Leber's congenital amaurosis

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Leber's congenital amaurosis
Specialty Ophthalmology   OOjs UI icon edit-ltr-progressive.svg
SymptomsVisual impairment, sensitivity to light [1]
Types> 12 types [1]
Causes Genetic (autosomal recessive) [1]
Frequency1 in 40,000 newborns [1]

Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life. [2]

Heredity Passing of traits to offspring from the speciess parents or ancestor

Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic information of their parents. Through heredity, variations between individuals can accumulate and cause species to evolve by natural selection. The study of heredity in biology is genetics.

Contents

One form of LCA was successfully treated with gene therapy in 2008. [3] [4] [5] [6]

Gene therapy therapeutic approach that involves inserting nucleic acids into the patients cells

In the medicine field gene therapy is the therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease. The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989. The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

It affects about 1 in 40,000 newborns. [1] LCA was first described by Theodor Leber in the 19th century. [7] [8] It should not be confused with Leber's hereditary optic neuropathy, which is a different disease also described by Theodor Leber.

Theodor Leber German ophtthalmologist

Theodor Karl Gustav von Leber was a German ophthalmologist from Karlsruhe.

Lebers hereditary optic neuropathy A mitochondrially inherited degeneration of retinal cells in human

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. LHON is only transmitted through the mother, as it is primarily due to mutations in the mitochondrial genome, and only the egg contributes mitochondria to the embryo. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria. Men cannot pass on the disease to their offspring.

Signs and symptoms

The term congenital refers to a condition present from birth (not acquired) and amaurosis refers to a loss of vision not associated with a lesion. However, beyond these general descriptions, the presentation of LCA can vary, because it is associated with multiple genes. [9] [10]

Amaurosis is vision loss or weakness that occurs without an apparent lesion affecting the eye. It may result from either a medical condition or excess acceleration, as in flight. The term is the same as the Latin gutta serena.

A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. Lesion is derived from the Latin laesio "injury". Lesions may occur in plants as well as animals.

LCA is typically characterized by nystagmus, [9] sluggish or absent pupillary responses, [10] and severe vision loss or blindness. [9]

Pupillary reflex refers to one of the reflexes associated with pupillary function.

Genetics

It is usually autosomal recessive; however, importantly for family planning, it is sometimes autosomal dominant. It is a disorder thought to be caused by abnormal development of photoreceptor cells. [9]

Photoreceptor cell specialized type of cell found in the retina that is capable of visual phototransduction

A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light into signals that can stimulate biological processes. To be more specific, photoreceptor proteins in the cell absorb photons, triggering a change in the cell's membrane potential.

OMIM currently recognizes 18 types of LCA. [9]

Type OMIM Gene Locus [9]
LCA1 204000 GUCY2D, [11] 17p13.1
LCA2 204100 RPE65 [12] 1p31.3-p31.2
LCA3 609868 SPATA7 14q31.3
LCA4 604393 AIPL1 [13] [14] 17p13.2
LCA5 604537 LCA5 [15] 6q14.1
LCA6 605446 RPGRIP1 14q11.2
LCA7 602225 CRX [16] 19q13.3
LCA8 604210 CRB1 [16] 1q31-q32.1
LCA9 608553 NMNAT1 [17] [18] [19] [20] 1p36.22
LCA10 610142 CEP290 12q21.32
LCA11 146690 IMPDH1 7q32.1
LCA12 180040 RD3 7q32.1
LCA13 608830 RDH12 1q32.3
LCA14 604863 LRAT 14q24.1
LCA15 602280 TULP1 4q31
LCA16 603208 KCNJ13 2q37
LCA17 601147 GDF6 8q22
LCA18 179605 PRPH2 6p21

The gene CEP290 has been associated with Joubert syndrome, as well as type 10 LCA. [21]

Diagnosis

Genetic tests and related research are currently being performed at Centogene AG in Rostock, Germany; John and Marcia Carver Nonprofit Genetic Testing Laboratory in Iowa City, IA; GENESIS Center for Medical Genetics in Poznan, Poland; Miraca Genetics Laboratories in Houston, TX; Asper Biogene in Tartu, Estonia; CGC Genetics in Porto, Portugal; CEN4GEN Institute for Genomics and Molecular Diagnostics in Edmonton, Canada; and Reference Laboratory Genetics - Barcelona, Spain. [22]

Treatment

One form of LCA, patients with LCA2 bearing a mutation in the RPE65 gene, has been successfully treated in clinical trials using gene therapy. The results of three early clinical trials were published in 2008 demonstrating the safety and efficacy of using adeno-associated virus to deliver gene therapy to restore vision in LCA patients. In all three clinical trials, patients recovered functional vision without apparent side-effects. [3] [4] [5] [6] These studies, which used adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease.

