Inherited Retinal Diseases (IRD)

Inherited retinal diseases (IRDs) are a group of clinically and genetically heterogeneous diseases, which cause visual loss due to improper development or premature death of the retinal photoreceptors. IRDs affect individuals of all ages, with different IRDs progressing at different rates. Many IRDs are degenerative, getting worse over time and causing severe vision loss or even blindness.

Electrophysiology (ffERG, mfERG, PERG, PhNR, EOG) responses are objective measures of retinal function and assist in accurately differentiating between IRDs as well as judging the severity of the specific IRD2. The information from these tests can also assist with counseling and developing life management skills. In addition, ERG and the psychophysical tests (DA and FST) assist with gene therapy trials that may improve outcomes for people born with an IRD.

 

References

Prokofyeva E Troeger E, Zrenner E. The special electrophysiological signs of inherited retinal dystrophies. The Open Ophthalmology Journal, 2012;6: 86-97.

Robson AG, Nilsson J, Li S, et al. ISCEV guide to visual electrodiagnostic procedures. Springer 2018;136:1-26.
Roman AJ, Cideciyan AV, Aleman TS, Jacobson SG. Full-field stimulus testing (FST) to quantify visual perception in severely blind candidates for clinical trials. Physiol. Meas. 28 (2007) N51–N56.

Sharon D, Ben-Yosef T, Goldenberg-Cohen N, et al. A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC). Human Mutation 2020;41:140-149.

 

Bestrophinopathies

Bestrophinopathies are a recognizable phenotype of degenerative eye diseases caused by inherited mutations in the BEST1 gene, including Best vitelliform macular dystrophy (BVMD), initially known as Best’s Disease, autosomal recessive bestrophinopathy (ARB) and autosomal dominant vitreoretinochoroidopathy (ADVIRC). BEST1 mutations may also play a role in other ophthalmic diseases like rod-cone dystrophy and early-onset cataracts.Bestrophinopathies are characterized by abnormal ocular development, which leads to impaired function in the retinal pigment epithelium (RPE) layer resulting in yellowish sub-retinal lesions. Besides the lesions, ARB patients may have hyperopia, amblyopia, angle closure glaucoma, and short axial length. Visual acuity usually begins decreasing by age 10 and progresses slowly over time. Patients with ADVIRC will often have a 360-degree peripheral retinal circumferential hyperpigmented band, punctate white opacities in the retina, retinal neovascularization, and a breakdown of the blood-retinal barrier.

All bestrophinopathies are characterized by a decreased electrooculogram (EOG) Arden ratio (light peak/dark trough). Both full-field ERG (ffERG) and multifocal ERG (mfERG) can assist in differentiating within the phenotype as well as tracking the progression of the condition.

 

References

Arden GB, Barrade A. analysis of the electro-oculograms of a series of normal subject. Role of the lens in the development of the standing potential. Brit. J. Ophthal 1962; 46:468-482.

Boon CJF, van den Born LI, Visser L, et al. Autosomal recessive bestrophinopathy. Ophthalmology 2013;120:809–820.

 

Congenital Achromatopsia

Congenital Achromatopsia is a hereditary vision disorder characterized by lack of cone vision due to malfunction of the retinal phototransduction pathway. The cone photoreceptors are unable to properly respond to a light stimulus. People with achromatopsia are partially or totally color blind. They also have poor visual acuity, photophobia, and pendular nystagmus. Currently, there are four known gene mutations that cause this disorder.There are two subtypes in this condition and both types have abnormal ERG recordings with preservation of the rod-mediated ERG. Patients with the more severe subtype show nondetectable cone function in an ERG test while patients with the less severe subtype show some residual cone function. Gene therapy studies of animal models of human achromatopsia have had some success in recovering cone function.

 

Reference

MA, Fishman GA, Rha J, et al. Photoreceptor structure and function in patients with congenital achromatopsia. Invest Ophthal Vis Sci, September 2011, Vol. 52, No. 10:7298-7308.

