Leber congenital amaurosis (LCA) is considered to be one of the most common (but also one of the most severe) hereditary disorders of impaired vision that develop during the first several years of life [1]. LCA is principally transferred through an autosomal recessive mode of inheritance, and first clinical signs appear after only 6 months in most patients [2] [3] [4] [5]. Phenotypic features are broad in this inherited retinal dystrophy, as numerous mutations cause variably progressive degeneration of the retina and loss of its function [2] [3] [6]. In virtually all cases, however, the clinical presentation is comprised of vision loss and diminished pupillary responses [2]. The inability of eye fixation is readily observed during the first few months of life, whereas refractive errors (hypermetropia, myopia), as well as photophobia, constant eye poking, pressing, or rubbing (known as Franceschetti signs) and consequent enophthalmos are commonly encountered [2] [7]. Other notable features include nystagmus, keratoconus, night blindness (in later life), and the development of juvenile cataracts [2] [7]. In many patients, unfortunately, visual acuity is severely reduced, and the perception of light is markedly impaired [2]. Thus, with a somewhat different clinical course, permanent and irreversible blindness ensues, but rare patients have known to improve overall visual function [2] [3] [6] [7].

• Photophobia

  LP LP Yes −1.5 −2.5 Extinguished Salt and pepper A57b GUCY2D L325R het 31 Photophobia LP LP Yes 0 0 Extinguished Salt and pepper 4 A30 GUCY2D R795Q 4 No LP LP Yes 0 0 Extinguished Salt and pepper 5 A6 GUCY2D R768W het 5 Light-gazing LP LP Yes 4.5 4.5 [iovs.arvojournals.org]

  Clinical features of the two siblings showed nystagmus, poor visual acuity, hyperopia, and photophobia since early childhood; but there was no oculo-digital sign, vessel attenuation or RPE mottling from the mid-retina to the periphery. [ncbi.nlm.nih.gov]

  […] dictionary of medical eponyms Related people Theodor Karl Gustav von Leber Syndrome characterised by severe visual deficiency, with total or nearly total blindness, present at birth or shortly thereafter; pendular or searching nystagmus, sunken eyeballs, photophobia [whonamedit.com]

• Night Blindness

  Case 2: A 30-year-old woman, who had night blindness and poor ocular pursuit during the first year of life, exhibited severe retinal degeneration and non-recordable ERG. [ncbi.nlm.nih.gov]

  Most patients with RPE65 mutations are profoundly night blind. Most patients also have sluggish pupils and hyperopia, although some patients such as this one are myopic. [eyerounds.org]

  Night blindness is the predominant symptom of this type of LCA[ 2 ]. [wjgnet.com]

• Enophthalmos

  The inability of eye fixation is readily observed during the first few months of life, whereas refractive errors (hypermetropia, myopia), as well as photophobia, constant eye poking, pressing, or rubbing (known as Franceschetti signs) and consequent enophthalmos [symptoma.com]

  The same process likely is responsible for giving the eyes a deep-set appearance known as enophthalmos. Genetics: At least 18 mutant genes have been associated with this condition. [disorders.eyes.arizona.edu]

  Eye poking was present in 17 patients and enophthalmos in seven patients (Patients 1, 2, 3, 5, 12, 13, and 17). Photophobia was not recorded as an early symptom in patients with vision. [molvis.org]

  The major sequelum is enophthalmos, a physical defect in which the eye recedes into the orbit, presumably from atrophy of orbital fat. This behavior is performed to in an effort to stimulate vision. Intellectual Disability. [imoe.it]

• Central Scotoma

  Visual field testing shows an enlarging central scotoma. Fluorescein angiography may be useful in the acute phase. [patient.info]

• Esotropia

  […] the arcades Nondetectable Concentric narrowing to >5° BE77905 F 3 Normal 0.01/0.01 Hyperopia (+5.0 OD, +4.0 OS) Granular fundus (salt-and-pepper pigmentation); macula and optic disc normal Nondetectable (1 year) NA 12786 F 15 Normal 0.30/0.30 (20/70) Esotropia [iovs.arvojournals.org]

• Ataxia

  Perrault et al. [ 8 ] observed transitory hypotonia, ataxia, mental retardation, and autistic behavior in a minority of their patients with surprising intra-familiar discrepancies. [molvis.org]

  […] with myopathy PRKAG2 Cardiomyopathy, hypertrophic 6; Glycogen storage disease of heart, lethal congenital; Wolff-Parkinson-White syndrome POLG Mitochondrial DNA depletion syndrome 4A; Mitochondrial DNA depletion syndrome 4B; Mitochondrial recessive ataxia [genelex.jp]

  Developmental delay/mental retardation, psychomotor degeneration, hypotonia, ataxia, seizures, spatiscity, and death are common characteristics seen in this syndrome. ERG shows early non-recordable responses[ 40, 41 ]. [wjgnet.com]

• Pendular Nystagmus

  Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. [ncbi.nlm.nih.gov]

