David S. Walton

Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene

Aniridia is a semidominant disorder in which development of the iris, lens, cornea and retina is disturbed. The mouse mutation Small eye (Sey), which has been proposed as a model for aniridia, results from defects in Pax–6, a gene containing paired–box and homeobox motifs that is specifically expressed in the developing eye and brain. To test the role of PAX6 in aniridia, we isolated human cDNA clones and determined the intron–exon structure of this gene. PAX6 spans 22 kilobases and is divided into 14 exons. Analysis of DNA from 10 unrelated aniridia patients revealed intragenic mutations in three familial and one sporadic case. These findings indicate that the human aniridia and murine Small eye phenotypes arise from homologous defects in PAX6.

Oncogenic Point Mutations in the Human Retinoblastoma Gene: Their Application to Genetic Counseling

Mutations of the retinoblastoma gene, most of which cannot be detected by conventional Southern blotting, are known to cause both the nonhereditary and hereditary forms of retinoblastoma and have been implicated in the development of other cancers. Nonhereditary retinoblastoma is caused by a somatic mutation. Hereditary retinoblastoma is caused by a germ-cell mutation, most often a new one, and thus there is usually no family history of the disease. Unlike patients with the nonhereditary disease, those with the hereditary form are at risk for additional retinoblastomas, and their progeny are at risk for the tumors. We used a sensitive technique of primer-directed enzymatic amplification, followed by DNA sequence analysis, to identify mutations as small as a single nucleotide change in tumors from seven patients with simplex retinoblastoma (with no family history of the disease). In four patients the mutation involved only the tumor cells, and in three it involved normal somatic cells as well as tumor cells but was not found in either parent; thus, these mutations appeared to be new, germ-cell mutations. In addition, we found point mutations in cells from a bladder carcinoma, a small-cell carcinoma of the lung, and another retinoblastoma. We conclude that the technique that we have described can distinguish hereditary from nonhereditary retinoblastoma and that it is useful in risk estimation and genetic counseling.

A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye

Mutations in the forkhead transcription-factor gene (FOXC1), have been shown to cause defects of the anterior chamber of the eye that are associated with developmental forms of glaucoma. Discovery of these mutations was greatly facilitated by the cloning and characterization of the 6p25 breakpoint in a patient with both congenital glaucoma and a balanced-translocation event involving chromosomes 6 and 13. Here we describe the identification of novel mutations in the FOXC1 gene in patients with anterior-chamber defects of the eye. We have detected nine new mutations (eight of which are novel) in the FOXC1 gene in patients with anterior-chamber eye defects. Of these mutations, five frameshift mutations predict loss of the forkhead domain, as a result of premature termination of translation. Of particular interest is the fact that two families have a duplication of 6p25, involving the FOXC1 gene. These data suggest that both FOXC1 haploinsufficiency and increased gene dosage can cause anterior-chamber defects of the eye.

Leukemic ophthalmopathy in children.

Abnormalities of the eye were detected in 52 of 657 children (9%) suffering from acute leukemia. The treatment for leukemia was single agent chemotherapy administered sequentially. “Prophylactic” treatment of the central nervous system was not administered. Major manifestations of leukemic ophthalmopathy comprised retinal hemorrhage (in 19) and infiltration of the optic nerve, retina, iris or orbit (29). The ophthalmopathy was treated by topical dexamethasone and radiation therapy. Concurrent bone marrow relapse occurred in most patients. Twenty‐seven of 29 patients whose cerebrospinal fluid was examined before or at the time of the onset of leukemic ophthalmopathy demonstrated meningeal leukemia. In contrast, this complication has not been observed in recent patients who received “prophylactic” treatment for meningeal leukemia. Leukemic invasion of the eye should receive appropriate recognition; the posterior pole should be included in the treatment of the central nervous system as a pharmacologic sanctuary.

Angle-closure Glaucoma: The Role of the Lens in the Pathogenesis, Prevention, and Treatment

Primary angle-closure glaucoma is a major cause of blindness worldwide. It is a disease of ocular anatomy that is related to pupillary-block and angle-crowding mechanisms of filtration angle closure. Eyes at increased risk for primary angle-closure are small with decreased axial length, anterior chamber depth, and filtration angle width, associated with a proportionately large lens. Angle-closure glaucoma afflicts Asian and Eskimo eyes more frequently than eyes in other races with similar predisposing dimensions. The treatment of primary angle closure addresses its causal mechanisms. Laser peripheral iridotomy equalizes the anterior and posterior pressures and widens the filtration angle by reducing the effect of pupillary block. Argon laser peripheral iridoplasty contracts the iris stroma to reduce angle crowding and is helpful for some affected eyes. Lensectomy dramatically widens the angle and eliminates pupillary block. Clinical reports of lensectomy with posterior chamber intraocular lens implantation in the treatment of acute, chronic, and secondary angle-closure glaucoma describe very favorable results. The appropriate role for lensectomy in the management of primary angle closure, however, remains unproven. Prospective, randomized clinical trials are ongoing to determine the value and comparative risks and efficacy of lensectomy versus medical therapy, laser peripheral iridotomy, laser iridoplasty, and filtration procedures for the treatment of acute and chronic primary angle closure and for the prevention of chronic angle-closure glaucoma, both after and in place of laser peripheral iridotomy.

