PURPOSE:Establishing a record of key contributions of early Black ophthalmologists can help illuminate future generations. We aimed to identify major physician pioneers in ophthalmology, delineate their contributions, and place their ascendance in a historical context to understand the institutional and cultural barriers they overcame to achieve success. METHODS:PubMed and other databases were searched, along with death notices and archeological records, using "Black," "African American," "eye surgeon," "Negro," "Journal of the National Medical Association" and other search terms. Librarians from the Library of Congress, National Institutes of Health, and key ophthalmology training institutions were consulted, as were the American Academy of Ophthalmology and American Board of Ophthalmology. Family members and colleagues of selected deceased pioneers were interviewed. RESULTS:Many early pioneers emerged from historically Black institutions, as Black students and practitioners were then typically excluded elsewhere. Mentorship is a key theme that emerged in the careers of many pioneers and the Black ophthalmologists they trained. CONCLUSIONS:Black ophthalmologists have contributed tremendously to eye-care practice, education, and innovation. Efforts to recruit and train Black ophthalmologists should include highlighting the roles of Black pioneers, increasing educational and training access for the underrepresented in medicine at the institutional level, and expanding pathway and mentorship programs. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Lesioning of the rat striatum with kainic acid may provide a useful animal model with which to study Huntington's Disease since, in both situations, changes in several neurochemical parameters appear similar. In this study, we examined the time course of dopaminergic (DA) and muscarinic cholinergic (MCHOL) receptor alterations after kainic acid injection into the rat striatum. As early as two days after unilateral, intrastriatal injection of kainic acid, most striatal perikaya in the injected area had been destroyed as seen by histological examination. A progressive decrease in the DA and MCHOL receptors continued which was not due to changes in their affinity for their respective receptors. By 48 days after injection, there was about 75% decrease in DA receptors and about a 65% decrease in MCHOL receptors. The DA receptor loss is similar in extent to the reported loss in activity of striatal, dopamine-stimulated adenylate cyclase after kainic acid lesion. The DA and MCHOLreceptor loss is similar to the reported loss of neostriatal DA and MCHOL receptors in Huntington's Disease.

"Genetic code is a divine writing." – Toba Beta This very quote has been exemplified by Dr. Irene Hussels Maumenee who has been a founder of ophthalmic genetics and an asset to the clinicians struggling to find a solution for their patients suffering from rare genetic disorders. She is a legend who envisioned a fusion of ophthalmology and medical genetics. She took several fellows under her wings, provided extensive training in ophthalmic genetics, and created a well-designed network worldwide. Born in Germany at the beginning of World War II to parents from the medical fraternity, Irene Hussels was always encouraged to excel. With a deep-rooted belief that "the only thing nobody can take away from you is your education," her parents instilled in her the urge to achieve the highest level of education and reach the zenith. As a child, alongside her siblings, she had keen interest in studying the minute details of the plants and animals around her, which included lamb's lettuce in the fields, white button mushrooms in the meadows, birch boletes, porcini, and chanterelles under the trees. Nature's beauty caught the attention of her curious mind, and she was fascinated by the colorful land snails and the captivating stages of development of various animals.[1] This way, she explored and comprehended her interest in genetics. Her strong sense of self-realization was the greatest service she could render to the world, as she found her life's work in the process. As she began studying French, she not only learnt the language, but also immersed herself in the unique French culture by spending her time with a French family. This not only enabled her to read and speak French at school, but also helped her in graduating from Göttingen Medical School in Germany.