Clinical Spectrum of Leber's Congenital Amaurosis in the Second to Fourth Decades of Life

doi:10.1016/S0161-6420(90)32442-9

Ophthalmology

Volume 97, Issue 9, September 1990, Pages 1156-1161

https://doi.org/10.1016/S0161-6420(90)32442-9 Get rights and content

Abstract

Leber's congenital amaurosis is a type of congenital retinitis pigmentosa in which the fundus abnormalities are extremely variable and to some extent age dependent. Most cases are seen in infancy. The retinal, electroretinogram, and fluorescein angiographic findings are described in ten patients with Leber's congenital amaurosis who ranged in age from 13 to 36 years when first seen. All of the patients were from Honduras and were unrelated except for one pair (a brother and sister). The polymorphic appearance of the fundus is emphasized and is particularly striking in the siblings. A macular lesion (a bull's-eye maculopathy) not previously associated with Leber's congenital amaurosis is reported as a variant fundus appearance in this entity.

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Cited by (28)

Intraperitoneal chromophore injections delay early-onset and rapid retinal cone degeneration in a mouse model of Leber congenital amaurosis
2021, Experimental Eye Research
Citation Excerpt :
Compared with healthy subjects, patients with retinitis pigmentosa were found to have significantly lower blood flow velocities in the retinal vessels (Beutelspacher et al., 2011). Smith et al. (1990) believed LCA to be a type of congenital retinitis pigmentosa. Therefore, we performed FFA to investigate whether the rd12 mice, a naturally occurring LCA2 rodent model, have abnormal retinal vessels.
Highly expressed in the retinal pigment epithelium (RPE), the RPE-specific 65-kDa (RPE65) enzyme is indispensable to generate 11-cis-retinal (11cRAL), a chromophore for rhodopsin and cone photopigments. RPE65 deficiency can lead to Leber congenital amaurosis type 2 (LCA2), in which the isomerization of photobleached all-trans-retinal into photosensitive 11cRAL is blocked, ultimately causing severe retinal dysfunction and degeneration. The related mouse models, which are constructed through gene knockout or caused by spontaneous mutations, morphologically present with early-onset and rapid retinal cone cells degeneration, including loss of short-wavelength-sensitive cone opsins (S-opsins) and mislocalization of medium-wavelength-sensitive cone opsins (M-opsins). Studies have shown that routine Rpe65 gene replacement therapy, mediated by an adeno-associated virus (AAV) vector, can restore RPE65 protein. However, AAV transfection and Rpe65 transgene expression require at least one to two weeks, and the treatment cannot fully block the early-onset cone degeneration. To determine the feasibility of delaying cone degeneration before gene therapy, we investigated the impact of 11cRAL treatment in an early-age LCA2 retinal degeneration 12 (rd12) mouse model. Similar to human patients, the mouse model carries a spontaneous mutation in the Rpe65 gene, which results in disrupted endogenous 11cRAL regeneration. We found that RPE65 deficiency did not notably affect rodent retinal vessels. Under red light illumination, the rd12 mice were intraperitoneally injected with exogenous 11cRAL from postnatal day (P) 14 to P21. Three days after the last injection, a notable recovery of retinal function was observed using scotopic and photopic electroretinograms. Using optical coherence tomography and histological analyses of the deficient retinas, we found changes in the thickness of the photoreceptor outer segment (OS); this change could be rescued by early 11cRAL treatment. In addition, the treatment notably preserved M- and S-opsins, both of which maintained appropriate localization inside cone cells, as shown by the wild-type mice. In contrast, the age-matched untreated rd12 mice were characterized by retinal S-opsin loss and M-opsin mislocalization from the photoreceptor OS to the inner segment, outer nuclear layer, or outer plexiform layer. Notably, 11cRAL treatment could not maintain retinal function for a long time. Ten days after the last injection, the rod and M-cone electroretinograms significantly decreased, and S-cone responses almost extinguished. Our findings suggest that early 11cRAL treatment is useful for restoring retinal function and rescuing morphology in the rd12 mouse model, and the early-onset and rapid cone degeneration can be delayed before gene therapy.
Leber's congenital amaurosis: An update
2003, European Journal of Paediatric Neurology
Leber's congenital amaurosis (LCA) is a clinically and genetically heterogeneous disorder characterized by severe loss of vision at birth. It accounts for 10–18% of cases of congenital blindness. Some patients exhibit only blindness of retinal origin whereas others show evidence of a multi-systemic involvement. We review the literature relating to this severe disorder, highlighting unresolved questions, in particular the nature of the association of LCA with mental retardation and with systemic findings and syndromic pictures. In recent years, genetic advances in the diagnosis of LCA have opened up new horizons, also from a therapeutic point of view. A better understanding of this pathology would be valuable for paediatric neurologists.
The Natural History of Leber's Congenital Amoaurosis: Age-related Findings in 35 Patients
1992, Ophthalmology
The authors studied 35 patients with Leber's congenital amaurosis and assessed visual acuity, fundus appearance, and systemic findings. The patients were arbitrarily divided into five age groups. Visual acuities were comparable at all ages. Of 22 patients seen for follow-up examinations (mean length of follow-up, 5 years), vision worsened slightly in only 4 patients (3 with macular coloboma-like lesions and 1 with keratoconus). Fifty percent of retinal examinations in patients younger than 1 year of age were normal. With increasing age, retinal pigmentary changes became evident. All but four patients seen on more than one occasion developed progressive retinal/retinal pigment epithelium changes. Cataracts (5 patients) and keratoconus (3 patients) were present only in older patients (9 to 33 years of age). In Leber's congenital amaurosis, which probably comprises a number of genetically heterogenous conditions, visual acuity remains stable despite progressive retinal pigmentary changes. The subgroup of patients with macular colobomas, however, may develop progressive decrease in vision. Cataracts and keratoconus are additional factors contributing to visual impairment in older patients.
Early-onset autosomal dominant retinitis pigmentosa with severe hyperopia
1991, American Journal of Ophthalmology
We studied a four-generation family with early-onset autosomal dominant retinitis pigmentosa, severe hyperopia, and axial eye lengths of less than 20 mm. The affected members had decreased vision, night blindness, typical peripheral retinal pigmentary changes, and electroretinographic abnormalities characteristic of retinitis pigmentosa. This pedigree suggests there is another variant of retinitis pigmentosa associated with hyperopia besides Leber's congenital amaurosis and preserved para-arteriole retinal pigment epithelium.
NMNAT1 variants cause cone and cone-rod dystrophy
2018, European Journal of Human Genetics
Mitochondrial myopathies and disorders
2017, Metabolic Diseases: Foundations of Clinical Management, Genetics, and Pathology

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Clinical Spectrum of Leber's Congenital Amaurosis in the Second to Fourth Decades of Life

Abstract

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Ueber retinitis pigmentosa und angeborene Amaurose

Archiv fur Ophthal

l'importance diagnostique et pronostique de l'électrorétinogramme (ERG) dans les dégénérescences tapétorétiniennes avec rétrécissement du champ visuel et héméralopie

Confinia Neurol

Hérédo-retinopathia congénitalis-monohybrida récessiva autosomalis

Hereditas

Amaurosis congenita (Leber)

Arch Ophthalmol

Clinical and genetic investigations in Leber's tapeto-retinal dystrophy: some characteristic aspects in Turkey

Ann Ophthalmol