macular degeneration

Doyne Honeycomb Macular Dystrophy

Clinical Characteristics
Ocular Features: 

Beginning usually in midlife, the retina has radially localized white, large drusen in the posterior pole.  These may begin as small drusen that later enlarge and become confluent creating a honeycomb pattern.  The disease begins as an accumulation of material between the Bruch membrane and the RPE.  Eventually drusen occupy the entire thickness of the Bruch membrane and are continuous with or internal to the RPE basement membrane.  Vision early is normal and a slow loss of vision occurs sometime after the drusen appear in most individuals.  In some patients geographic atrophy, pigmentary changes, and a subfoveal neovascular net develops with macular scarring, vitreous hemorrhage, and severe reduction of vision.

Systemic Features: 

No systemic disease is associated.

Genetics

Doyne honeycomb macular disease, or dominant drusen, is the result of mutations in the EFEMP1 gene at 2p16 in the majority of cases.  It is an autosomal dominant disorder. The mutant protein product (a member of the fibulin famiy) is folded abnormally and secreted inefficiently.  It is also resistant to degradation which may lead to receptor damage by limiting access to nutrients from the choriocapillaris.  Some genetic heterogeneity may exist since a few cases seem to be linked to a locus at 6q14.    Some have considered Malattia Leventinese and Doyne honeycomb retinal dystrophy as separate entities but mutations in the same gene seem to be responsible for both conditions suggesting they are clinical variations of the same disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The subfoveal net responds to photodynamic therapy.

References
Article Title: 

Nanophthalmos with Retinopathy

Clinical Characteristics
Ocular Features: 

This is a rare syndrome consisting of a pigmentary degeneration of the retina in association with nanophthalmos.  The globe is small with a thickened choroid and sclera and the macula becomes atrophic later in life. Some patients have cystic macular changes early without fluorescein leakage.  The anterior chamber is shallow, the angle is narrow, and the cornea may be small leading to angle closure glaucoma in most patients.  Extensive anterior and posterior synechiae can be seen.  The retina has a postequatorial bone spicule pattern of pigmentation with narrowing of arterial vessels.  Hyperopia is usually present and nightblindness may be noted in the first decade of life.  The ERG early shows loss of rod function and progression of the retinal disease subsequently leads to extinction of all rod and cone responses by midlife.  The EOG may be subnormal and visual fields are severely constricted.  Pallor and crowding of the optic nerve are common.  The vitreous may contain prominent fibrils and fine white granules.  Visual acuity is often 20/200 or worse.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is likely an autosomal recessive disorder based on frequent parental consanguinity and sibships with multiple affected individuals of both sexes.  However, the first reported family in 1958 with 13 affected individuals in 4 generations suggested autosomal dominant inheritance. No molecular defect has been identified.

This may be the same disorder as microphthalmia with retinitis pigmentosa (611040) in which so far no molecular mutation has been identified. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Narrow angles with shallow anterior chamber depth should be treated with prophylactic iridotomies.

References
Article Title: 

Retinoschisis, Juvenile

Clinical Characteristics
Ocular Features: 

Retinoschisis is a retinal disorder characterized by a cystic degeneration of the retina, leading to a split of retinal layers mainly at the level of the nerve fiber layer. Almost all patients have macular involvement, most commonly with foveal spoke-like streaks consisting of microcystic cavities that may coalesce over time. Retinal pigment epithelium atrophy and pigment clumping may occur.  Peripheral schisis is evident in about 50% of patients with large bullous cavities that may resolve spontaneously leaving a pigmented demarcation line. Other retinal findings are white retinal flecks, exudative retinopathy with retinal detachment, perivascular sheathing and dendritiform vessels in the periphery. Vitreous veils are commonly seen that are caused by separation of the thin inner wall of a peripheral schisis cavity and inner wall holes. Bridging vessels may rupture into the cystic cavity or the vitreous. The onset of the disorder has been detected as early as three months, but the majority of cases are five years old or older. Many present with mildly decreased vision that cannot be corrected with glasses and the diagnosis is often delayed. Visual acuity is highly variable ranging from 20/20 to 20/200, but may decline with age and with complications such as vitreous hemorrhage and macular detachment.  The disorder is also associated with axial hyperopia, posterior subcapsular cataract and strabismus. Fluorescein angiography shows minimal or no leakage as opposed to cystoid macular edema. Focal areas of vascular leakage into schisis cavity may be present as well as peripheral capillary nonperfusion. Electroretinograms exhibit a reduced b-wave and a preserved a-wave.

