night blindness

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.

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

Nasr MB, Symeonidis C, Mikropoulos DG, Kozeis N, Tsinopoulos I, Dimitrakos SA, Konstas AG. Disc swelling in abetalipoproteinemia: a novel feature of Bassen-Kornzweig syndrome. Eur J Ophthalmol. 2011 Sep-Oct;21(5):674-6.

PubMed ID: 
21484752
PubMed ID: 

Runge P, Muller DP, McAllister J, Calver D, Lloyd JK, Taylor D. Oral vitamin E supplements can prevent the retinopathy of abetalipoproteinaemia. Br J Ophthalmol. 1986 Mar;70(3):166-73.

PubMed ID: 
3954973

Gouras P, Carr RE, Gunkel RD. Retinitis pigmentosa in abetalipoproteinemia: Effects of vitamin A. Invest Ophthalmol. 1971 Oct;10(10):784-93.

PubMed ID: 
5124019

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.

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

Taban M, Memoracion-Peralta DS, Wang H, Al-Gazali LI, Traboulsi EI. Cohen syndrome: report of nine cases and review of the literature, with emphasis on ophthalmic features. J AAPOS. 2007 Oct;11(5):431-7.

PubMed ID: 
17383910

Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Träskelin 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

van de Kamp JJ, Niermeijer MF, von Figura K, Giesberts MA. Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C). Clin Genet. 1981 Aug;20(2):152-60.

PubMed ID: 
6796310

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.  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 are increased in number. 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.

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.

References

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

Kinori M, Pras E, Kolker A, Ferman-Attar G, Moroz I, Moisseiev J, Bandah-Rozenfeld D, Mizrahi-Meissonnier L, Sharon D, Rotenstreich Y. Enhanced S-cone function with preserved rod function: a new clinical phenotype. Mol Vis. 2011;17:2241-7. Epub 2011 Aug 18.

PubMed ID: 
21897746

Haider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, Beck G, Hockey R, Hanna DB, Gorman S, Duhl D, Carmi R, Bennett J, Weleber RG, Fishman GA, Wright AF, Stone EM, Sheffield VC. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet. 2000 Feb;24(2):127-31.

PubMed ID: 
10655056

Schorderet DF, Escher P. NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP). Hum Mutat. 2009 Nov;30(11):1475-85.

PubMed ID: 
19718767

Pachydaki SI, Klaver CC, Barbazetto IA, Roy MS, Gouras P, Allikmets R, Yannuzzi LA. Phenotypic features of patients with NR2E3 mutations. Hum Mutat. 2009 Mar;30(3):342-51.

PubMed ID: 
19139342

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.

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

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

PubMed ID: 
2695876

Michaelides M, Hunt DM, Moore AT. The genetics of inherited macular dystrophies. J Med Genet. 2003 Sep;40(9):641-50.

PubMed ID: 
12960208

Jacobson SG, Cideciyan AV, Regunath G, Rodriguez FJ, Vandenburgh K, Sheffield VC, Stone EM. Night blindness in Sorsby’s Fundus dystrophy reversed by vitamin A. Nat Genet 1995;11:27–32.

PubMed ID: 
7550309

Weber, B. H. F., Vogt, G., Pruett, R. C., Stohr, H., Felbor, U. Mutations in the tissue inhibitor metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nature Genet. 8: 352-356, 1994.

PubMed ID: 
7894485

Felbor U, Suvanto EA, Forsius HR, Eriksson AW, Weber BH. Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance. Am J Hum Genet. 1997 Jan;60(1):57-62.

PubMed ID: 
8981947

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.

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

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

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

Coussa RG, Traboulsi EI. Choroideremia: A review of general findings and pathogenesis. Ophthalmic Genet. 33:57-65, 2011.

PubMed ID: 
22017263

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

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

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

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.

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

Kaiser-Kupfer MI, Caruso RC, Valle D, Reed GF. Use of an arginine-restricted
diet to slow progression of visual loss in patients with gyrate atrophy. Arch
Ophthalmol. 2004 Jul;122(7):982-4.

PubMed ID: 
15249361

Potter MJ, Berson EL. Diagnosis and treatment of gyrate atrophy. Int
Ophthalmol Clin. 1993 Spring;33(2):229-36. Review.

PubMed ID: 
8325736

Weleber RG, Kurz DE, Trzupek KM. Treatment of retinal and choroidal
degenerations and dystrophies: current status and prospects for gene-based
therapy. Ophthalmol Clin North Am. 2003 Dec;16(4):583-93, vii. Review.

PubMed ID: 
14740999

Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, Robert MF,
Sipila I, Kaiser-Kupfer M, Valle D. Ornithine delta-aminotransferase mutations in
gyrate atrophy. Allelic heterogeneity and functional consequences.
J Biol Chem.
1992 Feb 15;267(5):3302-7.

PubMed ID: 
1737786