The results of a phase 1 trial conducted by the University of Pennsylvania and Children’s Hospital of Philadelphia and published in 2009 showed sustained improvement in 12 subjects (ages 8 to 44) with RPE65-associated LCA after treatment with AAV2-hRPE65v2, a gene replacement therapy. [23] Early intervention was associated with better results. [23] In that study, patients were excluded based on the presence of particular antibodies to the vector AAV2 and treatment was only administered to one eye as a precaution. [23] A 2010 study testing the effect of administration of AAV2-hRPE65v2 in both eyes in animals with antibodies present suggested that immune responses may not complicate use of the treatment in both eyes. [24] On 19 December 2017, the U.S. Food and Drug Administration approved voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy for children and adults with biallelic RPE65 gene mutations responsible for retinal dystrophy, including Leber congenital amaurosis. Patients must have viable retinal cells as a prerequisite for the intraocular administration of Luxturna. [25]

Eye Surgeon Dr. Al Maguire and gene therapy expert Dr. Jean Bennett developed the technique used by the Children's Hospital. [3] [26]

Dr. Sue Semple-Rowland at the University of Florida has recently restored sight in an avian model using gene therapy. [27]

See also

Related Research Articles

Retina light-sensitive tissue layer in the eye

The retina is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which translates that image into electrical neural impulses to the brain to create visual perception, the retina serving a function analogous to that of the film or image sensor in a camera.

Retinitis pigmentosa retinal degeneration characterized by the gradual deterioration of the photoreceptors or the retinal pigment epithelium of the retina leading to progressive sight loss

Retinitis pigmentosa (RP) is a genetic disorder of the eyes that causes loss of vision. Symptoms include trouble seeing at night and decreased peripheral vision. Onset of symptoms is generally gradual. As peripheral vision worsens, people may experience "tunnel vision". Complete blindness is uncommon.

Choroideremia rare, X-linked recessive form of hereditary retinal degeneration

Choroideremia is a rare, X-linked recessive form of hereditary retinal degeneration that affects roughly 1 in 50,000 males. The disease causes a gradual loss of vision, starting with childhood night blindness, followed by peripheral vision loss and progressing to loss of central vision later in life. Progression continues throughout the individual's life, but both the rate of change and the degree of visual loss are variable among those affected, even within the same family.

RPE65 protein-coding gene in the species Homo sapiens

Retinal pigment epithelium-specific 65 kDa protein, also known as retinoid isomerohydrolase, is an enzyme of the vertebrate visual cycle that is encoded in humans by the RPE65 gene. RPE65 is expressed in the retinal pigment epithelium and is responsible for the conversion of all-trans-retinyl esters to 11-cis-retinol during phototransduction. 11-cis-retinol is then used in visual pigment regeneration in photoreceptor cells. RPE65 belongs to the carotenoid oxygenase family of enzymes.

<i>CRX</i> (gene) protein-coding gene in the species Homo sapiens

Cone-rod homeobox protein is a protein that in humans is encoded by the CRX gene.

CRB1 protein-coding gene in the species Homo sapiens

Crumbs homolog 1 is a protein that in humans is encoded by the CRB1 gene.

NMNAT1 protein-coding gene in the species Homo sapiens

Nicotinamide mononucleotide adenylyltransferase 1 is an enzyme that in humans is encoded by the NMNAT1 gene. It is a member of the nicotinamide-nucleotide adenylyltransferases.

CEP290 protein-coding gene in the species Homo sapiens

Centrosomal protein of 290 kDa is a protein that in humans is encoded by the CEP290 gene. CEP290 is located on the Q arm of chromosome 12.

AIPL1 protein-coding gene in the species Homo sapiens

Aryl-hydrocarbon-interacting protein-like 1 is a protein that in humans is encoded by the AIPL1 gene.

RPGRIP1 protein-coding gene in the species Homo sapiens

X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 is a protein in the ciliary transition zone that in humans is encoded by the RPGRIP1 gene. RPGRIP1 is a multi-domain protein containing a coiled-coil domain at the N-terminus, two C2 domains and a C-terminal RPGR-interacting domain (RID). Defects in the gene result in the Leber congenital amaurosis (LCA) syndrome and in the eye disease glaucoma.

