater degree of intracellular muscle fat and extramuscular fat infiltration in OBZ versus NBZ rats. CONCLUSIONS: Genetically obese rats had a large degree of fat infiltration in the tongue compared to both skeletal muscle and tongue tissues of the non-obese age-matched littermates. The significant fat increase and sequestration in the obese tongue may play a role in altered tongue neuromuscular function, tongue stiffness or metabolic function.

Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy.

BACKGROUND: The leading cause of death among patients with hereditary retinoblastoma is second malignancy. Despite its high rate of efficacy, radiotherapy (RT) is often avoided due to fear of inducing a secondary tumor. Proton RT allows for significant sparing of nontarget tissue. The current study compared the risk of second malignancy in patients with retinoblastoma who were treated with photon and proton RT. METHODS: A retrospective review was performed of patients with retinoblastoma who were treated with proton RT at the Massachusetts General Hospital or photon RT at Boston Children's Hospital between 1986 and 2011. RESULTS: A total of 86 patients were identified, 55 of whom received proton RT and 31 of whom received photon RT. Patients were followed for a median of 6.9 years (range, 1.0 years-24.4 years) in the proton cohort and 13.1 years (range, 1.4 years-23.9 years) in the photon cohort. The 10-year cumulative incidence of RT-induced or in-field second malignancies was significantly different between radiation modalities (proton vs photon: 0% vs 14%; P = .015). The 10-year cumulative incidence of all second malignancies was also different, although with borderline significance (5% vs 14%; P = .120). CONCLUSIONS: Retinoblastoma is highly responsive to radiation. The central objection to the use of RT, the risk of second malignancy, is based on studies of patients treated with antiquated, relatively nonconformal techniques. The current study is, to the authors' knowledge, the first to present a series of patients treated with the most conformal of the currently available external-beam RT modalities. Although longer follow-up is necessary, the preliminary data from the current study suggest that proton RT significantly lowers the risk of RT-induced malignancy.

X-linked juvenile retinoschisis (XLRS): a review of genotype-phenotype relationships.

X-linked juvenile retinoschisis (XLRS) is one of the most common genetic causes of juvenile progressive retinal-vitreal degeneration in males. To date, more than 196 different mutations of the RS1 gene have been associated with XLRS. The mutation spectrum is large and the phenotype variable. This review will focus on the clinical features of XLRS and examine the relationship between phenotype and genotype.

Simple, inexpensive technique for high-quality smartphone fundus photography in human and animal eyes.

Purpose. We describe in detail a relatively simple technique of fundus photography in human and rabbit eyes using a smartphone, an inexpensive app for the smartphone, and instruments that are readily available in an ophthalmic practice. Methods. Fundus images were captured with a smartphone and a 20D lens with or without a Koeppe lens. By using the coaxial light source of the phone, this system works as an indirect ophthalmoscope that creates a digital image of the fundus. The application whose software allows for independent control of focus, exposure, and light intensity during video filming was used. With this app, we recorded high-definition videos of the fundus and subsequently extracted high-quality, still images from the video clip. Results. The described technique of smartphone fundus photography was able to capture excellent high-quality fundus images in both children under anesthesia and in awake adults. Excellent images were acquired with the 20D lens alone in the clinic, and the addition of the Koeppe lens in the operating room resulted in the best quality images. Successful photodocumentation of rabbit fundus was achieved in control and experimental eyes. Conclusion. The currently described system was able to take consistently high-quality fundus photographs in patients and in animals using readily available instruments that are portable with simple power sources. It is relatively simple to master, is relatively inexpensive, and can take advantage of the expanding mobile-telephone networks for telemedicine.

Radiation therapy: retinal tumors.

The major retinal tumor that requires radiotherapy (RT) is retinoblastoma (RB); to a lesser degree, RT is used for some cases of retinal capillary hemangioma and lymphoma of the retina. Although there are concerns about the risk of RT-induced second malignancy in patients who carry a germline mutation in the RB1 gene, RT remains a very important part of our approach to intra-ocular and extra-ocular RB. Technical innovations in RT allow more precise targeting of retinal tumors and decreased exposure of adjacent normal tissue, an advance that is particularly significant for patients with hereditary RB who are at risk of additional malignancies.

Measurement of choroidal perfusion and thickness following systemic sildenafil (Viagra(®) ).

