night blindness

Nanophthalmos Plus Syndrome

Clinical Characteristics
Ocular Features: 

This is a recently described type of nanophthalmos with characteristic clinical features plus retinal degeneration and optic disc drusen.  Hyperopia is common and, like another recessive form of nanophthalmos (267760), patients have a progressive retinal dystrophy beginning with granular and mottled RPE changes and progressing to a bone spicule pattern resembling retinitis pigmentosa.  No synechiae have been reported in this syndrome however.  Macular retinoschisis and cystic changes with reduced foveal reflexes are commonly present.  The anterior chamber and angles are narrow but no reported cases have had angle closure glaucoma such as frequently occurs in other forms of nanophthalmos (267760, 609549, 600165, 611897).  Drusen of the optic nerve head can be demonstrated by ultrasound.  Scleral and choroidal thickening are usually present.  There is progressive deterioration of photoreceptors beginning with rod dysfunction and eventually involving cones as documented on ERG recordings.  Nyctalopia and visual difficulties begin in childhood and the visual field is concentrically constricted.  Visual acuity is in the range of 20/100 to 20/200.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal recessive disorder caused by mutations in the membrane frizzled-related protein coding gene MFRP (11q23) expressed in retinal tissue.  Both homozygous and compound heterozygous mutations have been described.  It seems to be allelic to another nanophthalmos condition without retinal pigmentary degeneration which is caused by different mutations in MFRP (NNO2 609549).  However, there is considerable clinical overlap of the several nanophthalmos conditions and it is possible that this is simply clinical heterogeneity within the same disease.

A syndromic form (MCOP5) of autosomal recessive microphthalmia with retinitis pigmentosa (611040) is also caused by mutations in MFRP and may be the same disorder.

For other forms of nanophthalmos see:  267760, 609549, 600165, 611897.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Angle closure glaucoma is a constant threat in some nanophthalmic conditions but has not been reported in this disorder.  Nevertheless, it may be prudent to consider prophylactic iridotomies in high risk cases.

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: 

Wagner Syndrome

Clinical Characteristics
Ocular Features: 

This is one of several hereditary vitreoretinal degenerative disorders in which vitreous degeneration occurs and the risk of retinal detachment is high (others being Goldmann-Favre [268100], Stickler [609508, 108300], and Marshall [154780] syndromes).  An optically empty central vitreous is a common feature in this heterogeneous group.  Other reported ocular findings in Wagner syndrome include perivascular sheathing and pigmentation, progressive chorioretinal dystrophy, ectopic fovea with pseudoexotropia, tractional retinal detachments, glaucoma (neovascular in some), and vitreous veils with fibrillar condensation.  Cataracts occur in virtually all patients over the age of 45 years.  The ERG in the majority of patients shows elevated rod and cone thresholds on dark adaptation (63%) and subnormal b-wave amplitudes (87%).  Mild difficulties in dim light are noted by some patients.  Visual acuities are highly variable ranging from normal in many patients to blindness in others.  Peripheral visual fields may be severely constricted.

Systemic Features: 

Cleft palate has been seen in some patients but these likely had Stickler syndrome (609508, 108300, 604841 ) since hearing loss along with other joint and skeletal manifestations are absent.  Further, cases reported to have Wagner syndrome with palatoschisis have not been genotyped so it is likely that they were misdiagnosed.

Genetics

Wagner syndrome results from a mutation in the VCAN gene encoding versican (5q14.3), a chondroitin sulfate proteoglycan-2 found in the vitreous among other tissues.  It is an autosomal dominant disorder.  It has been proposed that erosive vitreoretinopathy (ERVR) (143200) is allelic to Wagner’s syndrome but it may also simply be a variable expression of the same disorder.  Both map to 5q13-q14.  Overlapping of clinical signs and symptoms among hereditary disorders of vitreoretinal degeneration has created some confusion in their classification but this will hopefully be clarified as more families are genotyped.  Stickler syndrome (609508, 108300), for example, is known to be caused by a mutation in an entirely different gene (COL2A1) on a different chromosome.