[1] By virtue of her love for nature and genetics, she wrote her thesis on X-linked retinitis pigmentosa at the University of Geneva Medical School, Switzerland. Due to the high number of cases of genetic blindness in Switzerland, Professor Adolphe Franceschetti, chair of ophthalmology at the University of Geneva, initiated a medical genetics program in their curriculum,[1] supporting her commitment to genetics and ophthalmology. Dr. Newton E. Morton, one of the founders of genetic epidemiology and a population geneticist from the University of Hawaii, was impressed by her abilities, talent, and observations on the increased frequency of rare diseases in areas with higher rates of consanguinity.[1] Dr. Hussels moved to Hawaii to work with Dr. Morton on his data in his population genetics laboratory. Meanwhile, she studied the rare genetic eye disease, achromatopsia, on the island of Pingelap in the Pacific region.[1] Popularly known as the father of medical genetics, Dr. Victor A. McKusick laid down the foundation of clinical genetics at the Johns Hopkins University in Baltimore. Dr. Hussels visited him for 2 months in 1969 and developed a special interest in inherited disorders of connective tissue, including Marfan syndrome. Her short pause evolved into a long journey of a postdoctoral fellowship in medical genetics at the Johns Hopkins University School of Medicine followed by a preceptorship at the Wilmer Eye Institute.[1] There she learnt the art of integrating mathematical principles into medical genetics. Dr. Hussels revers Dr. McKusick for selflessly showing her the right direction and considers him as her primary mentor. In her words, "To him, it didn't matter whether somebody was male or female, where they came from, or who they were – just whether the person had a passion for the field and could move it forward. He was singularly directed in his pursuit and tremendously knowledgeable. He would help you and foster your growth, and he was very generous with his time, input, and teaching. He was an extraordinary mentor." This not only shows her dedication to her mentor, but also underscores her clinical skills.[1] She joined the Department of Ophthalmology under Dr. A. Edward Maumenee, where she was successful in building a bridge between genetic eye diseases and laboratory research. Dr. A. Edward Maumenee and Dr. Irene Hussels married and were blessed with two sons. Dr. Irene Hussels Maumenee [Fig. 1] founded and directed the Johns Hopkins Centre for Hereditary Eye Diseases, an international referral center, and, under her supervision, more than 30,000 patients with rare eye disorders were diagnosed and managed.[1] She became the Ort Professor of Ophthalmology at the Johns Hopkins University, and she trained several legends including Dr. A. Lin Murphree, who contributed tremendously to the world of ocular oncology [Fig. 2a]. Every rare disease was a piece of mysterious puzzle to her. Her skill of putting the pieces together, by remembering and recalling the cases individually, was par excellence and unparalleled, allowing her to solve the puzzle and unravel the mystery.Figure 1: Dr. Irene Hussels Maumenee[14]Figure 2: (a) A priceless capture of Dr. Maumenee with one of her sons, Niels K. Maumenee (on the left) and her first ever fellow Prof. A. Linn Murphree (on the right), who was a tremendous force in ocular oncology known for decoding the retinoblastoma genetics (courtesy: Dr. Emily Chew). (b) Dr. Maumenee with Dr. Stephen H. Tsang (standing) and Dr. Peter M. J. Quinn (sitting) at the Columbia University, Vagelos College of Physicians and Surgeons in New York city (courtesy: Dr. Stephen H. Tsang)The Ophthalmic Genetics Study Club founded by Dr. Maumenee in 1976[1] gave opportunities for enthusiasts from the genetic world to discuss their respective cases and broaden their knowledge horizon. In 1978, a small meeting of Drs Ed Cotlier, N. Ohba, and Maumenee at a restaurant in Tokyo led to a grant by the International Council of Ophthalmology and the inception of the International Society for Genetic Eye Diseases and Retinoblastoma (ISGEDR).