Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview

Neruban Kumaran; Mark E Pennesi; Paul Yang; Karmen M Trzupek; Catherine Schlechter; Anthony T Moore; Richard G Weleber; Michel Michaelides

Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview

Synonyms: EOSRD, LCA

Kumaran N, Pennesi ME, Yang P, et al.

Publication Details

Estimated reading time: 17 minutes

Summary

The purpose of this overview is to increase the clinician's awareness of Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) and its clinical phenotypes, genetic causes, and management. The following are the goals of this overview.

Goal 1.

Describe the clinical characteristics of LCA/EOSRD.

Goal 2.

Review the genetic causes of LCA/EOSRD.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of LCA/EOSRD in a proband (when possible).

Goal 4.

Inform (when possible) medical management of LCA/EOSRD based on genetic cause.

Goal 5.

Inform genetic counseling for LCA/EOSRD.

1. Clinical Characteristics of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy

Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) comprises a spectrum of inherited retinal disorders that ranges from LCA at the severe end to EOSRD at the milder end.

LCA is characterized by severe visual impairment from birth or the first few months of life, roving eye movements or nystagmus, poor pupillary light responses, oculodigital sign (poking, rubbing, and/or pressing of the eyes), and undetectable or severely abnormal full-field electroretinogram (ERG).

EOSRD is characterized by the onset of visual impairment typically after infancy but before age five years, with variably preserved visual acuity and minimally preserved full-field ERG [Kumaran et al 2017].

The fundus in LCA/EOSRD can appear normal at presentation or show a variety of retinal abnormalities including pigmentary retinopathy, white deposits at the level of the retinal pigment epithelium, vascular attenuation, or pseudopapilledema and macular atrophy. Those with a normal fundus appearance at birth usually develop pigmentary retinopathy, optic disc pallor, and vascular attenuation with time. Other late changes include optic disc drusen, keratoconus, and lens opacities. Some genetic subtypes have a characteristic retinal phenotype.

The rate of visual loss varies, and some genes have been associated with faster progression (see Table 2). Infants with severe visual impairment may also have delays or difficulties with speech, social skills, and behavior, highlighting the importance of early involvement by a developmental pediatric specialist.

Persons with LCA/EOSRD usually present with isolated ocular signs and symptoms and have manifestations that remain confined to the eye. Some infants who present with visual impairment may later develop other systemic issues, particularly kidney disease. Nephronophthisis with subsequent end-stage kidney disease can be seen with certain genetic subtypes of LCA/EOSRD (e.g., IQCB1-, IFT140-, and CEP290-associated LCA) as part of syndromes including Senior-Loken syndrome and Joubert syndrome (see Table 2). Early molecular diagnosis can help identify individuals who require systemic investigations.

Differential Diagnosis

Table 1.

Retinal Disorders to be Considered in the Differential Diagnosis of LCA/EOSRD

2. Causes of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy

To date, mutation of 24 genes accounts for 70%-80% of individuals with Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) (Table 2).

Table 2.

Leber Congenital Amaurosis (LCA) / Early-Onset Severe Retinal Dystrophy (EOSRD): Genes and Distinguishing Clinical Features

3. Evaluation Strategies to Identify the Genetic Cause of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy in a Proband

Establishing a specific genetic cause of Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD):

Can aid in discussions of prognosis (which are beyond the scope of this GeneReview) and genetic counseling and management (see Section 5);
Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.

Medical history. See Table 2.

Physical examination and other studies. See Table 2.

Family history. A three-generation family history should be taken, with attention to relatives with manifestations of LCA/EOSRD and consanguinity. Document relevant findings in relatives through direct examination or review of medical records, including results of molecular genetic testing.

Molecular genetic testing. Because LCA/EOSRD is both genetically heterogeneous and indistinguishable from many other inherited retinal dystrophies, recommended molecular genetic testing approaches include either gene-targeted testing (multigene panel) or comprehensive genomic testing (exome/genome sequencing). Gene-targeted testing, typically done using multigene panel tests, requires prior characterization of the causative gene as a "retinal dystrophy gene." Genomic testing enables the clinician to explore genes not previously known to be associated with retinal dystrophy.