PURPOSE: To demonstrate anatomic and physiologic changes in the human choroid following systemic sildenafil citrate (Viagra®) using enhanced depth imaging spectral domain-optical coherence tomography (EDI-OCT) and swept-scan high-frequency digital ultrasound. METHODS: Seven healthy male subjects (mean age 32.7 years) were evaluated at baseline and 2 hr after ingesting 50 mg of sildenafil. Swept-scan high-frequency digital ultrasound and EDI-OCT were utilized to measure choroidal perfusion and thickness, respectively. Results were read by masked observers. The Wilcoxon signed-rank test and t-test were used to analyse differences in choroidal flow and thickness at baseline and 2 hr after ingestion of sildenafil. RESULTS: Two hours following sildenafil, increased choroidal perfusion was observed in 11 of 12 eyes measured by swept-scan high-frequency digital ultrasound. The mean increase was 3.46 (±2.00) times baseline with a range of 0.47-7.80 times baseline (p = 0.004). Increased choroidal thickness was observed in 12 of 12 eyes measured with EDI-OCT. The average choroidal thickness increased by 11.6% temporal to the fovea, 9.3% nasal to the fovea and 10.7% underneath the fovea (p < 0.001 for all values). CONCLUSIONS: Choroidal perfusion and thickness both increase in response to systemic sildenafil. These changes could secondarily affect retinal function, explain previously reported clinical symptoms and potentially be a useful adjunct for treatment of ocular diseases that would benefit from increased choroidal blood flow.

Delayed orbital hematoma after lateral canthoplasty.

A 76-year-old man was referred to the oculoplastic surgery service with a retrobulbar hemorrhage 1 day after intraocular surgery. A canthotomy and inferior cantholysis was performed. The patient then developed a new orbital hematoma in the region of the canthotomy 14 days later. The patient was treated conservatively with warm compresses and close observation with continued resolution of the secondary hematoma. Visual complications from the secondary hematoma may have been avoided by delaying closure of the initial canthotomy wound. Ophthalmologists should be aware of the risk of bleeding after lateral canthal procedures, particularly in patients who have already presented with ocular or periocular hemorrhagic complications. A brief review of orbital hemorrhage following eyelid surgery is provided.

Fundus autofluorescence and optical coherence tomography of congenital grouped albinotic spots.

PURPOSE: The purpose of this study was to describe the findings of fundus autofluores-cence (FAF) and optical coherence tomography in a series of patients with congenital grouped albinotic spots. METHODS: Three eyes of three patients with congenital grouped albinotic spots were evaluated with FAF and optical coherence tomography imaging to evaluate the nature of the albinotic spots. RESULTS: In all three eyes with congenital grouped albinotic spots, FAF imaging showed autofluorescent spots corresponding to the albinotic spots seen on stereo biomicroscopy. One eye also had additional spots detected on FAF imaging that were not visible on stereo biomicroscopy or color fundus photographs. Fundus autofluorescence imaging of the spots showed decreased general autofluorescence and decreased peripheral autofluorescence surrounding central areas of retained or increased autofluorescence. Optical coherence tomography showed a disruption in signal from the hyperreflective layer corresponding to the inner and outer segment junction and increased signal backscattering from the choroid in the area of the spots. Fluorescein angiography showed early and stable hyperfluorescence of the spots without leakage. CONCLUSION: In this case series, FAF showed decreased autofluorescence of the spots consistent with focal retinal pigment epithelium atrophy or abnormal material blocking normal autofluorescence and areas of increased autofluorescence suggesting retinal pigment epithelium dysfunction. The findings of optical coherence tomography and fluorescein angiography suggest photoreceptor and retinal pigment epithelium layer abnormalities. Fundus autofluorescence and optical coherence tomography are useful noninvasive diagnostic adjuncts that can aid in the diagnosis of congenital grouped albinotic spots, help determine extent of disease, and contribute to our understanding of its pathophysiology.

Fundus autofluorescence, optical coherence tomography, and electroretinogram findings in choroidal sclerosis.