Meeting cholera's challenge to Haiti and the world: a joint statement on cholera prevention and care.

Cholera in Haiti: Acute-on-Chronic Long before the devastating earthquake on January 12, 2010, Haiti struggled beneath the burdens of intractable poverty and ill health. The poorest country in the Western Hemisphere, Haiti also faces some of the highest rates of maternal and infant mortality—widely used indicators of the robustness of a health system—in the world ([S1] in Text S1; [2], [3]). The October 2010 cholera outbreak is the most recent of a long series of affronts to the health of Haitis population; it is yet another acute symptom of the chronic weakness of Haitis health, water, and sanitation systems. Water and sanitation conditions highlight these systemic weaknesses. In 2002, Haiti ranked last out of 147 countries for water security [4], [5]. Before the earthquake struck, only half of the population in the capital, Port-au-Prince, had access to latrines or other forms of modern sanitation, and roughly one-third had no access to tap water [6]. Across the country, access to sanitation and clean water is even more limited: only 17% of Haitians had access to adequate sanitation in 2008, and 12% received treated water [7]. Not surprisingly, diarrheal diseases have long been a significant cause of death and disability, especially among children under 5 years of age [6]. The cholera outbreak began less than a year after a 7.0-magnitude earthquake took the lives of more than 300,000 people and left nearly 1.5 million homeless [6]. Almost 1 million Haitians still live in spontaneous settlements known as internally displaced persons (IDP) camps [8]. While post-earthquake conditions in Haiti were ripe for outbreaks of acute diarrheal illness, cholera was deemed “very unlikely to occur” by the United States Centers for Disease Control and Prevention (CDC) and other public health authorities [9]. Cholera had never before been reported in Haiti [S2] [10], [11]; health providers were unprepared for an influx of patients presenting with acute watery diarrhea. The cholera epidemic has been most severe in rural areas and large urban slums. Rural communities were charged with hosting hundreds of thousands of displaced people after the earthquake, placing greater demands on their already-scarce resources, including water. Surface water drawn directly from the source or piped from rivers and streams constitutes the principal supply of drinking water in rural Haiti. The lack of adequate piping, filtration, and water treatment systems (including chlorination) made these rural regions vulnerable to the rapid spread of waterborne disease. While most IDP camps have been supplied with potable water, large urban slums have had to rely on existing water sources—some of them containing Vibrio cholerae—and have therefore been vulnerable to rapid disease spread. Most slums also have poor sanitation infrastructure. Since the first cases were reported in Saint-Marc and Mirebalais, cholera has spread to every department in Haiti, and to other countries, too [S3] [12]–[14]. Public suspicion (ultimately validated by genomic sequence analyses [15]) of the strains link to South Asia, home to a group of United Nations peacekeepers stationed in central Haiti, triggered blame and violence that interfered with response efforts. As we have learned from the global AIDS pandemic and other infectious disease epidemics, cycles of accusation can continue for years, diverting attention and resources from the delivery of care and prevention services [16]. Systemic problems that brought cholera to epidemic levels in Haiti will (unless addressed) continue to facilitate its spread. As a disease of poverty, cholera preys upon the bottom of the social gradient; international trade, migration, and travel—from South Asia or elsewhere—open direct channels for pathogens that follow social fault lines.

Primary congenital glaucoma: 2004 update.

BACKGROUND Primary congenital glaucoma is the most frequent childhood glaucoma and an important cause of blindness. We describe the current understanding regarding this disease, the evaluation of children with it, and its treatment. PATIENTS AND METHODS We accessed information derived from a review of 287 patients with primary congenital glaucoma and current published data related to primary congenital glaucoma. RESULTS The nomenclature for childhood glaucoma has been inconsistent, but is clarified for children with primary congenital glaucoma. The epidemiology of primary congenital glaucoma notes its variable incidence worldwide. Familial occurrence supports autosomal recessive transmission; chromosomal loci have been identified, and the CYP1B1 gene has been identified and clinically correlated. The histopathology of eyes with primary congenital glaucoma confirms the presence of a variable trabecular meshwork anomaly and the absence of an imperforate membrane. Children with primary congenital glaucoma are diagnosed after recognition of corneal signs and symptoms of glaucoma. CONCLUSIONS The examinations of patients with primary congenital glaucoma must be thorough to distinguish this glaucoma from other types of childhood glaucoma, to prepare for surgery, and to follow progress with treatment. Medical treatment must be tailored to the pediatric patient. Goniosurgery is the definitive procedure of choice for most children with primary congenital glaucoma, but other procedures are also used successfully after goniosurgery fails or is determined to be inappropriate. Future success will be determined by physicians who sustain continued progress for children with glaucoma.