Note: (1) Single-gene testing (sequence analysis of a given gene, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. (2) Single-gene sequence analysis and/or targeted deletion/duplication analysis MAY be considered if previous testing has identified a heterozygous pathogenic variant in a recessive LCA-associated gene. Of note, large deletions, insertions, and duplications very rarely account for the presumed second variant.

A multigene panel that includes some or all of the genes listed in Table 2 is most likely to identify the genetic cause of LCA/EOSRD while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of some of the genes associated with LCA/EOSRD some panels may not include all known LCA/EOSRD genes listed in Table 2. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered. Exome sequencing is most commonly used; genome sequencing is increasingly possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
Note: Unlike exome sequencing, genome sequencing can identify noncoding variants. Although most confirmed pathogenic variants identified by genome sequencing are within exons [Taylor et al 2015], likely pathogenic variants have been detected in noncoding regions of CRB1, GUCY2D, and IFT140 in individuals with inherited retinal dystrophies [Daich Varela et al 2023].
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

4. Medical Management of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Based on Genetic Cause

Management of most forms of Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) is symptomatic. The only form of LCA/EOSRD for which specific therapy (gene replacement therapy) is available is RPE65-LCA. See RPE65-Related Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy.

Visual Impairment

Symptomatic management. Affected children benefit from correction of refractive error, use of low vision aids when possible, and optimal access to educational and work-related opportunities.

Children and their parents should be referred to programs for visually impaired children within their state or locality.

Gene therapy for LCA/EOSRD. In the case of LCA, gene supplementation therapy compensates for loss-of-function variants by providing a healthy copy of the gene to cells where it is required [Kumaran et al 2018c]. Viral vectors, or more specifically recombinant adeno-associated virus (AAV) vectors, have been used in LCA clinical trials.

Subretinal gene therapy administration for LCA has been investigated most extensively in RPE65-associated LCA [Kumaran et al 2018b]. A total of five Phase I/II trials [Bainbridge et al 2008, Hauswirth et al 2008, Maguire et al 2008, Weleber et al 2016, Le Meur et al 2018] and one Phase III trial [Russell et al 2017] have shown that subretinal injection of a recombinant AAV vector containing the RPE65 cDNA can improve retinal function:

The Phase I/II clinical trials identified varied improvements in aspects of sight [Testa et al 2013, Bainbridge et al 2015, Jacobson et al 2015, Le Meur et al 2018, Pennesi et al 2018].
The Phase III trial of subretinal administration of an AAV2/2 vector has reported benefit at one year, reaching its primary end point for efficacy with improved performance on a novel test of multiluminance mobility [Russell et al 2017]. This product, voretingene neparvovec (Luxturna™, Spark Therapeutics Inc) has been approved by the FDA for the treatment of RPE65-associated retinopathy.

Following successful gene supplementation therapy in experimental models of AIPL1-, RDH12-, GUCY2D-, and RPGRIP-associated LCA, clinical trials in these subsets of LCA are likely in the future. A different technique of gene therapy utilizing antisense oligonucleotide-mediated exon skipping to abrogate the disease-causing variant has resulted in a clinical trial investigating the safety and tolerability of intravitreal injections of this type of gene therapy (ClinicalTrials.gov identifier: NCT03140969) for CEP290-associated LCA.

Developmental Delay / Intellectual Disability Management Issues

Children with LCA/EOSRD who have developmental delay should be referred to a developmental pediatrician and enrolled in a continuing program of care and support.

Advice on developmental delay / intellectual disability management issues will vary from country to country, or even region to region within a country, depending on support services available. Overarching principles should include the following:

Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers / schools for the visually impaired
Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable braille display
As affected individuals grow older, identifying further assistance (including financial or employment assistance), which in some countries is available through certification/registration processes

Some countries have registration services to record population data on the causes and effects of visual impairment.

Note: The following information represents typical management recommendations for individuals with developmental delay / intellectual disability management issues in the United States.

