Corneal Dystrophy, Endothelial X-Linked Clinical CharacteristicsOcular Features: Corneal opacification is severe in males and has been described as resembling ground glass, or having a milky white appearance throughout the entire cornea. Corneal clouding may be seen in infants but progresses with age in most cases. In a 7 generation Austrian family, nine males had severe corneal opacification, seven with band keratopathy and 2 with the typical ground glass appearance. Vision may be 20/20 even in adults but the majority have acuities in the range of 20/30 to 20/60 even into the 7th decade. A few have vision of 20/100 to 20/400 even as young adults and one 19 year old was reported with nystagmus. The corneas of twenty-two females and four males were said to have only a 'moon crater-like' appearance resulting from focal discontinuities in the endothelial layer. Tissue studies of a keratoplasty button from a 60 year old male revealed endothelial degeneration and thickening of the Descemet membrane. There may also be irregular thinning of the epithelial and Bowman layers. Systemic Features: No systemic disease associations have been reported. GeneticsThis is the only endothelial dystrophy that is X-linked (Xq25). A single family has been reported and the molecular mutation is unknown. Females may be affected but less severely than males and are usually asymptomatic. In a large pedigree in which 60 individuals were studied, no male-to-male transmission was found. Pedigree: X-linked dominant, father affectedX-linked dominant, mother affectedX-linked recessive, carrier motherX-linked recessive, father affectedTreatmentTreatment Options: The few reported cases and limited treatments used make generalizations difficult. But males have had penetrating keratoplasty with good results lasting for decades. ReferencesArticle Title: A new, X-linked endothelial corneal dystrophy Schmid E, Lisch W, Philipp W, Lechner S, Gottinger W, Schlotzer-Schrehardt U, Muller T, Utermann G, Janecke AR. A new, X-linked endothelial corneal dystrophy. Am J Ophthalmol. 2006 Mar;141(3):478-487. PubMed ID: 16490493 Read more about Corneal Dystrophy, Endothelial X-Linked
A new, X-linked endothelial corneal dystrophy Schmid E, Lisch W, Philipp W, Lechner S, Gottinger W, Schlotzer-Schrehardt U, Muller T, Utermann G, Janecke AR. A new, X-linked endothelial corneal dystrophy. Am J Ophthalmol. 2006 Mar;141(3):478-487. PubMed ID: 16490493
Aland Island Eye Disease Clinical CharacteristicsOcular Features: This is an X-linked disorder in which males have a variety of ocular defects. The fundus is hypopigmented and the fovea is incompletely developed. The hypopigmentation is most pronounced in the posterior pole and peripapillary region. Variable degrees of iris transillumination have also been noted. Progressive axial myopia, nystagmus, astigmatism, defective night vision, and a protan color vision defect are additional cardinal features. Females may be mildly affected with subtle nystagmus and color vision defects. It is sometimes mislabeled as X-linked albinism (OA1, #300500) but differs importantly from that disorder by the lack of misrouting of optic nerve axons. The eponymic label 'Forsius-Eriksson type ocular albinism' further adds to the confusion with ocular albinism. Systemic Features: No systemic abnormalities have been reported. GeneticsThis is an X-linked disorder resulting from a mutation in the CACNA1F gene located at Xp11.23. Molecular DNA studies suggest that there may be some heterogeneity in the causative mutations but in the original family reported by Forsius and Eriksson, a 425-bp deletion in the CACNA1F gene has been found to segregate as expected in the phenotypes. The highly variable and subtle nature of clinical manifestations in females limits their usefulness in determination of carrier status and genotyping is necessary. The CSNB2A type of congenital stationary night blindness (300071) is caused by mutations in the same gene suggesting allelism of the two disorders. Aland Island eye disease shares some clinical features such as night blindness and occasionally mild color vision defects but differs in the presence of progressive myopia and an abnormal fovea. CORDX3 (300476), a cone-rod dystrophy, is also allelic. Pedigree: X-linked recessive, carrier motherX-linked recessive, father affectedTreatmentTreatment Options: No treatment is available except for correction of the myopia. ReferencesArticle Title: A novel CACNA1F gene mutation causes Aland Island eye disease Jalkanen R, Bech-Hansen NT, Tobias R, Sankila EM, M?SSntyj?SSrvi M, Forsius H, de la Chapelle A, Alitalo T. A novel CACNA1F gene mutation causes Aland Island eye disease. Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2498-502. PubMed PMID:17525176. PubMed ID: 17525176 Genetic mapping of a cone and rod dysfunction (Aland Island eye disease) to the proximal short arm of the human X chromosome[nid:206] Glass IA, Good P, Coleman MP, Fullwood P, Giles MG, Lindsay S, Nemeth AH, Davies KE, Willshaw HA, Fielder A, et al. Genetic mapping of a cone and rod dysfunction (Aland Island eye disease) to the proximal short arm of the human X chromosome. J Med Genet. 1993 Dec;30(12):1044-50. PubMed ID: 7907666 Aland Island eye disease (Forsius-Eriksson syndrome) associated with contiguous deletion syndrome at Xp21. Similarity to incomplete congenital stationary night blindness Weleber RG, Pillers DA, Powell BR, Hanna CE, Magenis RE, Buist NR. Aland Island eye disease (Forsius-Eriksson syndrome) associated with contiguous deletion syndrome at Xp21. Similarity to incomplete congenital stationary night blindness. Arch Ophthalmol. 1989 Aug;107(8):1170-9. Review. PubMed ID: 2667510 Read more about Aland Island Eye Disease
A novel CACNA1F gene mutation causes Aland Island eye disease Jalkanen R, Bech-Hansen NT, Tobias R, Sankila EM, M?SSntyj?SSrvi M, Forsius H, de la Chapelle A, Alitalo T. A novel CACNA1F gene mutation causes Aland Island eye disease. Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2498-502. PubMed PMID:17525176. PubMed ID: 17525176
Genetic mapping of a cone and rod dysfunction (Aland Island eye disease) to the proximal short arm of the human X chromosome[nid:206] Glass IA, Good P, Coleman MP, Fullwood P, Giles MG, Lindsay S, Nemeth AH, Davies KE, Willshaw HA, Fielder A, et al. Genetic mapping of a cone and rod dysfunction (Aland Island eye disease) to the proximal short arm of the human X chromosome. J Med Genet. 1993 Dec;30(12):1044-50. PubMed ID: 7907666
Aland Island eye disease (Forsius-Eriksson syndrome) associated with contiguous deletion syndrome at Xp21. Similarity to incomplete congenital stationary night blindness Weleber RG, Pillers DA, Powell BR, Hanna CE, Magenis RE, Buist NR. Aland Island eye disease (Forsius-Eriksson syndrome) associated with contiguous deletion syndrome at Xp21. Similarity to incomplete congenital stationary night blindness. Arch Ophthalmol. 1989 Aug;107(8):1170-9. Review. PubMed ID: 2667510
Alport Syndrome (Collagen IV-Related Nephropathies) Clinical CharacteristicsOcular Features: X-linked Alport syndrome is a basement membrane disease with important ocular manifestations. The lens is usually normal at birth but lens opacities eventually occur in a significant number of individuals with the most characteristic type being anterior polar in location. Involvement of the anterior lens capsule often results in bilateral anterior lenticonus (25%) and may be progressive. It is claimed that the severity of the lenticonus is a valuable marker in judging the overall disease severity. In early stages it may be difficult to detect but its presence is suggested by an 'oil droplet' reflex during retinoscopy or slit lamp examination. All males with anterior lenticonus should be evaluated for Alport syndrome. Posterior polymorphous corneal dystrophy and posterior subcapsular opacities have also been noted. The defect in basement membranes may lead to recurrent corneal erosions, even in children, which can be incapacitating and difficult to treat. Involvement of Bruch's membrane has been considered the source of retinal pigment epithelial changes described as a flecked retina, or 'fundus albipunctatus', found in 85% of patients. More recent evidence using OCT suggests that the dot-and-fleck retinopathy results primarily from abnormalities in the internal limiting membrane and the nerve fiber layer. The yellowish and/or whitish flecks are most commonly located in the posterior pole and particularly in the macula. There is no night blindness or visual impairment from the retinal involvement. Fluorescein angiography shows patchy areas of hyperfluorescence. The amount of visual impairment depends primarily on the extent of lens involvement. Termporal macular thinning occurs to some extent in all types of Alport syndrome based on OCT findings. In one series all patients with X-linked disease had temporal thinning suggesting that this might be a useful diagnostic sign. However, similar thinning is also seen in Leber hereditary optic neuropathy (535000), and dominant optic atrophy (165500). Systemic Features: Nephritis with hematuria secondary to basement membrane disease of the glomeruli is the most life threatening aspect of this disorder. It occurs in both sexes but more commonly in males in which it has an earlier onset. Progressive sensorineural hearing loss beginning with high frequencies occurs in many patients, often with subtle onset in childhood, but many adults retain some hearing capacity. In males, the onset of hearing loss often occurs before kidney disease is evident. Hearing loss is less frequent and less severe in females. However, there