Snowflake type vitreoretinal degeneration (193230), another autosomal dominant disorder, has a superficial resemblance but mutations in a different gene (KCNJ13) are responsible.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no therapy specifically for this disorder but the usual treatments for retinal detachments, cataract and glaucoma should be applied where appropriate.

References
Article Title: 

Abetalipoproteinemia

Clinical Characteristics
Ocular Features: 

The major ocular manifestations of abetalipoproteinemia are in the retina which develops diffuse and sometimes patchy pigmentary changes often called atypical retinitis pigmentosa.  In other cases the picture resembles retinitis punctata albescens with perivascular white spots in the peripheral retina.  Night blindness is an early and prominent symptom with abnormal dark adaptation thresholds evident before fundus pigment changes are seen.  The ERG shows loss of rod function before that of cone function.  The macula may or may not be affected while peripheral fields are often severely constricted.  Loss of photoreceptors occurs throughout life and visual fields show progressive constriction, sometimes with central sparing.  A single case of bilateral disc swelling in a 9 year-old girl has been reported.

Systemic Features: 

Celiac disease and steatorrhea due to a deficiency of circulating chylomicra underlie the malabsorption of vitamins A and E which is probably responsible for the majority of systemic manifestations.  Red blood cells have a peculiar burr-like morphology that has led to the designation 'acanthocytes'.  Liver failure and cirrhosis sometimes occur.  Plasma lipids are generally low including cholesterol, triglycerides, and beta lipoproteins.  Central and peripheral nerve demyelination occurs leading to a progressive ataxia and other neurological symptoms.

Genetics

This autosomal recessive disease seems to result from an inability to synthesize the apoB peptide that is a part of the LDL and VLDL.   A mutation in MTTP (4q22-q24) results in a defect in micosomal triglyceride transfer protein.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with vitamins A and E may be beneficial.  Cone function improves before rod function with massive doses of vitamin A but usually only after months of treatment.  It has been reported that Vitamin A alone without vitamin E is insufficient to arrest the retinal disease.

References
Article Title: 

Cohen Syndrome

Clinical Characteristics
Ocular Features: 

Patients have early onset night blindness with defective dark adaptation and corresponding ERG abnormalities.  Visual fields are constricted peripherally and central visual acuity is variably reduced.  A pigmentary retinopathy is often associated with a bull’s eye maculopathy. The retinopathy is progressive as is high myopia.  The eyebrows and eyelashes are long and thick and the eyelids are highly arched and often ‘wave-shaped’.  Congenital ptosis, optic atrophy, and ectopia lentis have also been reported.

Systemic Features: 

Affected individuals have a characteristic facial dysmorphism in which ocular features play a role.  They have a low hairline, a prominent nasal root, and a short philtrum.  The tip of the nose appears bulbous. The head circumference is usually normal at birth but lags behind in growth so that older individuals appear microcephalic.  Delays in developmental milestones are noticeable in the first year of life.  Mild to moderate mental retardation is characteristic but does not progress.  Hypotonia is common early, and many individuals are short in stature.  Low white counts and frank neutropenia are often seen and some patients have frequent infections, especially of the oral mucosa and the respiratory tract.  A cheerful disposition is said to be characteristic.

Genetics

This is an autosomal recessive disorder caused by a mutation in the COH1 (VPS13B) gene on chromosome 8 (8q22-q23).  However, a variety of mutations have been reported including deletions and missense substitutions and, since these are scattered throughout the gene, complete sequencing is necessary before a negative result can be confirmed.

There is evidence of significant clinical heterogeneity between cohorts descended from different founder mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Corrective lenses for myopia can be helpful.  For patients with sufficient vision, low vision aids can be helpful.  Selected individuals may benefit from vocational and speech therapy.  Infections should be treated promptly.

References
Article Title: 

Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport

Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Tr?SSskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns JP, de la Chapelle A, Lehesjoki AE. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet. 2003 Jun;72(6):1359-69.

PubMed ID: 
12730828

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 called the photoreceptor-specific nuclear receptor, 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 mcaular 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.