 

Congenital Stationary Night Blindness

Congenital Stationary Night Blindness (CSNB) is a clinically and genetically heterogeneous group of hereditary retinal disorders primarily affecting the photoreceptors, although the retinal pigment epithelium and the bipolar cells may also be affected. Types within this group differ in electrophysiological characteristics as well as fundus appearance and mode of inheritance. People with this condition typically have difficulty adapting to low light situations due to impaired photoreceptor transmission. They also have reduced acuity, mild to severe nearsightedness, nystagmus, and strabismus. While these vision problems are present at birth, they tend to remain stable over time.

The full-field ERG can assist diagnosing different forms of CSNB.

 

Reference

Sergouniotis PI, Robson AG, Li Z, et al. A phenotypic study of congenital stationary night blindness (CSNB) associated with mutations in the GRM6 gene. Acta Ophthalmol. 2012: 90: e192–e197.

 

Leber Congenital Amaurosis

Leber Congenital Amaurosis (LCA) is a group of hereditary retinal diseases causing the most severe form of IRD in which both rods and cones are either nonfunctional at birth or are lost within the first years of life. It is also the most common cause of inherited blindness in children. Profound visual impairment is usually present from birth along with abnormal or absent pupillary response. People with this condition may also have photophobia, nystagmus, strabismus, and cataracts.

In addition to vision loss in infancy and sluggish pupillary response, LCA is characterized by a severely reduced or non-detectable scotopic and photopic ERG response. Recently, the US Food and Drug Association approved a gene therapy product, voretigene neparvovec-rzyl (LUXTURNA™) by Spark Therapeutics. LUXTURNA™ treats LCA caused by bi-allelic mutations in the RPE65 gene. This drug was the first US FDA approved gene therapy product for the eye. DiagnosysFST was not only used for the clinical trial but is now also used clinically for assessing vision pre and post LUXTURNA™ treatment.

 

References

Chao DL, Burr A, Pennesi M. RPE65-related Leber congenital amaurosis / early-onset severe retinal dystrophy. 2019 Nov 14. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Ciulla TA, Hussai RM, Berrocal AM, Nagiel A. Voretigene neparvovec-rzyl for treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development. Expert Opinion on Biological Therapy
 DOI: 10.1080/14712598.2020.1740676.

Collison FT, Park JC, Fishman GA, McAnany JJ, Stone EM. Full-field pupillary light responses, luminance thresholds, and light discomfort thresholds in CEP290 Leber congenital amaurosis patients. Invest Ophthalmol Vis Sci. 2015;56:7130–7136.

Maguire AM, Russell S, Wellman JA, et al. Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutationeassociated inherited retinal dystrophy. Ophthalmology 2019;126:1273- 1285

 

Leber’s Hereditary Optic Neuropathy

Leber Hereditary Optic Neuropathy (LHON) is the most common inherited mitochondrial disorder and typically affects young males more than females. The disorder leads to degeneration of the retinal ganglion cells with painless sub acute central vision loss in one or both eyes during the young adult years. Although not classically considered an IRD because it is an optic nerve issue, LHON is still often grouped with IRDs.

A recent study has shown the PhNR amplitude is significantly decreased in people with LHON, and can distinguish carriers from controls. Treatment options are limited but include the use of antioxidant supplements. Gene therapy trials are currently underway.

 

Reference

Karanjia R, Berezovsky A, Sacai PY, et al. The photopic negative response: an objective measure of retinal ganglion cell function in patients with Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2017;58:BIO300–BIO306.

 

Retinitis Pigmentosa

Retinitis Pigmentosa (RP), also known as rod-cone degeneration, is the most common form of IRD. RP is a group of eye disorders that causes progressive vision loss as the rod photoreceptors degenerate in the early stages of the disease, followed by cone cell death. Symptoms include trouble seeing at night, decreased peripheral vision often leading to tunnel vision, and possibly even blindness. RP generally presents as night blindness in adolescence with ensuing visual field loss from early adulthood.

Full-field electroretinograms (ffERGs) assist in the diagnosis of widespread forms of retinitis pigmentosa in early life, even before fundus abnormalities visible with an ophthalmoscope are detectable. Dark adaptometry (DA) may also be useful in detecting early cases because in RP dark adaptation is usually prolonged.

 

References

Arden GB, Carter RM, Hogg CR, et al. Rod and cone activity in patients with dominantly inherited retinitis pigmentosa: comparisons between psychophysical and electroretinographic measurements. Brit J Ophthal 1983 (67) 405-418.