Motor Dysfunction

Gross motor dysfunction

Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention-deficit/hyperactivity disorder) when necessary.

5. Genetic Counseling for Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) is typically inherited in an autosomal recessive manner.

Rarely, LCA/EOSRD is inherited in an autosomal dominant manner as a result of a heterozygous pathogenic variant in CRX, OTX2, or IMPDH1.

Note: In the estimated 30% of individuals with LCA/EOSRD in whom no molecular diagnosis is found, the mode of inheritance is most likely autosomal recessive with a small likelihood of autosomal dominant inheritance resulting from a de novo pathogenic variant.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

The parents of an affected child are obligate heterozygotes (i.e., carriers of one LCA/EOSRD-causing allelic variant).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with autosomal recessive LCA/EOSRD are obligate heterozygotes (carriers) for an LCA/EOSRD-causing allelic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an LCA/EOSRD-causing allelic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the LCA/EOSRD-causing allelic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

Some children diagnosed with autosomal dominant LCA/EOSRD have an affected parent.
Most children diagnosed with autosomal dominant LCA/EOSRD have the disorder as the result of a de novo CRX, OTX2, or IMPDH1 pathogenic variant [Jacobson et al 1998, Sohocki et al 1998, Swaroop et al 1999, Rivolta et al 2001, Perrault et al 2003].
Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.

Sibs of a proband. The risk to sibs of the proband depends on the clinical/genetic status of the proband's parents:

If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known LCA/EOSRD-causing allelic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
If the parents have not been tested for the LCA/EOSRD-causing allelic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with LCA/EOSRD has a 50% chance of inheriting the LCA/EOSRD-causing allelic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members are at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the LCA/EOSRD-causing allelic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

American Council of the Blind (ACB)
2200 Wilson Boulevard
Suite 650
Arlington VA 22201
Phone: 800-424-8666 (toll-free); 202-467-5081
Fax: 202-467-5085
Email: info@acb.org
www.acb.org
Foundation Fighting Blindness
7168 Columbia Gateway Drive
Suite 100
Columbia MD 21046
Phone: 800-683-5555 (toll-free); 800-683-5551 (toll-free TDD); 410-423-0600
Email: info@fightblindness.org
www.fightingblindness.org
National Federation of the Blind
Phone: 410-659-9314
Email: nfb@nfb.org
www.nfb.org
Retina International
Ireland
Phone: 353 1 961 9259
Email: info@retina-International.org
www.retina-international.org

Chapter Notes

Author Notes

UCL Gene and Cell Therapy Group website

Casey Eye Institute Ophthalmic Genetics Service website

Acknowledgments

MM and NK are supported by grants from the National Institute for Health Research, the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, the Medical Research Council, Fight for Sight, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Wellcome Trust, the Macula Society, Retinitis Pigmentosa Fighting Blindness, and the Foundation Fighting Blindness.

MEP is supported by grants from the Foundation Fighting Blindness. Casey Eye Institute is supported by an unrestricted grant from Research to Prevent Blindness and NIH P30 EY010572 grant.

Revision History

23 March 2023 (aa/gm) Revision: Daich Varela et al [2023] and information about likely pathogenic variants in noncoding regions detected by genome sequencing added to Evaluation Strategies to Identify the Genetic Cause of LCA/EOSRD in a Proband
4 October 2018 (bp) Overview posted live
13 December 2017 (mm,nk) Original submission