Systemic Features: 

No general systemic manifestations are associated with juvenile retinoschisis.

Genetics

Juvenile retinoschisis is an X-linked recessive disorder that affects mainly males. The causative mutations involve the gene RS1 located on the X chromosome at Xp22. Female carriers may have peripheral schisis amd many allelic variants have been reported.  The encoded protein retinoschisin is a secreted protein produced by photoreceptors and bipolar cells and may be involved in cell-cell adhesion or ion channel regulation.

Treatment
Treatment Options: 

There is presently no effective treatment for the disorder, but decreased vision later in life can be aided with low vision aids. Cases with posterior subcapsular cataract can be treated with cataract extraction.  Improvement in the cystic macular lesions, central foveal zone thickness, and visual acuity have been reported to benefit from topical dorzolamide treatment.

References
Article Title: 

Peripheral fundus findings in X-linked retinoschisis

Fahim AT, Ali N, Blachley T, Michaelides M. Peripheral fundus findings in X-linked retinoschisis. Br J Ophthalmol. 2017 Mar 27. pii: bjophthalmol-2016-310110. doi: 10.1136/bjophthalmol-2016-310110. [Epub ahead of print].

PubMed ID: 
28348004

X-linked retinoschisis: an update

Sikkink SK, Biswas S, Parry NR, Stanga PE, Trump D. X-linked retinoschisis: an update. J Med Genet. 2007 Apr;44(4):225-32. 2006 Dec 15.

PubMed ID: 
17172462

Macular Dystrophy, North Carolina

Clinical Characteristics
Ocular Features: 

North Carolina macular dystrophy is characterized by central macular defects that are present at birth but rarely progress. The fundus findings are highly variable and are usually more dramatic than expected from the visual acuity, which ranges from 20/40 to 20/200, with an average around 20/50. The clinical findings have been classified into different grades: In Grade I, fine drusen-like lesions at the level of the retinal pigmented epithelium are found in the central macular area. Grade II exhibits central confluent drusen with or without pigmentary changes, retinal pigment epithelium atrophy, disciform scar formation or neovascularization. Grade III is characterized by a well-delineated chorioretinal degeneration with hyperpigmentation at the border of the lesion. A central crater-like lesion that affects all retinal layers, as well as the deep choroidal tissue, is a typical finding. It is surrounded by an elevated ridge, which is 3-4 disc diameters size.  Color vision and electrophysiological testing are usually normal.

Some patients have choroidal neovascularization that may be responsive to anti-vascular endothelial growth factor treatment. 

Although first described in a 4 generation North Carolina family, it has since been found in a variety of ethnic groups and geographic locations.

Systemic Features: 

No general systemic manifestations are associated with North Carolina macular dystrophy.

Genetics

North Carolina macular dystrophy is an autosomal dominant disorder with high penetration.  One locus for the disorder, designated MCDR1 and containing a DNase 1 hypersensitivity site, has been mapped to 6q14-q16.2 and adversely impacts the retinal transcription factor gene PRDM13.  Multiple variants in this area have been identified.  However, other forms including MCDR2 (608051) resulting from mutations in PROM1 (4p15) and MCDR3 (608850) (linked to a locus at 5p13-p15) have been reported. 

The disorder was initially described in a family of Irish descent in North Carolina, and affected individuals have been identified in European, Asian and South American families as well.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

For patients with choroidal neovascularization, standard treatment for neovascularization may be used. Low vision aids can be useful for other forms of the disorder with decreased visual acuity.