is considerable clinical and genetic heterogeneity and not all patients have the complete syndrome of nephritis, deafness and ocular disease. In fact, it has been suggested that Alport syndrome can be subtyped into at least six categories based on the extent of organ involvement. GeneticsAlport syndrome is a member of a group of disorders known as collagen IV-related nephropathies. It is a genetically heterogeneous disease with 85% inherited in an X-linked pattern and most of the remainder occurring in an autosomal recessive pattern and only a few seemingly autosomal dominant. All result from a defect in type IV collagen found in basement membranes. About 80% of cases have a mutation in the COL4A5 gene which is located at Xq22.3. Males seem to be more severely affected than females in the X-linked form of the disease but clearly this disorder affects both sexes reflecting the genetic heterogeneity, much of which remains to be delineated. The autosomal disease generally results from mutations in the COL4A3 or COL4A4 genes and has been seen in both recessive and dominant patterns of transmission. Pedigree: Autosomal dominantAutosomal recessiveX-linked recessive, carrier motherX-linked recessive, father affectedTreatmentTreatment Options: Renal transplantation can be lifesaving but a minority of individuals develop a specific antiglomerular basement membrane antibody (anti-GBM) that may lead to graft rejection. Allograft survival rates are generally excellent though. Lens extraction is beneficial where the media is compromised. ReferencesArticle Title: Temporal retinal thinning and the diagnosis of Alport syndrome and Thin basement membrane nephropathy Chen Y, Colville D, Ierino F, Symons A, Savige J. Temporal retinal thinning and the diagnosis of Alport syndrome and Thin basement membrane nephropathy. Ophthalmic Genet. 2017 Nov 27:1-7. doi: 10.1080/13816810.2017.1401088. [Epub ahead of print]. PubMed ID: 29172845 MACULAR HOLES, VITELLIFORM LESIONS, AND MIDPERIPHERAL RETINOSCHISIS IN ALPORT SYNDROME Thomas AS, Baynham JT, Flaxel CJ. MACULAR HOLES, VITELLIFORM LESIONS, AND MIDPERIPHERAL RETINOSCHISIS IN ALPORT SYNDROME. Retin Cases Brief Rep. 2015 Jul 21. [Epub ahead of print]. PubMed ID: 26200386 Temporal Macular Thinning Associated With X-Linked Alport Syndrome Ahmed F, Kamae KK, Jones DJ, Deangelis MM, Hageman GS, Gregory MC, Bernstein PS. Temporal Macular Thinning Associated With X-Linked Alport Syndrome. JAMA Ophthalmol. 2013 Apr 9:1-6. PubMed ID: 23572034 Alport syndrome-insights from basic and clinical research Kruegel J, Rubel D, Gross O. Alport syndrome-insights from basic and clinical research. Nat Rev Nephrol. 2012 Nov 20. [Epub ahead of print]. PubMed ID: 23165304 Retinal basement membrane abnormalities and the retinopathy of Alport syndrome Savige J, Liu J, DeBuc DC, Handa JT, Hageman GS, Wang YY, Parkin JD, Vote B,Fassett R, Sarks S, Colville D. Retinal basement membrane abnormalities and the retinopathy of Alport syndrome. Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1621-7. PubMed ID: 19850830 Ocular manifestations and surgical results in patients with Alport syndrome Seymenofulu G, Baser EF. Ocular manifestations and surgical results in patients with Alport syndrome. J Cataract Refract Surg. 2009 Jul;35(7):1302-6. PubMed ID: 19545823 Alport syndrome. A review of the ocular manifestations Colville DJ, Savige J. Alport syndrome. A review of the ocular manifestations. Ophthalmic Genet. 1997 Dec;18(4):161-73. Review. PubMed ID: 9457747 Alport syndrome: a genetic study of 31 families M'Rad R, Sanak M, Deschenes G, Zhou J, Bonaiti-Pellie C, Holvoet-Vermaut L, Heuertz S, Gubler MC, Broyer M, Grunfeld JP, et al. Alport syndrome: a genetic study of 31 families. Hum Genet. 1992 Dec;90(4):420-6. PubMed ID: 1483700 Lens capsule abnormalities in Alport's syndrome Streeten BW, Robinson MR, Wallace R, Jones DB. Lens capsule abnormalities in Alport's syndrome. Arch Ophthalmol. 1987 Dec;105(12):1693-7. PubMed ID: 3689194 Read more about Alport Syndrome (Collagen IV-Related Nephropathies)
Temporal retinal thinning and the diagnosis of Alport syndrome and Thin basement membrane nephropathy Chen Y, Colville D, Ierino F, Symons A, Savige J. Temporal retinal thinning and the diagnosis of Alport syndrome and Thin basement membrane nephropathy. Ophthalmic Genet. 2017 Nov 27:1-7. doi: 10.1080/13816810.2017.1401088. [Epub ahead of print]. PubMed ID: 29172845
MACULAR HOLES, VITELLIFORM LESIONS, AND MIDPERIPHERAL RETINOSCHISIS IN ALPORT SYNDROME Thomas AS, Baynham JT, Flaxel CJ. MACULAR HOLES, VITELLIFORM LESIONS, AND MIDPERIPHERAL RETINOSCHISIS IN ALPORT SYNDROME. Retin Cases Brief Rep. 2015 Jul 21. [Epub ahead of print]. PubMed ID: 26200386