References

Literature Cited

Aboshiha J, Dubis AM, van der Spuy J, Nishiguchi KM, Cheeseman EW, Ayuso C, Ehrenberg M, Simonelli F, Bainbridge JW, Michaelides M. Preserved outer retina in Aipl1 Leber's congenital amaurosis: implications for gene therapy. Ophthalmology. 2015;122:862–4. [PubMed: 25596619]
Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan AO, Al-Owain M, Al-Zahrani J, Al-Abdi L, Hashem M, Al-Tarimi S, Sebai MA, Shamia A, Ray-Zack MD, Nassan M, Al-Hassnan ZN, Rahbeeni Z, Waheeb S, Alkharashi A, Abboud E, Al-Hazzaa SA, Alkuraya FS. Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013;23:236–47. [PMC free article: PMC3561865] [PubMed: 23105016]
Aldahmesh MA, Al-Owain M, Alqahtani F, Hazzaa S, Alkuraya FS. A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype. Mol Vis. 2010;16:207–12. [PMC free article: PMC2820108] [PubMed: 20157620]
Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, Georgiadis A, Mowat FM, Beattie SG, Gardner PJ, Feathers KL, Luong VA, Yzer S, Balaggan K, Viswanathan A, de Ravel TJ, Casteels I, Holder GE, Tyler N, Fitzke FW, Weleber RG, Nardini M, Moore AT, Thompson DA, Petersen-Jones SM, Michaelides M, van den Born LI, Stockman A, Smith AJ, Rubin G, Ali RR. Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med. 2015;372:1887–97. [PMC free article: PMC4497809] [PubMed: 25938638]
Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008;358:2231–9. [PubMed: 18441371]
Daich Varela M, Bellingham J, Motta F, Jurkute N, Ellingford JM, Quinodoz M, Oprych K, Niblock M, Janeschitz-Kriegl L, Kaminska K, Cancellieri F, Scholl HPN, Lenassi E, Schiff E, Knight H, Black G, Rivolta C, Cheetham ME, Michaelides M, Mahroo OA, Moore AT, Webster AR, Arno G. Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies. Hum Mol Genet. 2023;32:595–607. [PMC free article: PMC9896476] [PubMed: 36084042]
Estrada-Cuzcano A, Koenekoop RK, Coppieters F, Kohl S, Lopez I, Collin RW, De Baere EB, Roeleveld D, Marek J, Bernd A, Rohrschneider K, van den Born LI, Meire F, Maumenee IH, Jacobson SG, Hoyng CB, Zrenner E, Cremers FP, den Hollander AI. IQCB1 mutations in patients with leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2011;52:834–9. [PubMed: 20881296]
Henderson RH, Williamson KA, Kennedy JS, Webster AR, Holder GE, Robson AG, FitzPatrick DR, van Heyningen V, Moore AT. A rare de novo nonsense mutation in OTX2 causes early onset retinal dystrophy and pituitary dysfunction. Mol Vis. 2009;15:2442–7. [PMC free article: PMC2786888] [PubMed: 19956411]
Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a Phase I trial. Hum Gene Ther. 2008;19:979–90. [PMC free article: PMC2940541] [PubMed: 18774912]
Jacobson SG, Cideciyan AV, Huang Y, Hanna DB, Freund CL, Affatigato LM, Carr RE, Zack DJ, Stone EM, McInnes RR. Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene. Invest Ophthalmol Vis Sci. 1998;39:2417–26. [PubMed: 9804150]
Jacobson SG, Cideciyan AV, Roman AJ, Sumaroka A, Schwartz SB, Heon E, Hauswirth WW. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015;372:1920–6. [PMC free article: PMC4450362] [PubMed: 25936984]
Jacobson SG, Cideciyan AV, Peshenko IV, Sumaroka A, Olshevskaya EV, Cao L, Schwartz SB, Roman AJ, Olivares MB, Sadigh S, Yau KW, Heon E, Stone EM, Dizhoor AM. Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants. Hum Mol Genet. 2013;22:168–83. [PMC free article: PMC3606011] [PubMed: 23035049]
Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol. 2017;101:1147–54. [PMC free article: PMC5574398] [PubMed: 28689169]
Kumaran N, Ripamonti C, Kalitzeos A, Rubin GS, Bainbridge JWB, Michaelides M. Severe loss of tritan color discrimination in RPE65 associated Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2018a;59:85–93. [PMC free article: PMC5769497] [PubMed: 29332120]
Kumaran N, Robson AG, Michaelides M. A novel case series of NMNAT1-associated early-onset retinal dystrophy: extending the phenotypic spectrum. Retin Cases Brief Rep. 2021;15:139–44. [PubMed: 30004997]
Kumaran N, Rubin GS, Kalitzeos A, Fujinami K, Bainbridge JWB, Weleber RG, Michaelides M. A cross-sectional and longitudinal study of retinal sensitivity in RPE65-associated Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2018b;59:3330–9. [PMC free article: PMC6040235] [PubMed: 30025081]