Clinical Features of Five Pedigrees Genetically Linked to the Juvenile Glaucoma Locus on Chromosome 1q21-q31

BACKGROUND Primary juvenile glaucoma is a rare form of glaucoma that typically affects individuals between 3 and 20 years of ages and is inherited as an autosomal dominant trait. One gene responsible for this condition has been localized to the 1q21-q31 region of chromosome 1. To investigate the clinical features of this form of glaucoma, the authors have examined the affected members of five pedigrees demonstrating genetic linkage to the 1q21-q31 locus. METHODS Clinical characterization of 23 affected patients was performed. Genetic linkage to the 1q21-q31 locus was confirmed by segregation of the disease trait in each pedigree with genetic markers located in the 1q21-q31 region. RESULTS The clinical features of affected members of the five pedigrees presented are generally homogeneous. The average age of diagnosis was 18.5 years (range, 5-30 years), and the average initial intraocular pressure was 38.5 mmHg (range, 30-53 mmHg). Eighty-seven percent of affected individuals were myopic and 83% of affected individuals required surgical treatment for glaucoma. There were no uniformly associated systemic or ocular conditions. One possible nonpenetrant carrier was identified and a difference in phenotypic expression of the presumed disease gene was observed in a pair of affected monozygotic twins. We also identified two pedigrees with juvenile glaucoma and three pedigrees affected by the pigment dispersion syndrome that are not genetically linked to the 1q21-q31 region. CONCLUSION The form of juvenile glaucoma caused by a gene located in the q21-q31 region of chromosome 1 is generally phenotypically homogeneous. The severe elevation of intraocular pressure typically seen in affected patients suggests the product of the predisposing gene may participate in the outflow function of the eye.

Goniosurgery for prevention of aniridic glaucoma

OBJECTIVE To report the long-term success and complications of modified goniosurgery to prevent aniridic glaucoma, an entity that typically is difficult to control medically or surgically. DESIGN A retrospective review of the medical charts. RESULTS Fifty-five eyes in 33 patients who had aniridia without glaucoma and who underwent goniosurgery were identified. Ninety-one procedures were performed on the 55 eyes by 1 surgeon (D.S.W.). Each eye had an average of 1.65 procedures and an average of 200 degrees of goniosurgery. Average age at time of initial goniosurgery was 36.6 months. There were no operative complications. No eye had a decrease in visual acuity at last follow-up. All eyes had a preoperative intraocular pressure (IOP) less than 21 mm Hg. At last follow-up (average, 9 years 6 months; range, 8 months to 24 years), 49 eyes (89%) had IOPs less than 22 mm Hg without medications. The remaining 6 eyes (11%) had IOPs of 22 mm Hg or less with up to 2 types of eyedrops. CONCLUSIONS Without prophylactic goniotomy, aniridic glaucoma may be expected in half of patients, and when it occurs, it is extremely difficult to control. Prophylactic goniosurgery in selected eyes of young patients with aniridia may be effective in preventing aniridic glaucoma.

Ahmed valve surgery for refractory pediatric glaucoma : A report of 52 eyes

PURPOSE To describe the results of Ahmed valve surgery for refractory pediatric glaucoma. PATIENTS AND METHODS We performed a retrospective review of patients younger than 18 years of age who had Ahmed valve surgery from November 1994 to January 2003. Success was defined as a reduction of the intraocular pressure (IOP) to 22 mm Hg or lower with or without medications at the last two follow-up visits, no additional glaucoma surgery, and no visually significant complications. RESULTS There were 52 eyes of 41 patients. The two most common diagnoses were congenital glaucoma (38.5%) and aphakic glaucoma (36.5%). The mean number of glaucoma surgeries before Ahmed valve implantation was 1.7 +/- 1.7. The mean age at the time of implantation was 4.9 +/- 6.5 years. The mean IOP decreased from 38.1 +/- 6.4 mm Hg to 20.7 +/- 8.2 mm Hg at last follow-up. The final visual acuity was improved or within one Snellen line in 81.5% of the eyes. Cumulative probabilities of success were 85.1%, 63.2%, 51.7%, and 41.8% at 1, 2, 3, and 4 years, respectively. The mean postoperative follow-up period or time to failure for all patients was 2.2 +/- 1.8 years (range, 3 months to 7.5 years). CONCLUSIONS The Ahmed valve was found to be useful in the management of refractory pediatric glaucoma. Although our success rates were similar to those observed in adults, the rates of certain post-operative complications were different.