Temporal Macular Thinning Associated With X-Linked Alport Syndrome Ahmed F, Kamae KK, Jones DJ, Deangelis MM, Hageman GS, Gregory MC, Bernstein PS. Temporal Macular Thinning Associated With X-Linked Alport Syndrome. JAMA Ophthalmol. 2013 Apr 9:1-6. PubMed ID: 23572034
Alport syndrome-insights from basic and clinical research Kruegel J, Rubel D, Gross O. Alport syndrome-insights from basic and clinical research. Nat Rev Nephrol. 2012 Nov 20. [Epub ahead of print]. PubMed ID: 23165304
Retinal basement membrane abnormalities and the retinopathy of Alport syndrome Savige J, Liu J, DeBuc DC, Handa JT, Hageman GS, Wang YY, Parkin JD, Vote B,Fassett R, Sarks S, Colville D. Retinal basement membrane abnormalities and the retinopathy of Alport syndrome. Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1621-7. PubMed ID: 19850830
Ocular manifestations and surgical results in patients with Alport syndrome Seymenofulu G, Baser EF. Ocular manifestations and surgical results in patients with Alport syndrome. J Cataract Refract Surg. 2009 Jul;35(7):1302-6. PubMed ID: 19545823
Alport syndrome. A review of the ocular manifestations Colville DJ, Savige J. Alport syndrome. A review of the ocular manifestations. Ophthalmic Genet. 1997 Dec;18(4):161-73. Review. PubMed ID: 9457747
Alport syndrome: a genetic study of 31 families M'Rad R, Sanak M, Deschenes G, Zhou J, Bonaiti-Pellie C, Holvoet-Vermaut L, Heuertz S, Gubler MC, Broyer M, Grunfeld JP, et al. Alport syndrome: a genetic study of 31 families. Hum Genet. 1992 Dec;90(4):420-6. PubMed ID: 1483700
Lens capsule abnormalities in Alport's syndrome Streeten BW, Robinson MR, Wallace R, Jones DB. Lens capsule abnormalities in Alport's syndrome. Arch Ophthalmol. 1987 Dec;105(12):1693-7. PubMed ID: 3689194
Choroideremia Clinical CharacteristicsOcular Features: Choroideremia is characterized by a progressive atrophy of photoreceptors, retinal pigment epithelium (RPE) and choroid. Areas of RPE atrophy are present early in the mid-periphery and progress centrally. This is associated with loss of photoreceptors and the choriocapillaris. Night blindness is the first symptom often with onset during childhood. A ring-like perimacular scotoma develops that progresses into the periphery during life with corresponding visual field loss (peripheral constriction). Symptoms and fundus changes are highly variable. Visual acuity is generally well maintained into later stages of the disease but some males are blind by age 30 years whereas others over the age of 50 are symptom-free. An increased prevalence of myopia has been noted. Males with choroideremia (and some females) have progressive loss of the choriocapillaris eventually baring the sclera beneath. Female carriers can exhibit patchy areas of RPE atrophy in the periphery and these may enlarge. Female carriers are typically not symptomatic, but there are reports of females being fully affected. Females may also have visual field changes and defective dark adaptation. OCT in young women shows dynamic changes and remodeling of the outer retina with time with focal retinal thickening, drusenlike deposits and disruptions in photoreceptor inner and outer segment junctions even in younger individuals. The phenotype is more severe in older females as well suggesting that the retinal degeneration is progressive in both sexes. Electroretinography (ERG) initially shows a decreased dark-adapted response with intact light-adapted responses, indicating general dysfunction of rod photoreceptors. Cone dysfunction, however, develops with progression of the disease. Systemic Features: No general systemic manifestations are associated with choroideremia. This may be explained by systemic expression of REP2, Rab escort protein-2, compensating for the decreased level of REP1. There are occasional reports of associated deafness and obesity in some families with choroideremia (303110) but it is uncertain if this represents a unique disorder. GeneticsChoroideremia is an X-linked recessive disorder affecting males and occasional female carriers. The disorder is caused by mutations in the CHM gene on the X chromosome (Xq21.2) which leads to absence or truncation of the protein Rab escort protein-1 (REP1) that is part of Rab geranylgeranyltransferase, an enzyme complex involved in intracellular vesicular transport. A few patients with chromosomal translocations involving the relevant region of the X chromosome have been reported. A homozygous mutation in the CYP4V2 gene has been reported to be responsible for a choroideremia-like clinical phenotype. Pedigree: X-linked recessive, carrier motherX-linked recessive, father affectedTreatmentTreatment Options: Visual function can be improved with low vision aids. Recent early trials using adeno-associated viral vectors containing DNA coding for normal REP1 protein have documented improved rod and cone function with better visual acuity in affected males. ReferencesArticle Title: CHANGES IN RETINAL SENSITIVITY AFTER GENE THERAPY IN CHOROIDEREMIA Fischer MD, Ochakovski GA, Beier B, Seitz IP, Vaheb Y, Kortuem C, Reichel FFL, Kuehlewein L, Kahle NA, Peters T, Girach A, Zrenner E, Ueffing M, MacLaren RE, Bartz-Schmidt K, Wilhelm B. CHANGES IN RETINAL SENSITIVITY AFTER GENE THERAPY IN CHOROIDEREMIA. Retina. 