Kumaran N, Smith A, Michaelides M, Ali R, Bainbridge J. Gene therapy for Leber congenital amaurosis. Expert Rev Ophthalmol. 2018c;13:11–15.
Le Meur G, Lebranchu P, Billaud F, Adjali O, Schmitt S, Bézieau S, Péréon Y, Valabregue R, Ivan C, Darmon C, Moullier P, Rolling F, Weber M. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 Leber congenital amaurosis. Mol Ther. 2018;26:256–68. [PMC free article: PMC5763029] [PubMed: 29033008]
Mackay DS, Dev Borman A, Moradi P, Henderson RH, Li Z, Wright GA, Waseem N, Gandra M, Thompson DA, Bhattacharya SS, Holder GE, Webster AR, Moore AT. RDH12 retinopathy: novel mutations and phenotypic description. Mol Vis. 2011;17:2706–16. [PMC free article: PMC3209419] [PubMed: 22065924]
Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358:2240–8. [PMC free article: PMC2829748] [PubMed: 18441370]
Pennesi ME, Weleber RG, Yang P, Whitebirch C, Thean B, Flotte TR, Humphries M, Chegarnov E, Beasley KN, Stout JT, Chulay JD. Results at 5 years after gene therapy for RPE65-deficient retinal dystrophy. Hum Gene Ther. 2018;29:1428–37. [PubMed: 29869534]
Perrault I, Hanein S, Gerber S, Barbet F, Dufier JL, Munnich A, Rozet JM, Kaplan J. Evidence of autosomal dominant Leber congenital amaurosis (LCA) underlain by a CRX heterozygous null allele. J Med Genet. 2003;40:e90. [PMC free article: PMC1735514] [PubMed: 12843339]
Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR. UK10K Consortium, Hurles ME. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
Rivolta C, Berson EL, Dryja TP. Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX. Hum Mutat. 2001;18:488–98. [PubMed: 11748842]
Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, McCague S, Cross D, Marshall KA. Walshire J7, Kehoe TL, Reichert H, Davis M, Raffini L, George LA, Hudson FP, Dingfield L, Zhu X, Haller JA, Sohn EH, Mahajan VB, Pfeifer W, Weckmann M, Johnson C, Gewaily D, Drack A, Stone E, Wachtel K, Simonelli F, Leroy BP, Wright JF, High KA, Maguire AM. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390:849–60. [PMC free article: PMC5726391] [PubMed: 28712537]
Soens ZT, Li Y, Zhao L, Eblimit A, Dharmat R, Li Y, Chen Y, Naqeeb M, Fajardo N, Lopez I, Sun Z, Koenekoop RK, Chen R. Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1. Genet Med. 2016;18:1044–51. [PMC free article: PMC4965339] [PubMed: 26820066]
Sohocki MM, Sullivan LS, Mintz-Hittner HA, Birch D, Heckenlively JR, Freund CL, McInnes RR, Daiger SP. A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene. Am J Hum Genet. 1998;63:1307–15. [PMC free article: PMC1377541] [PubMed: 9792858]
Swaroop A, Wang QL, Wu W, Cook J, Coats C, Xu S, Chen S, Zack DJ, Sieving PA. Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. Hum Mol Genet. 1999;8:299–305. [PubMed: 9931337]
Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Németh AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sørensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D, Donnelly P, McVean G. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015;47:717–26. [PMC free article: PMC4601524] [PubMed: 25985138]
Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K, Banfi S, Surace EM, Sun J, Acerra C, Wright JF, Wellman J, High KA, Auricchio A, Bennett J, Simonelli F. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital amaurosis type 2. Ophthalmology. 2013;120:1283–91. [PMC free article: PMC3674112] [PubMed: 23474247]
Weleber RG, Pennesi ME, Wilson DJ, Kaushal S, Erker LR, Jensen L, McBride MT, Flotte TR, Humphries M, Calcedo R, Hauswirth WW, Chulay JD, Stout JT. Results at 2 years after gene therapy for RPE65-deficient Leber congenital amaurosis and severe early-childhood-onset retinal dystrophy. Ophthalmology. 2016;123:1606–20. [PubMed: 27102010]
Xu M, Yang L, Wang F, Li H, Wang X, Wang W, Ge Z, Wang K, Zhao L, Li H, Li Y, Sui R, Chen R. Mutations in human IFT140 cause non-syndromic retinal degeneration. Hum Genet. 2015;134:1069–78. [PMC free article: PMC4565766] [PubMed: 26216056]