[1] The now biennial meetings have promoted the spread of the knowledge of genetics across the international borders and have built interest in curious minds with a strong inclination toward ophthalmic genetics. Her caring nature and curiosity enabled her to work for decades as a consultant at the John F. Kennedy Institute for Visually and Mentally Handicapped Children and with the Maryland School for the Blind. Her desire to add more to the pool of available knowledge was always evident. In 2008, Dr. Maumenee joined the faculty of the Illinois Eye and Ear Infirmary and is currently a Professor of Ophthalmology at Columbia University, Vagelos College of Physicians and Surgeons in New York city [Fig. 2b].[12] Dr. Maumenee initiated a chain reaction of understanding genetics in ophthalmology and trained many fellows, instilling the same thirst for knowledge in them. Her contagious energy and abilities have created a strong sense of loyalty, love, and affection among her fellows, which have been acknowledged by many over the years with utmost respect [Fig. 3]. She is a calm, encouraging, and forgiving source of knowledge, radiating positivity all around, and those who have come in touch with her, even if only for a short while, have been inspired. She believes in dual board certification in both genetics (American Board of Medical Genetics) and ophthalmology (American Board of Ophthalmology) to serve patients and society.[3]Figure 3: (a) A precious keepsake - Dr. Maumenee with her fellows. From left to right – Drs Yasuhiko Tanaka, Jane D. Kivlin, Irene H. Maumenee, James Richard, Bronwyn Bateman, Shakur Hamidi Toosi (courtesy: Dr. Jane D. Kivlin). (b) Dr. Irene Hussels Maumenee with her proud former fellows at the American Academy of Ophthalmology Laureate Recognition Award ceremony in 2017. From left to right – Drs Emily Chew, Marilyn Miller (a friend), Irene Hussels Maumenee, Marilyn Mets, Bronwyn Bateman, Terri Young (courtesy – Dr. Emily Chew).Although there have been major advances in genetics over the span of her career, she still believes that the manpower required for discovering the world of genetics is sparse. "We have an estimated 22,000 genes and we know over 6000 single gene disorders and complex diseases, but causative mutations have been identified in fewer than 4000 genes. The complexity of gene function for most genes remains unknown," she said.[1] Her curiosity and urge to explore the unsolved mysteries of several rare diseases continues. She has encouraged collaborations between private practices and universities. She understands the issues of government funding for rare diseases and has included support groups and foundations to develop a strong funding for research and development for these diseases. Out of her innumerable contributions, a few of the landmark impacts are as follows: Marfan syndrome and other connective tissue disorders – diagnosis and management of ocular manifestations[4567] Genetic aspects of congenital cataract and their management[89] Ocular and genetic manifestations of mucopolysaccharidosis[1011] Leber's congenital amaurosis and hereditary optic neuropathy[1213] Identified the first gene for achromatopsia, CNGB3, among the Pingelapese Islanders.[1] In 2017, 13 years following Dr. Danièle S. Aron Rosa, Dr. Maumenee received the American Academy of Ophthalmology (AAO) Laureate Recognition Award.[1415] She mentioned in an interview that people considered her inclination toward genetics equivalent to "collecting butterflies," but she saw it as "a new opportunity in life and in the world." Despite making the impossible become possible, she feels she could have pursued more if it were not for responsibilities toward family. However, she quoted, "It's hard to know if I would have done anything really differently. I certainly would not want to be without a family." As she put it, "My knowledge of French had opened the door." We have all the reasons to believe that her knowledge of French opened the doors of genetics to the entire world. We are forever indebted to her for her accomplishments. Her life-long dedication to ophthalmic genetics to identify and understand rare hereditary ophthalmic disorders has revolutionized the management of such cases due to her grit, inventiveness, optimism, generosity, and imagination. "Heredity provides for the modification of its own machinery." – James Mark Baldwin