2018 Oct 9. doi: 10.1097/IAE.0000000000002360. [Epub ahead of print]. PubMed ID: 30308560 Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia Xue K, Jolly JK, Barnard AR, Rudenko A, Salvetti AP, Patricio MI, Edwards TL, Groppe M, Orlans HO, Tolmachova T, Black GC, Webster AR, Lotery AJ, Holder GE, Downes SM, Seabra MC, MacLaren RE. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med. 2018 Oct;24(10):1507-1512. PubMed ID: 30297895 Retinal dystrophy and subretinal drusenoid deposits in female choroideremia carriers Murro V, Mucciolo DP, Passerini I, Palchetti S, Sodi A, Virgili G, Rizzo S. Retinal dystrophy and subretinal drusenoid deposits in female choroideremia carriers. Graefes Arch Clin Exp Ophthalmol. 2017 Jul 27. doi: 10.1007/s00417-017-3751-5. [Epub ahead of print]. PubMed ID: 28752371 Clinical and Genetic Features of Choroideremia in Childhood Khan KN, Islam F, Moore AT, Michaelides M. Clinical and Genetic Features of Choroideremia in Childhood. Ophthalmology. 2016 Aug 6. pii: S0161-6420(16)30583-8. doi: 10.1016/j.ophtha.2016.06.051. [Epub ahead of print] PubMed. PubMed ID: 27506488 A novel homozygous CYP4V2 variant (p.S121Y) associated with a choroideremia-like phenotype Katagiri S, Hayashi T, Gekka T, Tsuneoka H. A novel homozygous CYP4V2 variant (p.S121Y) associated with a choroideremia-like phenotype. Ophthalmic Genet. 2016 Jun 27:1-2. PubMed ID: 27348340 Optical Jain N, Jia Y, Gao SS, Zhang X, Weleber RG, Huang D, Pennesi ME. OpticalCoherence Tomography Angiography in Choroideremia: Correlating ChoriocapillarisLoss With Overlying Degeneration. JAMA Ophthalmol. 2016 May 5. doi:10.1001/jamaophthalmol.2016.0874. [Epub ahead of print]. PubMed ID: 27149258 Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial Maclaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014 Jan 15. [Epub ahead of print]. PubMed ID: 24439297 Clinical Characteristics of a Large Choroideremia Pedigree Carrying a Novel CHM Mutation Huang AS, Kim LA, Fawzi AA. Clinical Characteristics of a Large Choroideremia Pedigree Carrying a Novel CHM Mutation. Arch Ophthalmol. 2012 Sep 1;130(9):1184-9. PubMed ID: 22965595 Choroideremia: A review of general findings and pathogenesis Coussa RG, Traboulsi EI. Choroideremia: A review of general findings and pathogenesis. Ophthalmic Genet. 33:57-65, 2011. PubMed ID: 22017263 Clinical and Functional Findings in Choroideremia Due to Complete Deletion of the CHM Gene Mura M, Sereda C , Jablonski MM, MacDonald IM; Iannaccone A. Clinical and Functional Findings in Choroideremia Due to Complete Deletion of the CHM Gene. Arch Ophthalmol. 2007;125(8):1107-1113. PubMed ID: 17698759 Choroideremia: new findings from ocular pathology and review of recent literature MacDonald IM, Russell L, Chan CC. Choroideremia: new findings from ocular pathology and review of recent literature. Surv Ophthalmol. 2009 May-Jun;54(3):401-7. PubMed ID: 19422966 Choroideremia: analysis of the retina from a female symptomatic carrier Bonilha VL, Trzupek KM, Li Y, Francis PJ, Hollyfield JG, Rayborn ME, Smaoui N, Weleber RG. Choroideremia: analysis of the retina from a female symptomatic carrier. Ophthalmic Genet. 2008 Sep;29(3):99-110. PubMed ID: 18766988 Read more about Choroideremia
CHANGES IN RETINAL SENSITIVITY AFTER GENE THERAPY IN CHOROIDEREMIA Fischer MD, Ochakovski GA, Beier B, Seitz IP, Vaheb Y, Kortuem C, Reichel FFL, Kuehlewein L, Kahle NA, Peters T, Girach A, Zrenner E, Ueffing M, MacLaren RE, Bartz-Schmidt K, Wilhelm B. CHANGES IN RETINAL SENSITIVITY AFTER GENE THERAPY IN CHOROIDEREMIA. Retina. 2018 Oct 9. doi: 10.1097/IAE.0000000000002360. [Epub ahead of print]. PubMed ID: 30308560
Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia Xue K, Jolly JK, Barnard AR, Rudenko A, Salvetti AP, Patricio MI, Edwards TL, Groppe M, Orlans HO, Tolmachova T, Black GC, Webster AR, Lotery AJ, Holder GE, Downes SM, Seabra MC, MacLaren RE. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med. 2018 Oct;24(10):1507-1512. PubMed ID: 30297895
Retinal dystrophy and subretinal drusenoid deposits in female choroideremia carriers Murro V, Mucciolo DP, Passerini I, Palchetti S, Sodi A, Virgili G, Rizzo S. Retinal dystrophy and subretinal drusenoid deposits in female choroideremia carriers. Graefes Arch Clin Exp Ophthalmol. 2017 Jul 27. doi: 10.1007/s00417-017-3751-5. [Epub ahead of print]. PubMed ID: 28752371
Clinical and Genetic Features of Choroideremia in Childhood Khan KN, Islam F, Moore AT, Michaelides M. Clinical and Genetic Features of Choroideremia in Childhood. Ophthalmology. 2016 Aug 6. pii: S0161-6420(16)30583-8. doi: 10.1016/j.ophtha.2016.06.051. [Epub ahead of print] PubMed. PubMed ID: 27506488
