Leber Congenital Amaurosis
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
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’.
Systemic Features
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.
Genetics
Inheritance
Leber congenital amaurosis is genetically heterogeneous with at least 18 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 links to the genotypic and phenotypic features of the 19 known types of LCA. All cause disease in the homozygous or compound heterozygous state.
LCA type OMIM# Locus Gene Symbol
LCA 11 613837 7q31.3-q332 IMPDH1
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).
**(Mutations in RPE65 has been described as also causing retinitis pigmentosa (RP20; 613794) with choroidal involvement.)
***Mutations in PRPH2 (RDS) has also been reported to cause retinitis pigmentosa 7, choroidal dystrophy, and vitelliform macular dystrophy (179605) among others.
See also Leber Congenital Amaurosis with Early-Onset Deafness.
Mutations in the GUCY2D gene seem to be the most common being present in about 21% of LCA patients with CRB1 next at 10%.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.