IMPORTANCE:The study establishes the importance of genetic background for the expression of Down syndrome phenotype.OBJECTIVE:To define the ocular manifestations of Down syndrome in infants and children in Cairo, Egypt, a historically isolated region, and compare them with systemic features and with findings in other geographic groups.DESIGN AND PARTICIPANTS:We prospectively studied the ocular status and systemic features of 90 infants and children with Down syndrome and monitored all patients for 3 years. The complete ophthalmic examinations were performed along with ultrasonography, if media opacities were evident. Thyroid and cardiac status were assessed. An extensive literature search for comparison was performed.SETTING:Outpatient clinical genetics department at the National Research Centre in Cairo, Egypt.MAIN OUTCOMES AND MEASURES:Ocular and systemic manifestations of Down syndrome in infants and children in Cairo, and comparison of these features with patients with this anomaly from other geographic regions and ethnic populations.RESULTS:Fifty-two infants or children (58%) had at least 1 abnormal ocular finding identified at the first visit. Significant refractive errors (in 37 [41%] patients) were the most common. Nasolacrimal duct obstruction, blepharoconjuctivitis, or conjunctivitis was found in 18 (20%), strabismus in 13 (14%), cataract in 5 (6%), nystagmus in 3 (3%), and optic nerve dysplasia in 2 (2%). Brushfield spots were not found. Additional ocular features developed over time. Thirty-six patients (40%) had congenital heart defects, and many (31 [86%]) had associated ocular disorders; a statistically significant correlation with myopia was established. Chromosomal translocations were high. The phenotype in Cairo was distinct.CONCLUSIONS AND RELEVANCE:More than half of infants and children with Down syndrome in Cairo had ophthalmic abnormalities; myopia was correlated with congenital heart defects. Comparison of the specific ocular features in our population with those in previous worldwide studies shows differences that may be related to overexpression or polymorphisms of key, modifying genes or other mutations in this historically isolated region along the Nile River. Down syndrome is more common in the highly consanguineous and multiparous Middle Eastern populations, and our Cairo findings underscore regional differences.

Toshiaki Abe Tadamichi Akagi Masayuki Akimoto Shiro Amano Makoto Araie Kaoru Araki-Sasaki Reiko Arita Ryo Asaoka Noriyuki Azuma Takayuki Baba Hiroko Bissen-Miyajima Shih-Jen Chen (Taiwan) Gemmy Cheung (Singapore) Tai-ichiro Chikama Jacqueline Chua (Singapore) Hideki Chuman Hiroshi Eguchi Hiroshi Enaida Takashi Fujikado Naoya Fujimoto Takeo Fukuchi Masahiko Fukuda Nobuo Fuse Fumi Gomi Eiki Goto Teruhiko Hamanaka Masanori Hangai Naoto Hara Seiyo Harino Satoshi Hasebe Shin Hatou Yoshikazu Hatsukawa Atsushi Hayashi Ken Hayashi Takaaki Hayashi Takao Hayashi Tomomi Higashide Taiichi Hikichi Koji Hirano Takahiro Hiraoka Kazunori Hirasawa Yoshimune Hiratsuka Kazuyuki Hirooka Toshio Hisatomi Kenneth Joseph Hoffer (United States) Megumi Honjo Yuichi Hori Yukihiro Horie Masayuki Horiguchi Naoichi Horio Yoshihiro Hotta Tomohiro Iida Hiroyuki Iijima Hanako Ohashi Ikeda Tsunehiko Ikeda Kengo Ikesugi Yasushi Ikuno Masaru Inatani Makoto Inoue Toshihiro Inoue Yoshitsugu Inoue Yasushi Isashiki Susumu Ishida Mami Ishihara Hiroshi Ishikawa Makoto Ishikawa Satoshi Ishiko Yasuki Ito Keiichiro Iwao Aiko Iwase Takeshi Iwase Toshikatsu Kaburaki Kazuaki Kadonosono Yuichi Kaji Motohiro Kamei Kazutaka Kamiya Junko Kamo Akiyasu Kanamori Satoru Kase Kenji Kashiwagi Ryo Kawasaki Kazuhide Kawase Takeshi Kezuka Akiko Kimura Hideya Kimura Itaru Kimura Shuhei Kimura Shoji Kishi Mihori Kita Takashi Kitaoka Yasushi Kitaoka Yoshiaki Kiuchi Shinichiro Kobayakawa Akira Kobayashi Tatsuo Kodama Akiko Kogure Shizuka Koh Hideki Koizumi Noriko Koizumi Shota Kojima Hiroyuki Kondo Mineo Kondo Toshiaki Kubota Hiroshi Kunikata Kazuki Kuniyoshi Daijiro Kurosaka Shunji Kusaka Andrew Lee (United States) Shiying Li (China) Shigeki Machida Fumiatsu Maeda Naoyuki Maeda Takatoshi Maeno

