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.

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

Zenteno JC, Buentello-Volante B, Quiroz-Gonzalez MA, Quiroz-Reyes MA. Compound heterozygosity for a novel and a recurrent MFRP gene mutation in a family with the nanophthalmos-retinitis pigmentosa complex. Mol Vis. 2009 Sep 5;15:1794-8.

PubMed ID: 
19753314

Crespi J, Buil JA, Bassaganyas F, Vela-Segarra JI, Diaz-Cascajosa J, Ayala-Ramirez R, Zenteno JC. A novel mutation confirms MFRP as the gene causing the syndrome of nanophthalmos-renititis pigmentosa-foveoschisis-optic disk drusen. Am J Ophthalmol. 2008 Aug;146(2):323-328.

PubMed ID: 
18554571

Ayala-Ramirez R, Graue-Wiechers F, Robredo V, Amato-Almanza M, Horta-Diez I, Zenteno JC. A new autosomal recessive syndrome consisting of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is caused by a MFRP gene mutation. Mol Vis. 2006 Dec 4;12:1483-9.

PubMed ID: 
17167404

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. 

Treatment Options

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

References

MacKay CJ, Shek MS, Carr RE, Yanuzzi LA, Gouras P. Retinal degeneration with nanophthalmos, cystic macular degeneration, and angle closure glaucoma. A new recessive syndrome. Arch Ophthalmol. 1987 Mar;105(3):366-71.

PubMed ID: 
3827713

Ghose S, Sachdev MS, Kumar H. Bilateral nanophthalmos, pigmentary retinal dystrophy, and angle closure glaucoma--a new syndrome? Br J Ophthalmol. 1985 Aug;69(8):624-8.

PubMed ID: 
4016062

Mandal AK, Das T, Gothwal VK. Angle closure glaucoma in nanophthalmos and pigmentary retinal dystrophy: a rare syndrome. Indian J Ophthalmol. 2001 Dec;49(4):271-2.

PubMed ID: 
12930123

Herman P. Le syndrome microphalmie-retinite pigmentaire-glaucoma. Arch Ophthalmol 1958 18:17-24.

PubMed ID: 

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.

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

Graemiger RA, Niemeyer G, Schneeberger SA, Messmer EP. Wagner vitreoretinal degeneration. Follow-up of the original pedigree. Ophthalmology. 1995 Dec;102(12):1830-9.

PubMed ID: 
9098284

Miyamoto T, Inoue H, Sakamoto Y, Kudo E, Naito T, Mikawa T, Mikawa Y, Isashiki Y, Osabe D, Shinohara S, Shiota H, Itakura M. Identification of a novel splice site mutation of the CSPG2 gene in a Japanese family with Wagner syndrome. Invest Ophthalmol Vis Sci. 2005 Aug;46(8):2726-35.

PubMed ID: 
16043844

Ronan SM, Tran-Viet KN, Burner EL, Metlapally R, Toth CA, Young TL. Mutational hot spot potential of a novel base pair mutation of the CSPG2 gene in a family with Wagner syndrome. Arch Ophthalmol. 2009 Nov;127(11):1511-9.

PubMed ID: 
19901218

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, 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

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.  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.

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

Hull S, Arno G, Sergouniotis PI, Tiffin P, Borman AD, Chandra A, Robson AG, Holder GE, Webster AR, Moore AT. Clinical and Molecular Characterization of Enhanced S-Cone Syndrome in Children. JAMA Ophthalmol. 2014 Jul 31. [Epub ahead of print].

PubMed ID: 
25079116

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

Hajali M, Fishman GA. Dorzolamide use in the management of macular cysts in a patient with enhanced s-cone syndrome. Retin Cases Brief Rep. 2009 Spring;3(2):121-4.

PubMed ID: 
25391052

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