References
Article Title: 

Goldmann-Favre Syndrome/ESCS

Clinical Characteristics
Ocular Features: 

Enhanced S-cone syndrome, sometimes called Goldman-Favre syndrome, is a retinal disorder characterized by increased sensitivity to blue light, night blindness from an early age, and decreased vision.  Additional features include an optically empty liquefied vitreous, progressive foveal or peripheral retinoschisis, macular cysts, chorioretinal atrophy and pigmentary retinopathy as well as posterior subcapsular cataract formation.  Hyperopia is a feature, at least in childhood.   Enhanced S-cone syndrome is the only retinal disorder that has a gain of a subtype of photoreceptors, in this case the S-cones (short wave length) that detect blue light. Rod photoreceptors and red and green cone receptors are degenerated to a variable degree. Electroretinography shows an extinct rod photoreceptor response and hypersensitivity to shorter wavelengths.

There is considerable variation in the clinical features of NR2E3 mutations which has led to some confusion in the nosology.  Some cases are called juvenile retinoschisis, others are called retinitis pigmentosa, or clumped pigment retinopathy.  Central acuity ranges from near normal (20/40) in young people to 20/200 or worse especially in older adults.  Visual field constriction likewise varies from patient to patient.  Retinal pigmentary changes and the amount of cystic changes in the macula are somewhat age dependent.

Systemic Features: 

No general systemic manifestations are associated with enhanced S-cone syndrome and Goldman-Favre syndrome.

Genetics

This is an autosomal recessive retinal disorder caused by mutations in NR2E3, also known as PNR, located on chromosome 15q23.  It is a part of a transcription factor complex necessary for the development of photoreceptors.  Mutations in NR2E3 cause degeneration of rod photoreceptors and an increased number of S-cone photoreceptors resulting in an increased ratio of blue to red-green cone photoreceptors. Mutations in the NR2E3 gene can also cause a clinical picture resembling simple autosomal recessive retinitis pigmentosa.

Two brothers with an enhanced S-cone phenotype and normal rod function have been reported.  Scotopic b-wave ERG amplitudes were normal but OCT showed flattening of the macular area and thinning of the photoreceptor layer.  This may be the result of a different mutation in this family but no molecular defect was found.

Several Moroccan families have been reported with homozygous or compound heterozygous mutations in the NRL gene (162080).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is presently no effective treatment for the disorder, but visual function can be improved with low vision aids. Cataract surgery may be beneficial.

Improvement in vision has been reported with the use of topical carbonic anhydrase inhibitors.

References
Article Title: 

Expanded Clinical Spectrum of Enhanced S-Cone Syndrome

Yzer S, Barbazetto I, Allikmets R, van Schooneveld MJ, Bergen A, Tsang SH, Jacobson SG, Yannuzzi LA. Expanded Clinical Spectrum of Enhanced S-Cone Syndrome. JAMA Ophthalmol. 2013 Aug 29.  [Epub ahead of print] PubMed PMID: 23989059.

PubMed ID: 
23989059

Phenotypic variation in enhanced S-cone syndrome

Audo I, Michaelides M, Robson AG, Hawlina M, Vaclavik V, Sandbach JM, Neveu MM, Hogg CR, Hunt DM, Moore AT, Bird AC, Webster AR, Holder GE. Phenotypic variation in enhanced S-cone syndrome. Invest Ophthalmol Vis Sci. 2008 May;49(5):2082-93.

PubMed ID: 
18436841

Macular Dystrophy, Vitelliform 2

Clinical Characteristics
Ocular Features: 

Best disease primarily affects the macular and paramacular areas.  The classical lesion resembles an egg yolk centered on the fovea.  Most patients, however, never exhibit the typical vitelliform lesion and may instead have normal maculae, or irregular yellowish deposits that may even be extrafoveal.  Histologically the RPE contains increased amounts of lipofuscin.  The ‘egg yolk’ is located beneath the neurosensory retina and the overlying retinal circulation often remains intact.  It can evolve into a ‘scrambled egg’ appearance and an apparent fluid level may be evident.  Some patients exhibit only RPE changes including hyper-  or hypopigmentation throughout the macula.  Choroidal neovasculariztion with hemorrhage leading to scarring and gliosis are uncommon but present a serious risk to vision.  The common end point for symptomatic patients is some degree of photoreceptor damage.