Publication Details

Author Information and Affiliations

Neruban Kumaran, BSc, MBBS, FRCOphth

UCL Institute of Ophthalmology
University College London
Moorfields Eye Hospital
London, United Kingdom

Email: ku.ca.lcu@naramuk.n

Mark E Pennesi, MD, PhD

Casey Eye Institute
Oregon Health Sciences University
Portland, Oregon

Email: ude.usho@misennep

Paul Yang, MD, PhD

Casey Eye Institute
Oregon Health Sciences University
Portland, Oregon

Email: ude.usho@pgnay

Karmen M Trzupek, MS, CGC

InformedDNA
St Petersburg, Florida

Email: moc.anddemrofni@kepuzrtk

Catherine Schlechter, MS, MBI, CGC

Ophthalmic Genetics Clinic
Casey Eye Institute
Oregon Health Sciences University
Portland, Oregon

Email: ude.usho@eittaeb

Anthony T Moore, MA, BM BCh, FRCS, FRCOphth, FMedSci

University of California San Francisco
San Francisco, California

UCL Institute of Ophthalmology
University College London
London, United Kingdom

Email: ude.fscu@eroom.ynot

Richard G Weleber, MD, DABMG, FACMG

Ophthalmic Genetics Clinic
Casey Eye Institute
Oregon Health Sciences University
Portland, Oregon

Email: ude.usho@rrebelew

Michel Michaelides, BSc, MBBS, MD(Res), FRCOphth, FACS

UCL Institute of Ophthalmology
University College London
Moorfields Eye Hospital
London, United Kingdom

Email: ku.ca.lcu@sedileahcim.lehcim

Publication History

Initial Posting: October 4, 2018; Last Revision: March 23, 2023.

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Publisher

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NLM Citation

Kumaran N, Pennesi ME, Yang P, et al. Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview. 2018 Oct 4 [Updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Disorder		Gene(s)	MOI	Distinguishing Clinical Features / Assessments
Nonsyndromic	Achromatopsia	CNGB3 CNGA3 GNAT2 PDE6C ATF6 PDE6H	AR	In achromatopsia: Absent / markedly reduced cone responses w/normal rod ERG responses Stationary natural history In LCA/EOSRD: Non-recordable / markedly reduced full-field ERGs Progressive disease
	Congenital stationary night blindness (See X-Linked Congenital Stationary Night Blindness.)	>10 genes ¹	XL AR AD	Can be differentiated by ERG phenotype & natural history
	Ocular (OMIM 300500) & oculocutaneous (OMIM PS203100) albinism (See OCA Type 4 and OCA and OA Overview.)	>10 genes ²	XL AR	Clinical exam (hypopigmentation of skin, hair, eyebrows/eyelashes, iris, retina) Retinal imaging (OCT & FAF); OCT can highlight foveal hypoplasia Normal ERG & chiasmal misrouting on VEP
Syndromic	Neuronal ceroid lipofuscinoses (NCL) (OMIM PS256730)	13 genes ³	AR AD ⁴	Infantile NCL presents w/congenital or early-onset (age <6 mos) blindness. Late-infantile & juvenile-onset NCL present at ages 2-4 & ≥6 yrs, respectively. ERG can show a negative waveform. NCL is assoc w/neurocognitive decline & epilepsy.
	Joubert syndrome	>30 genes ⁵	AR XL ⁶	Presents w/severe visual impairment, ocular motor abnormalities Characteristic MRI appearance incl "molar tooth sign" Nephronophthisis in later childhood
	Zellweger spectrum disorder	13 genes ⁷	AR	Assoc features: Sensorineural deafness Dysmorphic features Developmental delay Hepatomegaly Early death
	Alström syndrome	ALMS1	AR	Presenting features: Infantile-onset nystagmus Photophobia Cone-rod dystrophy Other systemic features: Childhood obesity Hyperinsulinemia Type 2 diabetes mellitus Hepatic dysfunction Heart failure Sensorineural hearing loss Kidney failure
	Cobalamin C deficiency (See Disorders of Intracellular Cobalamin Metabolism.)	MMACHC	AR	Variable phenotype. Severely affected persons have progressive, infantile-onset, metabolic, neurologic, & ophthalmic manifestations: Infantile nystagmus Bull's-eye maculopathy ↓ responses on ERG