PURPOSE: The purpose of this study was to describe fundus autofluorescence (FAF), optical coherence tomography, and electroretinogram findings in choroidal sclerosis. METHODS: This is a retrospective case series. Eight eyes of four patients with choroidal sclerosis were evaluated with FAF, optical coherence tomography, and electroretinogram testing. RESULTS: In all eight eyes, FAF imaging showed hypofluorescent placoid lesions corresponding to areas of chorioretinal atrophy seen on stereo biomicroscopy. Prominent hyperfluorescent linear markings underlying regions of atrophic disease were observed in all eyes, likely representative of normal choroidal vessel autofluorescence. In two eyes, FAF showed punctate hypofluorescent lesions in the fovea that were not visualized on biomicroscopy. In one eye, FAF identified a central island of preserved retinal pigment epithelium that was not realized on ophthalmoscopic examination. Optical coherence imaging was significant for loss of choroidal fine tubular structures, retinal pigment epithelium, and outer nuclear layer in regions of chorioretinal atrophy. Full-field electroretinogram testing showed generalized rod-cone dysfunction in all patients with a lower B- to A-wave ratio in two patients. CONCLUSION: Fundus autofluorescence and optical coherence tomography are nonin-vasive diagnostic adjuncts that can aid in the diagnosis of choroidal sclerosis. Fundus autofluorescence may be a more sensitive marker of disease extent and progression than clinical examination alone. Electroretinogram testing can result in an electronegative maximal response.

Telemedical diagnosis of retinopathy of prematurity intraphysician agreement between ophthalmoscopic examination and image-based interpretation.

OBJECTIVE: To evaluate the intraphysician agreement between ophthalmoscopic examination and image-based telemedical interpretation for retinopathy of prematurity (ROP) diagnosis, when performed by the same expert physician grader. DESIGN: Prospective, nonrandomized, comparative study. PARTICIPANTS: Sixty-seven consecutive premature infants who underwent ROP examination at a major university medical center whose parents consented for participation. METHODS: Infants underwent standard dilated ophthalmoscopy by one of two pediatric ophthalmologists, followed by retinal imaging with a commercially available wide-angle fundus camera by a trained neonatal nurse. Study examinations were performed at 31 to 33 weeks postmenstrual age (PMA) and/or 35 to 37 weeks PMA. Images were uploaded to a Web-based telemedicine system developed by the authors. After a 4- to 12-month period, telemedical interpretations were performed in which each physician graded images from infants upon whom he had initially performed ophthalmoscopic examinations. Diagnoses were classified using an ordinal scale: no ROP, mild ROP, type 2 prethreshold ROP, and treatment-requiring ROP. MAIN OUTCOME MEASURES: Absolute intraphysician agreement and kappa statistic between ophthalmoscopic examination and telemedical interpretation were calculated by eye. All intraphysician discrepancies were reviewed, and underlying causes were classified by eye as no ROP identified by ophthalmoscopic examination, no ROP identified by telemedical interpretation, discrepancy about presence of zone 1 ROP, discrepancy about presence of plus disease, or other discrepancy in classification of ROP stage. RESULTS: Absolute intraphysician agreement between ophthalmoscopic examination and telemedical interpretation was 86.3%. The kappa statistic for intraphysician agreement between examinations ranged from 0.657 (substantial agreement) for diagnosis of treatment-requiring ROP to 0.854 (near-perfect agreement) for diagnosis of mild or worse ROP. Among 206 eye examinations (103 infant examinations), there were 28 (13.6%) intraphysician discrepancies in diagnosis, 8 of which resulted from uncertainty about presence of zone 1 disease and 4 from uncertainty about presence of plus disease. CONCLUSIONS: Intraphysician agreement between ophthalmoscopic examination and telemedical interpretation for ROP was very high. Neither examination modality appeared to have a systematic tendency to overdiagnose or underdiagnose ROP. Diagnosis of zone 1 disease and plus disease were major sources of clinically significant discrepancies.

Prostate MR imaging at 3T with a longitudinal array endorectal surface coil and phased array body coil.

PURPOSE: To demonstrate the feasibility of using a double loop phased array endorectal coil combined with a phased array body coil to image the prostate at 3T. MATERIALS AND METHODS: We designed and constructed a novel prostate coil employing two arrayed 4.0 x 5.0 cm loops, tuned the device for optimal performance at 3T, and characterized the signal-to-noise ratio (SNR) associated with it. RESULTS: The coil Q factor was calculated to be approximately 50 unloaded, and 30 when loaded on human tissue. SNR maps at multiple orientations were constructed and images were acquired on both a phantom and a human. As expected, SNR was highest along the midpoint of the array and demonstrated strong signal even at 4 cm from the coil. CONCLUSION: The double loop phased array endorectal coil combined with a phased array body coil at 3T is feasible in vivo and compelling enough to warrant future clinical trials to evaluate its efficacy. These trials are currently under way.