PURPOSE: To investigate the frequency and types of systemic findings in patients with apparently isolated uveal coloboma.DESIGN: Cross-sectional observational study.METHODS: SETTING: Single-center ophthalmic genetics clinic. STUDY POPULATION: Ninety-nine patients with uveal coloboma seen at the National Eye Institute. OBSERVATIONAL PROCEDURE: Results of audiology testing, echocardiogram, brain magnetic resonance imaging, renal ultrasound, and total spine radiographs. MAIN OUTCOME MEASURE: Prevalence of abnormal findings on systemic testing.RESULTS: Uveal coloboma affected only the anterior segment in 8 patients, only the posterior segment in 23 patients, and both anterior and posterior segments in 68 patients. Best-corrected visual acuity (BCVA) of eyes with coloboma was >= 20/40 in 45% of eyes; 23% of eyes had BCVA of <= 20/400. The majority of patients (74%) had good vision (>20/60) in at least 1 eye. Ten of the 19 patients (53%) who underwent echocardiography had abnormalities, with ventral septal defects being the most prevalent. Abnormal findings were observed in 5 of 72 patients (7%) who had a renal ultrasound and in 5 of 29 patients (17%) who underwent a brain MRI. Audiology testing revealed abnormalities in 13 of 75 patients (17%), and spine radiographs showed anomalies in 10 of 77 patients (13%). Most findings required no acute intervention.CONCLUSIONS: Although some patients with coloboma had evidence of extraocular abnormalities, the majority of findings on routine clinical examination did not require acute intervention, but some warranted follow-up. Results from the systemic evaluation of patients with coloboma should be interpreted with caution and in view of their clinical context. (Published by Elsevier Inc.)

Purpose: To report the association of Duane syndrome with nystagmus and a patterned hyperpigmentation of the retinal pigment epithelium, developmental delay, micro- and pachygyria and craniopharyngioma. Case Report: We describe a 12-year old girl with developmental delay, hearing loss, cortical micro- and pachygyria, and a cystic craniopharyngioma; her ocular features include unilateral Duane syndrome, monocular nystagmus under binocular conditions, and a patterned hyperpigmentation of the retinal pigment epithelium. Her mother had similar retinal pigment epithelial abnormalities. Conclusions: The combination of two neuronal migrational disorders, the unusual retinal pigment epithelial abnormalities in the proband and her mother, and evidence that each feature may be genetic and are suggestive of a genetic basis for this constellation of features.

We studied 28 individuals from a four-generation Chilean family (ADC54) including 13 affected individuals with cataracts, microcornea and/or corneal opacity. All individuals underwent a complete ophthalmologic exam. We screened with a panel of polymorphic DNA markers for known loci that cause autosomal dominant cataracts, if mutated, and refined the locus using the ABI Prism Linkage Mapping Set Version 2.5, and calculated two-point lod scores. Novel PCR primers were designed for the three coding exons, including intron-exon borders, of the candidate gene alpha A crystallin (CRYAA). Clinically, affected individuals had diverse and novel cataracts with variable morphology (anterior polar, cortical, embryonal, fan-shaped, anterior subcapsular). Microcornea and corneal opacity was evident in some. Marker D21S171 gave a lod score of 4.89 (theta(m) = theta(f) = 0). CRYAA had a G414A transition that segregated with the disease and resulted in an amino acid alteration (R116H). The phenotypic variability within this family was significant with novel features of the cataracts and a corneal opacity. With the exception of iris coloboma, the clinical features in all six previously reported families with mutations in the CRYAA gene were found in this family. We identified a novel G414A transition in exon 3 of CRYAA that co-segregated with an autosomal dominant phenotype. The resulting amino acid change R116H is in a highly conserved region and represents a change in charge. The genotype-phenotype correlation of this previously unreported mutation provides evidence that other factors, genetic and/or environmental, may influence the development of cataract as a result of this alteration.