Until recently, most reports of Best macular dystrophy did not include genotypic data.  It is therefore difficult to classify families with variants of the disease, such as adult-onset or atypical vitelliform dystrophy but these at least suggest that this may be a heterogeneous disorder.  At the present time, the diagnosis should be reserved for those with an abnormal light-to-dark (Arden) ratio on electro-oculography and a mutation in the BEST1 gene. 

Visual function varies widely and has considerable fluctuation.   As many as 7-9 percent of patients are asymptomatic throughout life and few have vision loss to 20/200.  Many individuals maintain vision of 20/40 or better throughout life.  Some experience episodic acute vision loss to 20/80 or worse but often recover to at least 20/30.  It has been reported that as many as 76 per cent under the age of 40 retain 20/40 and 30 per cent retain this level of vision into the 5th and 6th decade of life.

Other ocular manifestations include hyperopia, esotropia, and, rarely, shallow anterior chambers with angle closure glaucoma.

Systemic Features: 

None have been reported.

Genetics

A mutation in the bestrophin gene (BEST1) located on chromosome 11 (11q13) is responsible for the disease in most patients.  Best disease is usually transmitted in an autosomal dominant pattern from parent to offspring.  A large number of mutations have been found in the BEST1 gene but so far no correlation with severity of disease is possible.  In fact, there is a great deal of clinical variation within families having identical mutations resembling that of the variation found among different mutations.

Several families have also been reported with autosomal recessive inheritance.  Affected offspring had homozygous mutations in the bestrophin gene with reduced light/dark responses and vision loss.  Some have atypical vitelliform retinal and sometimes multifocal lesions.  They may develop angle closure glaucoma.  Their heterozygous parents  have either normal or abnormal EOGs and no visible fundus disease.  So far no families with presumed recessive inheritance of Best macular dystrophy have demonstrated parent-to-child transmission of typical vitelliform lesions.

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease described here we know of at least four more variants and specific mutations have been identified in three.  No mutation or locus has yet been identified in VMD1 (153840) but it is likely a unique condition since mutations in other genes known to cause vitelliform dystrophy have been ruled out.  Other forms are VMD3 (608161) due to mutations in the PRPH2 gene, VMD4 (616151) resulting from mutations in the IMPG1 gene, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Autosomal dominant vitreoretinochoroidopathy (193220) is an allelic disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

None known for disease.  Subretinal neovascularization may benefit from ablation treatments.

References
Article Title: 

Mutations in IMPG1 Cause Vitelliform Macular Dystrophies. Am

Manes G, Meunier I, Avila-Fern?degndez A, Banfi S, Le Meur G, Zanlonghi X, Corton M, Simonelli F, Brabet P, Labesse G, Audo I, Mohand-Said S, Zeitz C, Sahel JA, Weber M, Dollfus H, Dhaenens CM, Allorge D, De Baere E, Koenekoop RK, Kohl S, Cremers FP, Hollyfield JG, S?(c)n?(c)chal A, Hebrard M, Bocquet B, Garc??a CA, Hamel CP. Mutations in IMPG1 Cause Vitelliform Macular Dystrophies. Am J Hum Genet. 2013 Aug 29. [Epub ahead of print] PubMed PMID: 23993198.

PubMed ID: 
23993198

Biallelic mutation of BEST1 causes a distinct retinopathy in humans

Burgess R, Millar ID, Leroy BP, Urquhart JE, Fearon IM, De Baere E, Brown PD, Robson AG, Wright GA, Kestelyn P, Holder GE, Webster AR, Manson FD, Black GC. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet. 2008 Jan;82(1):19-31. PubMed PMID: 18179881

PubMed ID: 
18179881

Identification of the gene responsible for Best macular dystrophy

Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AA, McGarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT, Wadelius C. Identification of the gene responsible for Best macular dystrophy. Nat Genet. 1998 Jul;19(3):241-7.

PubMed ID: 
9662395

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