Berson EL. Long-term visual prognoses in patients with retinitis pigmentosa the Ludwig von Sallmann lecture. Exp Eye Res. 2007 July; 85(1):7–14.

 

Stargardt Disease

Stargardt Disease is the most common form of inherited macular degeneration. The progressive vision loss is caused by degeneration of photoreceptor cells in the macula (cones, then rods) due to abnormal accumulation of fatty yellow clumps called lipofuscin. People with Stargardt disease may also have problems with night vision and possibly with color vision. The signs and symptoms of Stargardt disease typically appear in late childhood to early adulthood and worsen over time. It is most commonly caused by mutations in the ABCA4 gene.

While there is currently no cure, research is ongoing to help minimize vision loss due to this condition. This research also includes gene therapy trials. Electroretinograms (ERGs) provide useful information to assist in counseling and life management skills. Additionally, ERGs and psychophysical tests are being used in clinical trials.

 

References

Fujinami K, Lois N, Davidson AE, Mackay DS, et al. A longitudinal study of Stargardt disease: clinical and electrophysiological assessment, progression, and genotype correlations. Am J Ophthalmol 2013; 155:1075-1088.

Sears AE, Bernstein PS, Cideciyan AV, Hoyng C, et al. Towards Treatment of Stargardt disease: workshop organized and sponsored by the Foundation Fighting Blindness. Trans Vis Sci Tech 2017; 6(5):6-17.

 

Usher Syndrome

Usher Syndrome is the most common inherited condition that causes combined progressive hearing and vision loss. Vision loss is due to retinitis pigmentosa (RP) while hearing loss is due to abnormalities within the inner ear. Newborns often have moderate to severe hearing impairment while symptoms of RP start shortly after adolescence.

Retinitis Pigmentosa (RP), also known as rod-cone degeneration, is the most common form of IRD. RP is a group of eye disorders that causes progressive vision loss as the rod photoreceptors degenerate in the early stages of the disease, followed by cone cell death. Symptoms include trouble seeing at night, decreased peripheral vision often leading to tunnel vision, and possibly even blindness. RP generally presents as night blindness in adolescence with ensuing visual field loss from early adulthood.

Full-field electroretinograms (ffERGs) assist in the diagnosis of widespread forms of retinitis pigmentosa in early life, even before fundus abnormalities visible with an ophthalmoscope are detectable. Dark adaptometry (DA) may also be useful in detecting early cases because in RP dark adaptation is usually prolonged.

 

Reference

Stingl, K., Kurtenbach, A., Hahn, G. et al. Full-field electroretinography, visual acuity and visual fields in Usher syndrome: a multicentre European study. Doc Ophthalmol 2019; 139:151–160.

 

X-linked Retinoschisis

X-linked Retinoschisis (XLRS) is an inherited disease caused by mutations in the Retinoschisin 1 gene that causes loss of central and peripheral vision characterized by abnormal splitting within the inner retinal layers. Patients may also have nystagmus, strabismus, hyperopia, foveal ectopia, hemorrhage, or retinal detachment. It is the leading cause of macular degeneration in males. Vision loss happens between 10 and 20 years of age.

The full-field ERG (ffERG) can be useful in diagnosis of XLRS because under dark adapted conditions, the b-wave amplitude can be disproportionately reduced with a preserved a-wave. This electronegative response is a common feature among XLRS patients. A recent study has discovered an abnormal pupil response in XLRS patients when tested with low to moderate flash luminance levels. In addition, the full field stimulus threshold (FST) is normal or nearly normal in XLRS. The use of multiple functional tests provides insight into the different aspects of XLRS abnormality and may be of use in future clinical trials.

 

References

Collison FT, Fishman GA. Structural and functional monitoring of extramacular cystoid spaces in a case of X-linked retinoschisis treated with acetazolamide. Retinal Cases & Brief Reports 2016; 0:1–4.

McAnany JJ, Park JC, Fishman GA, Collison FT. Full-field electroretinography, pupillometry, and luminance thresholds in X-linked retinoschisis. Invest Ophthalmol Vis Sci 2020;61(6):53. 1-9.

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