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Leber congenital amaurosis is a collective term applied to multiple recessively inherited conditions with early-onset retinal dystrophy causing infantile or early childhood blindness. There are no established diagnostic criteria. First signs are usually noted before the age of 6 months. These consist of a severe reduction in vision accompanied by nystagmus, abnormal pupillary responses, and photophobia. Ametropia in the form of hyperopia is common. Keratoconus (and keratoglobus) is frequently found in older children but it is uncertain if this is a primary abnormality or secondary to eye rubbing as the latter is commonly observed. Repeated pressure on the eye may also be responsible for the relative enophthalmos often seen in these patients. The ERG is reduced or absent early and permanently. Final visual acuity is seldom better than 20/400 and perhaps one-third of affected individuals have no light perception. Some individuals experience a period of vision improvement.
The retina usually has pigmentary changes but these are not diagnostic. Retinal vessels are generally attenuated. The RPE may have a finely granulated appearance or, in some cases, whitish dots, and even ‘bone spicules’.
A variety of metabolic and physical abnormalities have been reported with LCA but many publications are from the pre-genomic era and the significance of such associations remains uncertain. Most extraocular signs result from delays in mental development but it is uncertain what role, if any, that visual deprivation plays. Perhaps 20% of patients are mentally retarded or have significant cognitive deficits.
Leber congenital amaurosis is genetically heterogeneous with 16 known gene mutations associated with the phenotype. It is also clinically heterogeneous both within and among families and this is the major obstacle to the delineation of individual clinicogenetic entities. As more patients are genotyped, it is likely that more precise genotype-phenotype correlations will emerge. At the present time, however, it is not possible to use clinical findings alone to distinguish individual conditions.
Below are the relevant genetic features of the 17 known types of LCA. All cause disease in the homozygous or compound heterozygous state.
LCA type OMIM# Locus Gene Symbol
LCA 1 204000 7p13.1 GUCY2D
LCA 2 204100 1p31 RPE65**
LCA 3 604232 14q31.3 SPATA7
LCA 4 604393 17p13.1 AIPL1
LCA 5 604537 6q14.1 LCA5
LCA 6 613626 14q11 RPGRIP1
LCA 7 613829 19q13.1 CRX*
LCA 8 613835 1q31-q32 CRB1
LCA 9 608553 1p36 NMNAT1
LCA 10 611755 12q21 CEP290
LCA 11 613837 7q31.3-q332 IMPDH1
LCA 12 601612 1q32.3 RD3
LCA 13 612712 14q24.1 RDH12
LCA 14 613341 4q31 LRAT
LCA 15 613843 6P21-31 TULP1
LCA 16 193230 2q37 KCNJ13
It is likely that more mutant genes will be identified since these are found in only about half of patients studied in large series.
*(Heterozygous mutations in CRX may also cause a cone-rod dystrophy).
Until recently, no treatment was available for LCA. However, results from early clinical trials with adeno-associated virus vector mediated gene therapy for RPE65 mutations in LCA 2 show promise. Subretinal placement of recombinant adeno-virus carrying RPE65 complementary DNA results in both subjective and objective improvements in visual function. Patients generally report subjective improvement in light sensitivity and visual mobility. Some recovery of rod and cone photoreceptor function has been documented. Studies have also documented an improvement in visual acuity, size of visual field, pupillary responses, and in the amouunt of nystagmus. More than 230 patients have now been treated and improvements seem to be maintained for at least 3 or more years. However, we have also learned that along with the enzymatic dysfunction of RPE65 that disrupts the visual cycle, there is also degeneration of photoreceptors which continues after treatment and the long term prognosis remains guarded. Multiple phase I clinical trials have demonstrated the safety of this approach and phase III trials are now underway.
It is crucial for patients to be enrolled early in sensory stimulation programs to ensure optimum neural development. For patients with residual vision, low vision aids can be beneficial. Vocational and occupational therapy should be considered for appropriate patients.