Leber congenital amaurosis explained

Leber congenital amaurosis
Synonyms:Leber's congenital amaurosis
Symptoms:Visual impairment, sensitivity to light
Types:> 12 types
Causes:Genetic (autosomal recessive)
Frequency:1 in 40,000 newborns

Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.[1]

It affects about 1 in 40,000 newborns.[2] LCA was first described by Theodor Leber in the 19th century.[3] It should not be confused with Leber's hereditary optic neuropathy, which is a different disease also described by Theodor Leber.

One form of LCA was successfully treated with gene therapy in 2008.[4] [5] [6] [7]

Signs and symptoms

LCA symptoms typically begin in the first few months of life, most commonly with involuntary twitching of the eye (nystagmus). Affected infants may show misaligned eyes when looking at something (strabismus), aversion to light (photophobia), and poke or rub at their eyes (Franceschetti’s oculodigital sign). Those with LCA invariably experience vision problems. Affected infants show decreased visual response to objects. Loss of visual acuity is severe, with affected individuals' vision ranging from 20/200 to 20/400. Around a third of those affected completely lose perception of light.

At an eye exam, the pupils may not respond normally to light. Some affected individuals have cloudy eyes (cataracts), and irregularly shaped corneas (keratoconus). Retinal exams typically look normal, especially in the young, though retinal abnormalities can appear later in life.

Aside from eye problems, children with LCA are typically healthy.

Cause

LCA is a genetic disease and can be caused by pathogenic variants in at least 28 different genes. Variants in three of these genes – IMPDH1, OTX2, and CRX – can cause LCA in an autosomal dominant manner, meaning inheriting a single copy of a pathogenic variant can result in disease. Variants in the remaining genes associated with LCA cause disease in an autosomal recessive manner, meaning one must inherit copies of the pathogenic variant from both parents to develop LCA. Genes associated with LCA have a variety of roles in the development of the eye:

Pathogenic variants of any of these genes cause dysfunction in those associated processes, which leads to severe vision loss. Variants in DTHD1 and NMNAT1 also cause LCA, though these genes' roles in vision development are not yet known.

Among the gene variants that cause LCA, CEP290 and GUCYD variants are the most common, each causing up to 20% of LCA cases. Other common variants are in CRB1 (around 10% of cases), RPE65 (up to 10%), AIPL1 (up to 8%), RDH12 (up to 5%), and RPGRIP1 (around 5%). Around 25% of people with LCA do not have any of the known LCA-causing pathogenic gene variants; the cause of their LCA is unknown.

Diagnosis

LCA is diagnosed clinically, by a combination of vision loss, an abnormal response of the pupils to light, and by abnormal response to electroretinography, a test that measures the electrical response of the retina to light.

Treatment

One form of LCA, in 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.[4] [5] [6] [7] These studies, which used adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease. 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.[8] Another recent trial from The OHSU Casey Eye Institute used CRISPR to treat LCA starting in 2020. The experimental treatment consisted in editing a mutation of the CEP290 gene, which provides instructions to create a protein that is critical for sight. Results were released in 2023 with 79% of the patients showing improvement in at least one of four measured outcomes. [9]

For those who cannot benefit from gene therapy, LCA treatment is supportive, and meant to facilitate living with visual impairment. Some benefit from vision aids such as glasses, magnifiers, and enhancers. Other resources helpful for those with visual impairment include educational programs, special education teachers, and service animals.

Epidemiology

Around 2–3 out of every 100,000 people have LCA – an estimated 180,000 people worldwide. LCA is a common cause of blindness in the young; around 20% of children in schools for the blind have LCA.[10]

History

LCA was originally described as a variety of retinitis pigmentosa by Theodor Leber in 1869.

Popular culture

Notable cases

See also

References

Works cited

Further reading

External links

Notes and References

  1. Stone EM . 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 . December 2007 . 17964524 . 10.1016/j.ajo.2007.08.022 . free .
  2. Web site: Leber congenital amaurosis. Genetics Home Reference. 14 May 2017. en. August 2010.
  3. Leber T . Über Retinitis pigmentosa und angeborene Amaurose . Archiv für Ophthalmologie . 15 . 3 . 1–25 . 1869 . de . 10.1007/BF02721213. 543893 .
  4. 6. Maguire AM, Simonelli F, Pierce EA, Pugh EN, 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. May 2008. Safety and efficacy of gene transfer for Leber's congenital amaurosis . The New England Journal of Medicine . 358 . 21 . 2240–8 . 10.1056/NEJMoa0802315 . 2829748 . 18441370.
  5. 6. Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A. 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. 10.1038/mt.2009.277. 2839440. 19953081.
  6. 6. Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EA, Conlon TJ, Sumaroka A, Roman AJ, Byrne BJ, Jacobson SG. August 2009. Vision 1 year after gene therapy for Leber's congenital amaurosis. The New England Journal of Medicine. 361. 7. 725–7. 10.1056/NEJMc0903652. 2847775. 19675341.
  7. 6. 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. May 2008. Effect of gene therapy on visual function in Leber's congenital amaurosis. The New England Journal of Medicine. 358. 21. 2231–9. 10.1.1.574.4003. 10.1056/NEJMoa0802268. 18441371.
  8. Approved Products - LUXTURNA. FDA. 2019-04-05.
  9. Web site: Participants of pioneering CRISPR gene editing trial see vision improve . 2024-05-12 . ScienceDaily . en.
  10. Web site: Leber Congenital Amaurosis . 1 May 2023 . American Association for Pediatric Ophthalmology and Strabismus . April 2023.
  11. Web site: 4 yr old Gavin using his white cane to navigate down a curb independently. https://ghostarchive.org/varchive/youtube/20211221/BsXa-mAKDVs . 2021-12-21 . live. .

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