Folding myoglobin within a sol-gel glass: protein folding constrained to a small volume.

The unfolding and refolding reaction of myoglobin was examined in solution and within a porous silica sol-gel glass. The sol-gel pores constrain the protein to a volume that is the same size and shape as the folded native state accompanied by a few layers of water solvation. Denaturants such as low pH buffers can be diffused through the gel pores to the protein to initiate unfolding and refolding. Acid-induced unfolding was hindered by the steric constraints imposed by the gel pores such that more denaturing conditions were required within the gel than in solution to create the unfolded state. No new folding intermediates were observed. Refolding of myoglobin was not complete in millimolar pH 7 buffer alone. Addition of 25% glycerol to the pH 7 buffer resulted in nearly complete refolding, and the use of 1 M phosphate buffer resulted in complete refolding. The role of this cosolvent and salt in disrupting the ordered water surrounding the protein within the gel is discussed in light of the Hofmeister series and entropic trapping via a diminished hydrophobic effect within the gel. These results are consistent with the premises of folding models in which secondary and tertiary structures are considered to form within a compact conformation of the protein backbone.

De novo identification of MIZ-1 (ZBTB17) encoding a MYC-interacting zinc-finger protein as a new favorable neuroblastoma gene.

PURPOSE: Neuroblastoma is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. Favorable neuroblastoma genes (EPHB6, EFNB2, EFNB3, NTRK1, and CD44) are genes whose high-level expression predicts favorable neuroblastoma disease outcome. Accordingly, the forced expression of these genes or their reactivation by gene silencing inhibitors in unfavorable neuroblastoma cells results in suppression of tumor growth and metastases. This study was undertaken to design an experimental strategy to identify additional favorable neuroblastoma genes. EXPERIMENTAL DESIGN: Favorable neuroblastoma gene candidates were first identified by gene expression profiling analysis on IMR5 neuroblastoma cells treated with inhibitors of DNA methylation and histone deacetylase against the untreated control cells. Among the candidates, we focused on MIZ-1, which encodes a MYC-interacting zinc-finger protein, because it is known to enhance the expression of growth suppressive genes, such as CDKN1A. RESULTS: High-level MIZ-1 expression was associated with favorable disease outcome of neuroblastoma (P = 0.0048). Forced MIZ-1 expression suppressed in vitro growth of neuroblastoma cell lines. High MIZ-1 expression was correlated with the small-size neuroblastoma xenografts treated with gene silencing inhibitors or a glucocorticoid. In addition, forced MIZ-1 expression enhanced the expression of CD44 and EFNB2 in neuroblastoma cell lines in vitro. Furthermore, MIZ-1 expression was positively correlated with the expression of favorable neuroblastoma genes (EFNB2, EFNB3, EPHB6, and NTRK1) in the human neuroblastoma xenograft therapeutic models. CONCLUSION: MIZ-1 is a new favorable neuroblastoma gene, which may directly or indirectly regulate the expression of other favorable neuroblastoma genes.

X-linked retinoschisis: novel mutation in the initiation codon of the XLRS1 gene in a large family.

PURPOSE: To describe a novel point mutation in the initiation codon of the XLRS1 gene in a large family and the clinical features of males affected with X-linked juvenile retino-schisis. METHODS: Genealogic investigation and mutation screening of the XLRS1 gene were performed for a 4-generation family consisting of 72 members. Affected males were evaluated clinically between 1986 and 2004 with up to 18 years of follow-up. RESULTS: We identified a novel point mutation (1A>T transversion) in the initiation codon of the XLRS1 gene in affected males resulting in an amino acid substitution of methionine to leucine (Met1Leu), therefore abolishing the translation initiation Met codon. CONCLUSION: Identification of the disease-causing mutation in this family with long-term follow-up allows for earlier and more accurate identification of individuals at risk for this inherited progressive macular degeneration, provides for more accurate genetic counseling, and contributes to our understanding of the pathophysiology of this disorder.