Objectives:To describe the phenotype of Leber congenital amaurosis (LCA) in 26 probands with mutations in aryl hydrocarbon receptor interacting proteinlike 1 protein (AIPL1) and compare it with phenotypes of other LCA-related genes. To describe the electroretinogram (ERG) in heterozygote carriers.
Methods:Patients with AIPL1-related LCA were identified in a cohort of 303 patients with LCA by polymerase chain reaction single-strand confirmational polymorphism mutation screening and/or direct sequencing. Phenotypic characterization included clinical and ERG evaluation. Seven heterozygous carrier parents also underwent ERG testing.Results: Seventeen homozygotes and 9 compound heterozygotes were identified. The W278X mutation was most frequent (48% of alleles). Visual acuities ranged from light perception to 20/400. Variable retinal appearances, ranging from near normal to varying degrees of chorioretinal atrophy and intraretinal pigment migra-tion, were noted. Atrophic and/or pigmentary macular changes were present in 16 (80%) of 20 probands. Keratoconus and cataracts were identified in 5 (26%) of 19 patients, all of whom were homozygotes. The ERG of a parent heterozygote carrier revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.
Conclusions:The phenotype of LCA in patients with AIPL1 mutations is relatively severe, with a maculopathy in most patients and keratoconus and cataract in a large subset. Rod ERG abnormalities may be present in heterozygous carriers of AIPL1 mutations.Clinical Relevance: Understanding and recognizing the phenotype of LCA may help in defining the course and severity of the disease. Identifying the gene defect is the first step in preparation for therapy since molecular diagnosis in LCA will mandate the choice of treatment.
Hermansky-Pudlak syndrome (HPS) (MIM #203300) is a heterogeneous group of autosomal recessive disorders characterized by oculocutaneous albinism (OCA), bleeding tendency, and lysosomal dysfunction. HPS is very common in Puerto Rico (PR), particularly in the northwest part of the island, with a frequency of approximately 1:1,800. Two HPS genes and mutations have been identified in PR, a 16-base pair (bp) duplication in HPS1 and a 3,904-bp deletion in HPS3. In Puerto Ricans with more typical OCA, the most common mutation of the tyrosinase (TYR) (human tyrosinase (OCA1) gene) gene was G47D. We describe screening 229 Puerto Rican OCA patients for these mutations, and for mutations in the OCA2 gene. We found the HPS1 mutation in 42.8% of cases, the HPS3 deletion in 17%, the TYR G47D mutation in 3.0%, and a 2.4-kb deletion of the OCA2 gene in 1.3%. Among Puerto Rican newborns, the frequency of the HPS1 mutation is highest in northwest PR (1:21; 4.8%) and lower in central PR (1:64; 1.6%). The HPS3 gene deletion is most frequent in central PR (1:32; 3.1%). Our findings provide insights into the genetics of albinism and HPS in PR, and provide the basis for genetic screening for these disorders in this minority population.
Results of this study suggest that patients with OCA (all types included) and patients with HPS-1 have thicker foveas than the general population. This may be due to the absence of foveal pit as part of foveal hypoplasia associated with OCA. Conversely, participants have lower macular volumes than the general population. This finding is compatible with loss of retinal nuclear layers in patients with OCA.
The authors examined two patients with deletions of the terminal end of the long arm of chromosome 18. The ocular findings in one patient with 46, XX, del 18 (q21) consisted of hypertelorism, epicanthus, strabismus, myopia, microphthalmia, microcornea, corneal opacities, iris hypoplasia with full thickness defects, corectopia and large peripapillary staphylomata. The second patient with 46, XX, del (18) (pter --> q21.2 :: q22 --> qter), inv (21) (q21 --> p12 :: q21 --> qter) only had epicanthus, strabismus, myopia and peripapillary crescents. Based on the findings in these two patients and on a review of previously reported patients with del 18 qter it appears that the loss of band 18q23 may be responsible for malformations of the anterior segment in the 18q-syndrome.
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