Gene ¹	% of All LCA/ EOSRD	Distinguishing Clinical Features		Other	References
Gene ¹	% of All LCA/ EOSRD	Visual function	Fundus appearance	Other	OMIM	Selected citations
ALMS1	?				606844
AIPL1	<5%	LCA: early profound visual loss	Can be relatively normal in infancy	On OCT: Relative preservation of outer retinal structure before age 4 yrs Progressive loss from birth to total macular atrophy	604393	Aboshiha et al [2015]
CABP4	?				608965	Aldahmesh et al [2010]
CEP290	15%-20%	LCA: Significant variability; severe VA loss in most No clear progression in 1st decade	Can be relatively normal in infancy	On OCT: residual outer retinal structure often present until 4th decade Assoc w/nephronophthisis, Joubert syndrome	611755
CLUAP1	?				616787	Soens et al [2016]
CRB1	10%	Phenotypes: LCA/ EOSRD, RP, & others ² Severity & rate of progression vary significantly.	Variably present: Nummular pigmentation Maculopathy Relative preservation of para-arteriolar RPE	On OCT: retinal thickening & loss of lamination reported	613835
CRX	1%				613829	Jacobson et al [1998]
DTHD1	?				616979	Abu-Safieh et al [2013]
GDF6	?				615360
GUCY2D	10%-20%	LCA: Early profound visual loss Lack of color perception Significant photophobia Substantial residual rod-driven visual function	Relatively normal		204000	Jacobson et al [2013]
IFT140	?			Assoc w/nephronophthisis, Joubert syndrome	614620	Xu et al [2015]
IMPDH1	5%				613837
IQCB1	?			Assoc w/nephronophthisis, Joubert syndrome	609237	Estrada-Cuzcano et al [2011]
KCNJ13	?				614186
LCA5	1%-2%				604537
LRAT	<1%	EOSRD: similar to RPE65-LCA			613341
NMNAT1	?	LCA/EOSRD: Majority have early-onset profound vision loss & extensive maculopathy. Minority have milder phenotype.	Marked maculopathy		608553	Kumaran et al [2021]
OTX2	?				600037	Henderson et al [2009]
RD3	<1%				610612
RDH12	10%	LCA phenotype	Early, widespread RPE & retinal atrophy Minimal intraretinal pigmentation in early childhood Dense intraretinal bone-spicule pigmentation developing over time Early progressive macular atrophy	On OCT: macular excavation On FAF: loss of autofluorescence	612712	Mackay et al [2011]
RPE65	5%-10%	EOSRD: Profound night blindness from birth Minimal nystagmus Poor color discrimination Residual cone-mediated vision in 1st 3 decades w/progressive visual field loss	May show blonde fundus w/peripheral, white, punctate lesions	FDA-approved gene therapy available (See RPE65-Related LCA/EOSRD.)	204100	Kumaran et al [2018a], Kumaran et al [2018b]
RPGRIP1	5%	Initial rapid decline in vision followed by lack of progression			613826
PRPH2	?				608133
SPATA7	3%				604232
TULP1	<1%		Maculopathy		613843