A novel homozygous CYP4V2 variant (p.S121Y) associated with a choroideremia-like phenotype Katagiri S, Hayashi T, Gekka T, Tsuneoka H. A novel homozygous CYP4V2 variant (p.S121Y) associated with a choroideremia-like phenotype. Ophthalmic Genet. 2016 Jun 27:1-2. PubMed ID: 27348340
Optical Jain N, Jia Y, Gao SS, Zhang X, Weleber RG, Huang D, Pennesi ME. OpticalCoherence Tomography Angiography in Choroideremia: Correlating ChoriocapillarisLoss With Overlying Degeneration. JAMA Ophthalmol. 2016 May 5. doi:10.1001/jamaophthalmol.2016.0874. [Epub ahead of print]. PubMed ID: 27149258
Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial Maclaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014 Jan 15. [Epub ahead of print]. PubMed ID: 24439297
Clinical Characteristics of a Large Choroideremia Pedigree Carrying a Novel CHM Mutation Huang AS, Kim LA, Fawzi AA. Clinical Characteristics of a Large Choroideremia Pedigree Carrying a Novel CHM Mutation. Arch Ophthalmol. 2012 Sep 1;130(9):1184-9. PubMed ID: 22965595
Choroideremia: A review of general findings and pathogenesis Coussa RG, Traboulsi EI. Choroideremia: A review of general findings and pathogenesis. Ophthalmic Genet. 33:57-65, 2011. PubMed ID: 22017263
Clinical and Functional Findings in Choroideremia Due to Complete Deletion of the CHM Gene Mura M, Sereda C , Jablonski MM, MacDonald IM; Iannaccone A. Clinical and Functional Findings in Choroideremia Due to Complete Deletion of the CHM Gene. Arch Ophthalmol. 2007;125(8):1107-1113. PubMed ID: 17698759
Choroideremia: new findings from ocular pathology and review of recent literature MacDonald IM, Russell L, Chan CC. Choroideremia: new findings from ocular pathology and review of recent literature. Surv Ophthalmol. 2009 May-Jun;54(3):401-7. PubMed ID: 19422966
Choroideremia: analysis of the retina from a female symptomatic carrier Bonilha VL, Trzupek KM, Li Y, Francis PJ, Hollyfield JG, Rayborn ME, Smaoui N, Weleber RG. Choroideremia: analysis of the retina from a female symptomatic carrier. Ophthalmic Genet. 2008 Sep;29(3):99-110. PubMed ID: 18766988
Megalocornea Clinical CharacteristicsOcular Features: The corneal diameter is enlarged at birth to between 13.0 and 16.5 mm and the anterior chamber is deep. Male patients may develop early arcus, and eventually a crocodile shagreen pattern in the cornea. Presenile cataracts, iris thinning, and iridodenesis have also been reported. Glaucoma does not seem to be a part of this syndrome. The ERG has revealed mild cone system dysfunction in some patients.. Systemic Features: Isolated megalocornea is not associated with systemic disease by definition but systemic evaluation must be performed to rule out other syndromes. Some patients have been reported to have a focal loss of white matter myelination with superior cognitive abilities. GeneticsOnly a few pedigrees have been reported. X-linked (male only) inheritance is most common. Carrier females do not have ocular disease. Multiple mutations in CHRDL1 (Xq23) have been found in at least 7 families. The gene encodes ventroptin, a morphogenic protein antagonist with multiple functions including specification of topographic retinotectal projections.. The gene is expressed in corneal development, anterior segment, and retina as well as brain. Notably, megalocornea not only occurs as an isolated trait but also may be a part of systemic syndromes such as the Marfan syndrome (154700), Down syndrome andRieger syndrome (180500 ). It is also a part of an autosomal recessive mental retardation syndrome, sometimes called Neuhauser syndrome (249310). Autosomal inheritance (usually recessive) has also been suggested but no locus has been found on autosomes. Homozygous mutations in LTBP2 have been reported in consanguineous families in which sibs have congenital Megalocornea, Ectopia Lentis, and Spherophakia. Pedigree: X-linked recessive, carrier motherX-linked recessive, father affectedTreatmentTreatment Options: There is no treatment for the overall condition but correction of refractive errors, cataract surgery, and low vision aids could be helpful. ReferencesArticle Title: Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhäuser Syndrome and Central Corneal Thickness Davidson AE, Cheong SS, Hysi PG, Venturini C, Plagnol V, Ruddle JB, Ali H, Carnt N, Gardner JC, Hassan H, Gade E, Kearns L, Jelsig AM, Restori M, Webb TR, Laws D, Cosgrove M, Hertz JM, Russell-Eggitt I, Pilz DT, Hammond CJ, Tuft SJ, Hardcastle AJ. Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhauser Syndrome and Central Corneal Thickness. PLoS One. 2014 Aug 5. PubMed ID: 25093588 X-Linked Megalocornea Caused by Mutations in CHRDL1 Identifies an Essential Role for Ventroptin in Anterior Segment Development Webb TR, Matarin M, Gardner JC, Kelberman D, Hassan H, Ang W, Michaelides M, Ruddle JB, Pennell CE, Yazar S, Khor CC, Aung T, Yogarajah M, Robson AG, Holder GE, Cheetham ME, Traboulsi EI, Moore AT, Sowden JC, Sisodiya SM, Mackey DA, Tuft SJ, Hardcastle AJ. X-Linked Megalocornea Caused by Mutations in CHRDL1 Identifies an Essential Role for Ventroptin in Anterior Segment Development. Am J Hum Genet. 2012 Jan 24. [Epub ahead of print]. PubMed ID: 22284829 Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma - a distinct phenotype caused by recessive LTBP2 mutations Khan AO, Aldahmesh MA, Alkuraya FS. Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma - a distinct phenotype caused by recessive LTBP2 mutations. Mol Vis. 2011;17:2570-9. PubMed ID: 22025892 Description of X-linked megalocornea with identification of the gene locus Mackey, D. A.; Buttery, R. G.; Wise, G. M.; Denton, M. J. : Description of X-linked megalocornea with identification of the gene locus. Arch. Ophthal. 109: 829-833, 1991. PubMed ID: 2043071 X-linked megalocornea: close linkage to DXS87 and DXS94 Chen, J. D.; Mackey, D.; Fuller, H.; Serravalle, S.; Olsson, J.; Denton, M. J. : X-linked megalocornea: close linkage to DXS87 and DXS94. Hum. Genet. 83: 292-294, 1989. PubMed ID: 2571565 Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited Neuhauser, G.; Kaveggia, E. G.; France, T. D.; Opitz, J. M.: Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited. Z. Kinderheilk. 120: 1-18, 1975. PubMed ID: 1172332 Read more about Megalocornea
Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhäuser Syndrome and Central Corneal Thickness Davidson AE, Cheong SS, Hysi PG, Venturini C, Plagnol V, Ruddle JB, Ali H, Carnt N, Gardner JC, Hassan H, Gade E, Kearns L, Jelsig AM, Restori M, Webb TR, Laws D, Cosgrove M, Hertz JM, Russell-Eggitt I, Pilz DT, Hammond CJ, Tuft SJ, Hardcastle AJ. Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhauser Syndrome and Central Corneal Thickness. PLoS One. 2014 Aug 5. PubMed ID: 25093588
X-Linked Megalocornea Caused by Mutations in CHRDL1 Identifies an Essential Role for Ventroptin in Anterior Segment Development Webb TR, Matarin M, Gardner JC, Kelberman D, Hassan H, Ang W, Michaelides M, Ruddle JB, Pennell CE, Yazar S, Khor CC, Aung T, Yogarajah M, Robson AG, Holder GE, Cheetham ME, Traboulsi EI, Moore AT, Sowden JC, Sisodiya SM, Mackey DA, Tuft SJ, Hardcastle AJ. X-Linked Megalocornea Caused by Mutations in CHRDL1 Identifies an Essential Role for Ventroptin in Anterior Segment Development. Am J Hum Genet. 2012 Jan 24. [Epub ahead of print]. PubMed ID: 22284829
Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma - a distinct phenotype caused by recessive LTBP2 mutations Khan AO, Aldahmesh MA, Alkuraya FS. Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma - a distinct phenotype caused by recessive LTBP2 mutations. Mol Vis. 2011;17:2570-9. PubMed ID: 22025892
Description of X-linked megalocornea with identification of the gene locus Mackey, D. A.; Buttery, R. G.; Wise, G. M.; Denton, M. J. : Description of X-linked megalocornea with identification of the gene locus. Arch. Ophthal. 109: 829-833, 1991. PubMed ID: 2043071
X-linked megalocornea: close linkage to DXS87 and DXS94 Chen, J. D.; Mackey, D.; Fuller, H.; Serravalle, S.; Olsson, J.; Denton, M. J. : X-linked megalocornea: close linkage to DXS87 and DXS94. Hum. Genet. 83: 292-294, 1989. PubMed ID: 2571565
Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited Neuhauser, G.; Kaveggia, E. G.; France, T. D.; Opitz, J. M.: Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited. Z. Kinderheilk. 120: 1-18, 1975. PubMed ID: 1172332
Nystagmus 1, Congenital, X-linked Clinical CharacteristicsOcular Features: Congenital nystagmus is a feature of numerous ocular and systemic disorders. Isolated idiopathic congenital nystagmus (CN), however, refers to a diverse group of abnormal eye movements which are identified usually in the first 6 months of life when no other ocular abnormalities are present. Horizontal eye movements are typical, but vertical and rotary eye movements have also been reported. If the nystagmus is horizontal, the eye movement is usually "to-and-fro". In general, as the patient gets older, the amplitude of the nystagmus decreases and the frequency of the nystagmus increases, particularly when the patient tries to fixate or look directly at an object. This nystagmus can increase in size and frequency when the patient is tired, sick, or fatigued. Some very young patients are noted to have head nodding or head shaking, but these usually disappear over time. Vision is reduced and varies through the day. Balance may also be affected. Many patients have a "null point" where the eye movement is reduced and vision is improved. They may alter