Purpose: To map and identify the mutated gene for autosomal dominant cataract (ADC) in a large Chilean family (ADC53).Design: Experimental study.Participants: Large Chilean family with ADCs.Methods: Linkage analyses using genome-wide polymorphic DNA markers were performed on a family with variable expression of cataracts to map the mutated gene to a chromosome; 2-point lod scores were calculated. Candidate genes in the region of the maximum lod score were sequenced. We compared haplotypes (alleles at closely linked markers) in families with previously reported mutations of the crystallin, beta-B2 gene (CPYBB2).Main Outcome Measures: Identification of the causative mutation in the ADC53 family.Results: The ADC locus mapped to chromosome 22 in the region of a cluster of lens 0 crystallin genes (CRYBB3, CRYBB2, CRYBB1, and CRYBA4 and the pseudogene CRYBB2P1). We sequenced CRYBB1 and CRYBB2 and found a previously reported mutation and a variant in exon 6 of CRYBB2 that cosegregate with the disease; these changes in CRYBB2 are in the reference (normal) sequence of an adjacent gene CRYBB2P1, a pseudogene. The haplotypes in the ADC53 Chilean family were different from the 2 previously reported families with the mutation.Conclusions: The cataracts in the ADC53 Chilean family are caused by a mutation in the CRYBB2 gene; as the 2 variations in CPYBB2 are identical to the reference sequence of pseudogene CRYBB2P1, which has over 97% homology to CRYBB2, a gene conversion probably has occurred. Based on haplotype analyses, the mutation and variant are likely to be caused by independent gene conversions in our family and the previously reported families.

ALDH3A1 ( aldehyde dehydrogenase 3A1) is abundant in the mouse cornea but undetectable in the lens, and ALDH1A1 is present at lower ( catalytic) levels in the cornea and lens. To test the hypothesis that ALDH3A1 and ALDH1A1 protect the anterior segment of the eye against environmentally induced oxidative damage, Aldh1a1(-/ -)/Aldh3a1( -/ -) double knock-out and Aldh1a1(-/-) and Aldh3a1(-/-) single knock-out mice were evaluated for biochemical changes and cataract formation ( lens opacification). The Aldh1a1/ Aldh3a1- and Aldh3a1- null mice develop cataracts in the anterior and posterior subcapsular regions as well as punctate opacities in the cortex by 1 month of age. The Aldh1a1-null mice also develop cataracts later in life ( 6 - 9 months of age). One-to three-month-old Aldh-null mice exposed to UVB exhibited accelerated anterior lens subcapsular opacification, which was more pronounced in Aldh3a1(-/-) and Aldh3a1(-/-)/ Aldh1a1(-/-) mice compared with Aldh1a1(-/-) and wild type animals. Cataract formation was associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and increased levels of 4-hydroxy-2-nonenal- and malondialdehyde-protein adducts. In conclusion, these findings support the hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via nonenzymatic ( light filtering) and enzymatic ( detoxification) functions.

Purpose To document intrafamilial and interocular phenotypic variability of autosomal dominant cataract (ADC). Design Prospective observational case series. Methods We performed ophthalmologic examination in four Chilean ADC families. Results The families exhibited variability with respect to morphology, location with the lens, color and density of cataracts among affected members. We documented asymmetry between eyes in the morphology, location within the lens, color and density of cataracts, and a variable rate of progression. Conclusions The cataracts in these families exhibit wide intrafamilial and interocular phenotypic variability, supporting the premise that the mutated genes are expressed differentially in individuals and between eyes; other genes or environmental factors may be the bases for this variability. Marked progression among some family members underscores the variable clinical course of a common mutation within a family. Like retinitis pigmentosa, classification of ADC will be most useful if based on the gene and specific mutation.