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

Sorsby Pseudoinflammatory Fundus Dystrophy

Clinical Characteristics
Ocular Features: 

Sorsby Pseudoinflammatroy Fundus Dystrophy is characterized by progressive degeneration of the central macula of the retina with edema, hemorrhages and exudates with pigment changes.  The onset is typically in the second to fourth decade with development of a disciform central macular atrophy with white and yellow spots (not drusen).  This is followed by subretinal neovascular membranes in the majority of patients.  Further degeneration occurs over years and can spread from the center to the periphery of the retina with a corresponding visual field defect.  Night blindness or difficulties adapting to changes in light intensity may be noted before the central macular degeneration occurs.  In histopathologic studies, a subretinal deposit can be observed in Bruchs membrane.

Systemic Features: 

No general systemic manifestations are associated with Sorsby Pseudoinflammatory Fundus Dystrophy.

Genetics

Sorsby Pseudoinflammatory Fundus Dystrophy is an autosomal dominant disorder, caused by mutations in the TIMP3 gene, located at 22q12.1-q13.2.  Evidence for a separate recessive form (264420) is somewhat refuted by the fact that genotyping found heterozygosity of the TIMP3 mutation in some families.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

In patients with early stages of the disease, a daily dose of 50,000 IU Vitamin A given by mouth has been shown to reverse the symptoms of night blindness.  Treatment with anti-angiogenic agents or steroids has shown improvement in visual acuity in some patients. Patients with decreased vision may find benefit with low vision aids.

References
Article Title: 

Sorsby's fundus dystrophy

Hamilton WK, Ewing CC, Ives EJ, Carruthers JD. Sorsby's fundus dystrophy. Ophthalmology 1989 Dec;96(12):1755-62.

PubMed ID: 
2695876

Choroideremia

Clinical Characteristics
Ocular 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 carries 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.

Genetics

Choroideremia 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.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

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

Recent early trials using adeno-associated viral vectors containing DNA coding the REP1 protein have documented improved rod and cone function in 6 affected males.

References
Article Title: 

Optical

Jain N, Jia Y, Gao SS, Zhang X, Weleber RG, Huang D, Pennesi ME. Optical
Coherence Tomography Angiography in Choroideremia: Correlating Choriocapillaris
Loss With Overlying Degeneration
. JAMA Ophthalmol. 2016 May 5. doi:
10.1001/jamaophthalmol.2016.0874. [Epub ahead of print].

PubMed ID: 
27149258

Gyrate Atrophy

Clinical Characteristics
Ocular Features: 

Gyrate atrophy is characterized by night blindness, myopia, and multiple round islands of peripheral chorioretinal degeneration which often appear in the first decade of life, sometimes as early as five years of age. Night blindness often begins in late childhood. The atrophic areas slowly progress to the posterior pole and may eventually affect central vision. Both eyes are usually symmetrically affected. All patients have myopia, some with refractive errors ranging up to -20 D. Fluorescein angiography shows hyperfluorescent at the edges of the peripheral atrophy. A zone of pigmentary changes can be seen between normal and atrophic areas.  The electroretinogram may show reduced rod and cone responses with rods affected more than cones in early phases. Dark-adapted ERG documents elevated rod thresholds.  Swollen mitochondria have been described in photoreceptors, corneal epithelium, and in the nonpigmented ciliary epithelium.  Elevated levels of ornithine are found in plasma, urine, spinal fluid and aqueous humor.  Macular edema is commonly present and posterior subcapsular cataracts requiring surgery are common.

Systemic Features: 

Mild muscle weakness may occur due to tubular aggregates in type 2 muscle fibers, which can be visualized with electron microscopy and may lead to loss of these fibers and muscle wasting. Fine, straight hairs have been observed with patches of alopecia. Slow wave background changes on EEG have been described in about one-third of patients and peripheral neuropathy is sometimes a feature.  Hearing loss has been described as well. Some newborns have hyperamonnemia but once treated usually does not recur.

Genetics

Gyrate atrophy is an autosomal recessive disorder, caused by mutations in the OAT (ornithine aminotransferase) gene on chromosome 10 (10q26).  The enzyme is part of a nuclear-encoded mitochondrial matrix complex.  Many allelic variants have been found.  A large number of affected patients of Finnish origin, most of who share the common L402P mutation, have been described.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A low protein and especially an arginine-restricted diet have been shown to slow loss of function as measured by ERG and visual field changes.
 

References
Article Title: 

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