their head position in an effort to maximize their acuity. Strabismus and amblyopia often develop. Systemic Features: No consistent systemic abnormalities have been reported. GeneticsDifferent heritable patterns of idiopathic congenital nystagmus, including autosomal dominant and recessive, and X-linked recessive, have been found. A variety of mutations in the FRMD7 (Xq26.2) gene (containing 12 exons) have been identified in many families with an X-linked recessive pattern. Another mutation associated with X-linked congenital nystagmus is GPR143 at Xp22.3 causing NYS6 (300814). A locus at Xp11.4-p11.3 contains an as yet unknown mutation responsible for an infantile periodic alternating type: NYS5 (300589). Several autosomal dominant forms have been linked to chromosomal regions 6p12 (NYS2; 164100), 7p11 (NYS3, 608345), 13q (NYS4, 193003), 1q31.3-q32.1, and NYS7 (614826). Autosomal recessive inheritance has been proposed for several pedigrees but adequate documentation is lacking (see 257400). Pedigree: Autosomal dominantAutosomal recessiveX-linked recessive, carrier motherX-linked recessive, father affectedTreatmentTreatment Options: Congenital nystagmus cannot be cured. However, several treatments may be beneficial. Glasses and contact lenses, and, occasionally, extraocular muscle surgery may be helpful. The latter should be considered especially when patients adopt a consistent head position for best vision. This avoids long-term secondary changes in neck muscles and many individuals experience an improvement of two or more lines in visual acuity. Low vision aids should be offered. ReferencesArticle Title: Incidence and Types of Pediatric Nystagmus Nash DL, Diehl NN, Mohney BG. Incidence and Types of Pediatric Nystagmus. Am J Ophthalmol. 2017 Jul 19. pii: S0002-9394(17)30301-X. doi: 10.1016/j.ajo.2017.07.006. [Epub ahead of print]. PubMed ID: 28734813 Confirmation and refinement of an autosomal dominant congenital motor nystagmus locus in chromosome 1q31.3-q32.1 Li L, Xiao X, Yi C, Jiao X, Guo X, Hejtmancik JF, Zhang Q. Confirmation and refinement of an autosomal dominant congenital motor nystagmus locus in chromosome 1q31.3-q32.1. J Hum Genet. 2012 Aug 23. [Epub ahead of print] PubMed PMID: 22914672. PubMed ID: 22914672 Infantile nystagmus: current concepts in diagnosis and management Abel, L.A.: Infantile nystagmus: current concepts in diagnosis and management. Clin. Exp. Optom. 89: 57-65, 2006. PubMed ID: 16494607 The molecular genetics of congenital idiopathic nystagmus Self, J., and Lotery, A.: The molecular genetics of congenital idiopathic nystagmus. Semin. Ophthalmol. 21: 87-90, 2006. PubMed ID: 16702075 Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus Tarpey, P., Thomas, S., Sarvananthan, N., Mallya, U., Lisgo, S., Talbot, C.J., Roberts, E.O., Awan, M., Surendran, M., McLean, R.J., Reinecke, R.D., Langmann, A., et al.: Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus. Nature Genet. 38: 1242-1244, 2006. PubMed ID: 17013395 X-linked infantile periodic alternating nystagmus Hertle, R.W., Yang, D., Kelly, K., Hill, V.M., and Seward, A.: X-linked infantile periodic alternating nystagmus. Ophthal. Genet. 26: 77-84, 2005. PubMed ID: 16020310 Read more about Nystagmus 1, Congenital, X-linked
Incidence and Types of Pediatric Nystagmus Nash DL, Diehl NN, Mohney BG. Incidence and Types of Pediatric Nystagmus. Am J Ophthalmol. 2017 Jul 19. pii: S0002-9394(17)30301-X. doi: 10.1016/j.ajo.2017.07.006. [Epub ahead of print]. PubMed ID: 28734813
Confirmation and refinement of an autosomal dominant congenital motor nystagmus locus in chromosome 1q31.3-q32.1 Li L, Xiao X, Yi C, Jiao X, Guo X, Hejtmancik JF, Zhang Q. Confirmation and refinement of an autosomal dominant congenital motor nystagmus locus in chromosome 1q31.3-q32.1. J Hum Genet. 2012 Aug 23. [Epub ahead of print] PubMed PMID: 22914672. PubMed ID: 22914672
Infantile nystagmus: current concepts in diagnosis and management Abel, L.A.: Infantile nystagmus: current concepts in diagnosis and management. Clin. Exp. Optom. 89: 57-65, 2006. PubMed ID: 16494607
The molecular genetics of congenital idiopathic nystagmus Self, J., and Lotery, A.: The molecular genetics of congenital idiopathic nystagmus. Semin. Ophthalmol. 21: 87-90, 2006. PubMed ID: 16702075
Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus Tarpey, P., Thomas, S., Sarvananthan, N., Mallya, U., Lisgo, S., Talbot, C.J., Roberts, E.O., Awan, M., Surendran, M., McLean, R.J., Reinecke, R.D., Langmann, A., et al.: Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus. Nature Genet. 38: 1242-1244, 2006. PubMed ID: 17013395
X-linked infantile periodic alternating nystagmus Hertle, R.W., Yang, D., Kelly, K., Hill, V.M., and Seward, A.: X-linked infantile periodic alternating nystagmus. Ophthal. Genet. 26: 77-84, 2005. PubMed ID: 16020310