TULP1 protein-coding gene in the species Homo sapiens

Tubby-related protein 1 is a protein that in humans is encoded by the TULP1 gene.

RDH12 protein-coding gene in the species Homo sapiens

Retinol dehydrogenase 12 is an enzyme that in humans is encoded by the RDH12 gene.

LCA5 protein-coding gene in the species Homo sapiens

Lebercilin, also known as leber congenital amaurosis 5 (LCA5), is a protein that in humans is encoded by the LCA5 gene. This protein is thought to be involved in centrosomal or ciliary functions.

Gene therapy using lentiviral vectors is being explored in early stage trials.

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.

Robert MacLaren Professor of Ophthalmology

Robert E. MacLaren FMedSci FRCOphth FRCS FACS VR is a British ophthalmologist who has led pioneering work in the treatment of blindness caused by diseases of the retina. He is Professor of Ophthalmology at the University of Oxford and Honorary Professor of Ophthalmology at the UCL Institute of Ophthalmology. He is a Consultant Ophthalmologist at the Oxford Eye Hospital and an Honorary Consultant Ophthalmologist at the Great Ormond Street Hospital. He is also an Honorary Consultant Vitreo-retinal Surgeon at the Moorfields Eye Hospital. MacLaren is an NIHR Senior Investigator, or lead researcher, for the speciality of Ophthalmology. In addition, he is a member of the research committee of Euretina: the European Society of Retina specialists, Fellow of Merton College, in Oxford and a Fellow of the Higher Education Academy.

Voretigene neparvovec (Luxturna) is a novel gene therapy for the treatment of Leber's congenital amaurosis. It was developed by Spark Therapeutics and Children's Hospital of Philadelphia. It is the first in vivo gene therapy approved by the FDA.

Congenital Blindness Gene Therapy

Congenital blindness refers to a group of diseases and conditions occurring in childhood or early adolescence of below 16 years old, which, if left untreated, result in blindness or severe visual impairment that are likely to be permanent blindness later in life. Congenital blindness is a hereditary disease and can be cured by gene therapy. Visual loss in children or infant can occur either at the stage of prenatal or postnatal stage. There are lots of causes that can promote congenital blindness but the most concern and highest cause of it is a genetic mutation. 60% of congenital blindness are contributed from prenatal stage and another 40% are contributed from inherited disease. However, most of the congenital blindness cases show that it can be avoidable or preventable with early treatment.