Although several forms of inherited retinal disorders may be included in the differential diagnosis, initial recognition of LCA in early life can be made with a comprehensive clinical assessment. Firstly, a detailed patient history addressing the course and progression of symptoms should be obtained from the parents, after which a complete physical examination needs to be carried out. If the ocular exam is conducted properly, typical signs and symptoms of LCA can be observed and a presumptive diagnosis of a retinal dystrophy might be made [2]. In fact, the physical examination is considered to be the pivotal part of the diagnostic workup, as both physical and ophthalmoscopy findings (a myriad of fundus abnormalities is seen, such as the salt-and-pepper appearance of the retina) are highly indicative of LCA [2] [6]. A more concrete diagnosis is made through the use of an electroretinogram (ERG), which shows reduced or completely absent activity of the retina, pointing toward retinal dysfunction as the cause of symptoms [1] [2] [4] [6]. In addition, optical coherence tomography (OCT) is also recommended by some authors, as it allows measuring of the retinal thickness that is often reduced in LCA patients [1] [4] [6]. To exclude other retinal dystrophies and confirm LCA as the underlying disorder, genetic testing is mandatory. More than 20 different genes have been linked with the pathogenesis of LCA (most important being GUCY2D and RPE65), and a detailed evaluation of respective genes is helpful in determining the exact mutations that have led to LCA [1] [2] [3] [4] [6].

• Central Scotoma

  Visual field testing shows an enlarging central scotoma. Fluorescein angiography may be useful in the acute phase. [patient.info]

Such clinical and genetic heterogeneity poses great challenges for treatment, with personalized therapies anticipated to be the best treatment candidates. [ncbi.nlm.nih.gov]

In the active treatment group, patients received single doses of [Spark's] gene therapy treatment SPK-REP65, containing the normal RPE65 gene, in both eyes via sub-retinal injection. [visionaware.org]

[…] and Causes The prognosis varies depending on the symptoms of the stage or type. [proschool.weebly.com]

Prognosis - Leber congenital amaurosis Not supplied. Treatment - Leber congenital amaurosis Resources - Leber congenital amaurosis Not supplied. [checkorphan.org]

Diagnosis and Prognosis: The diagnosis requires an eye examination by an ophthalmologist. [disorders.eyes.arizona.edu]

Long term visual prognosis remains to be defined. Visual acuity in patients with LCA is usually limited to the level of counting fingers or detecting hand motions or bright lights. Some patients are also extremely sensitive to light (photophobia). [provisu.ch]

Unraveling the individual genetic etiology of disease is a prerequisite for personalized therapies, and could identify potential treatment candidates, inform patient management, and discriminate syndromic forms of disease. [ncbi.nlm.nih.gov]

Etiology To date, mutations in genes encoding retina specific proteins have been reported to cause LCA. [orpha.net]

Author information 1 National Center for Birth Defect Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China; Laboratory of Molecular Epidemiology for Birth Defect, West China Institute of Women and Children's Health, Sichuan [ncbi.nlm.nih.gov]

Summary Epidemiology The prevalence of LCA is 1/50,000 - 1/33,000 live births and accounts for 5% of all retinal dystrophies and 20% of blindness in school age children. [orpha.net]

Summary: RPE65-associated Leber Congenital Amaurosis (LCA) EPIDEMIOLOGY 1 of 81,000 births have LCA RPE65 accounts for 8% of these SIGNS Poor fixation as an infant Nystagmus Eye rubbing (Oculodigital reflex) Keratoconus Pink disks Sluggish pupils Variable [eyerounds.org]

Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photoreceptors or extremely early degeneration of cells that have developed normally. [ncbi.nlm.nih.gov]

Hamel Laboratoire de Biochimie Génétique, Institut de Biologic, Montpellier, France Corinne Bareil & Mireille Claustres Pathophysiology of Vision, University Eye Hospital, Tübingen, Germany Eberhart Zrenner Cabinet d'Opthalmologie, 6, rue Saint Clair, [doi.org]

Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. [ncbi.nlm.nih.gov]

Leber's amaurosis, Congenital retinal blindness, Congenital absence of the rods and cones, Leber's congenital tapetoretinal degeneration, LCA Symptoms - Leber congenital amaurosis Causes - Leber congenital amaurosis Prevention - Leber congenital amaurosis [checkorphan.org]

1. Wang H, den Hollander AI, Moayedi Y, et al. Mutations in SPATA7 Cause Leber Congenital Amaurosis and Juvenile Retinitis Pigmentosa. Am J Hum Genet. 2009;84(3):380-387.
2. Chacon-Camacho OF, Zenteno JC. Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015;3(2):112-124.
3. Simonelli F, Maguire AM, Testa F, et al. Gene Therapy for Leber’s Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration. Mol Ther. 2010;18(3):643-650.
4. Pennesi ME, Stover NB, Stone EM, Chiang P-W, Weleber RG. Residual Electroretinograms in Young Leber Congenital Amaurosis Patients with Mutations of AIPL1. Invest Ophthalmol Vis Sci. 2011;52(11):8166-8173.
5. McAnany JJ, Genead MA, Walia S, et al. Visual Acuity Changes in Patients with Leber Congenital Amaurosis (LCA) and Mutations in the CEP290 Gene. JAMA Ophthalmol. 2013;131(2):178-182.
6. Simonelli F, Ziviello C, Testa F, et al. Clinical and molecular genetics of Leber's congenital amaurosis: a multicenter study of Italian patients. Invest Ophthalmol Vis Sci. 2007;48:4284–4290.
7. Yzer S, den Hollander AI, Lopez I, et al. Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290. Mol Vis. 2012;18:412-425.