References

  1. 1 2 3 4 5 "Leber congenital amaurosis". Genetics Home Reference. August 2010. Retrieved 14 May 2017.
  2. ↑ Stone EM (December 2007). "Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture". American Journal of Ophthalmology. 144 (6): 791–811. doi:10.1016/j.ajo.2007.08.022. PMID   17964524.
  3. 1 2 3 Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, et al. (May 2008). "Safety and efficacy of gene transfer for Leber's congenital amaurosis". The New England Journal of Medicine. 358 (21): 2240–8. doi:10.1056/NEJMoa0802315. PMC   2829748 . PMID   18441370.
  4. 1 2 Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, et al. (March 2010). "Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration". Molecular Therapy. 18 (3): 643–50. doi:10.1038/mt.2009.277. PMC   2839440 . PMID   19953081.
  5. 1 2 Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, et al. (August 2009). "Vision 1 year after gene therapy for Leber's congenital amaurosis". The New England Journal of Medicine. 361 (7): 725–7. doi:10.1056/NEJMc0903652. PMC   2847775 . PMID   19675341.
  6. 1 2 Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, et al. (May 2008). "Effect of gene therapy on visual function in Leber's congenital amaurosis". The New England Journal of Medicine. 358 (21): 2231–9. CiteSeerX   10.1.1.574.4003 . doi:10.1056/NEJMoa0802268. PMID   18441371.
  7. ↑ Leber's congenital amaurosis at Who Named It?
  8. ↑ Leber T (1869). "Über Retinitis pigmentosa und angeborene Amaurose". Archiv für Ophthalmologie (in German). 15 (3): 1–25. doi:10.1007/BF02721213.
  9. 1 2 3 4 5 6 Online Mendelian Inheritance in Man (OMIM) LEBER CONGENITAL AMAUROSIS, TYPE I; LCA1 -204000
  10. 1 2 Weleber, R. G.; Francis, P. J.; Trzupek, K. M.; Beattie, C.; Adam, M. P.; Ardinger, H. H.; Pagon, R. A.; Wallace, S. E.; Bean LJH; Stephens, K.; Amemiya, A. (1993). "Leber Congenital Amaurosis". GeneReviews. PMID   20301475.
  11. ↑ Perrault I, Rozet JM, Calvas P, Gerber S, Camuzat A, Dollfus H, et al. (December 1996). "Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis". Nature Genetics. 14 (4): 461–4. doi:10.1038/ng1296-461. PMID   8944027.
  12. ↑ Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, et al. (October 1997). "Mutations in RPE65 cause Leber's congenital amaurosis". Nature Genetics. 17 (2): 139–41. doi:10.1038/ng1097-139. PMID   9326927.
  13. ↑ Yzer S, Leroy BP, De Baere E, de Ravel TJ, Zonneveld MN, Voesenek K, et al. (March 2006). "Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis". Investigative Ophthalmology & Visual Science. 47 (3): 1167–76. doi:10.1167/iovs.05-0848. PMID   16505055.
  14. ↑ "Inherited child blindness probed". BBC News. 2005-09-19. Retrieved 2007-09-21.
  15. ↑ Dharmaraj S, Li Y, Robitaille JM, Silva E, Zhu D, Mitchell TN, et al. (January 2000). "A novel locus for Leber congenital amaurosis maps to chromosome 6q". American Journal of Human Genetics. 66 (1): 319–26. doi:10.1086/302719. PMC   1288337 . PMID   10631161.
  16. 1 2 Preising MN, Paunescu K, Friedburg C, Lorenz B (June 2007). "[Genetic and clinical heterogeneity in LCA patients. The end of uniformity]". Der Ophthalmologe (in German). 104 (6): 490–8. doi:10.1007/s00347-007-1533-x. PMID   17525851.
  17. ↑ Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, et al. (September 2012). "Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration". Nature Genetics. 44 (9): 1035–9. doi:10.1038/ng.2356. PMC   3657614 . PMID   22842230.
  18. ↑ Falk MJ, Zhang Q, Nakamaru-Ogiso E, Kannabiran C, Fonseca-Kelly Z, Chakarova C, et al. (September 2012). "NMNAT1 mutations cause Leber congenital amaurosis". Nature Genetics. 44 (9): 1040–5. doi:10.1038/ng.2361. PMC   3454532 . PMID   22842227.
  19. ↑ Chiang PW, Wang J, Chen Y, Fu Q, Zhong J, Chen Y, et al. (September 2012). "Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis". Nature Genetics. 44 (9): 972–4. doi:10.1038/ng.2370. PMID   22842231.
  20. ↑ Perrault I, Hanein S, Zanlonghi X, Serre V, Nicouleau M, Defoort-Delhemmes S, et al. (September 2012). "Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy". Nature Genetics. 44 (9): 975–7. doi:10.1038/ng.2357. PMID   22842229.
  21. ↑ Traboulsi EI, Koenekoop R, Stone EM (December 2006). "Lumpers or splitters? The role of molecular diagnosis in Leber congenital amaurosis". Ophthalmic Genetics. 27 (4): 113–5. doi:10.1080/13816810601013146. PMID   17148037.
  22. ↑ "GeneTests: Leber Congenital Amaurosis".
  23. 1 2 3 Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, et al. (November 2009). "Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial". Lancet. 374 (9701): 1597–605. doi:10.1016/S0140-6736(09)61836-5. PMC   4492302 . PMID   19854499.
  24. ↑ Amado D, Mingozzi F, Hui D, Bennicelli JL, Wei Z, Chen Y, et al. (March 2010). "Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness". Science Translational Medicine. 2 (21): 21ra16. doi:10.1126/scitranslmed.3000659. PMC   4169124 . PMID   20374996.
  25. ↑ "Approved Products - LUXTURNA". FDA. 2019-04-05.
  26. ↑ "ABC News: Miracle Cure for Nearly Blind Youth" . Retrieved 2008-04-27.
  27. ↑ Williams ML, Coleman JE, Haire SE, Aleman TS, Cideciyan AV, Sokal I, et al. (June 2006). "Lentiviral expression of retinal guanylate cyclase-1 (RetGC1) restores vision in an avian model of childhood blindness". PLoS Medicine. 3 (6): e201. doi:10.1371/journal.pmed.0030201. PMC   1463903 . PMID   16700630.
  28. ↑ "4 yr old Gavin using his white cane to navigate down a curb independently".

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