[Genetic and clinical heterogeneity in LCA patients. The end of uniformity]. / Genetische und klinische Heterogenität bei LCA-Patienten. Das Ende der Einheitlichkeit.

BACKGROUND: Leber congenital amaurosis (LCA) usually describes patients with severely reduced vision due to a retinal dystrophy in early childhood. METHODS: In 135 families in a case series with severely reduced vision due to a retinal dystrophy in early childhood a complete ophthalmologic examination was extended by two-color threshold perimetry, fundus autofluorescence (FAF), und optical coherence tomography (OCT). Mutation screening included AIPL1, CRB1, CRX, GUCY2D, LRAT, RPE65, RPGRIP, and TULP1. RESULTS: GUCY2D mutations caused the most severe phenotype with severely reduced vision from birth but unremarkable fundus appearance. RPE65 mutations were correlated with an obvious lack of FAF. CRB1 mutations showed a significantly thickened retina on OCT. CRX mutations were associated with a progressive form of cone-rod dystrophy. CONCLUSION: A genotype-phenotype correlation for selected genes allows an optimized strategy for the molecular genetic work-up.

Genotype-phenotype correlation in a German family with a novel complex CRX mutation extending the open reading frame.

PURPOSE: To describe the genotype-phenotype correlation in a German family with a novel CRX mutation and to perform a comparative analysis of published cases. DESIGN: Retrospective observational case series, systematic review, and comparative analysis of the literature. PARTICIPANTS: Four related patients with progressive retinal degeneration. METHODS: Mutation screening by single-strand polymorphism analysis and direct sequencing. Clinical examination included kinetic visual fields (VFs), 2-color threshold perimetry (2CTP), full-field electroretinography, fundus photography, optical coherence tomography, and fundus autofluorescence (FA) recording. MAIN OUTCOME MEASURES: Visual fields, subjective and objective cone- and rod-specific function, fundus aspect, retinal stratification, and FA. RESULTS: A novel heterozygous complex mutation (c.816delCACinsAA) in CRX predicting the substitution of 27 C-terminal amino acids by 44 novel amino acids, thus abolishing the OTX tail, was identified in a 2-generation family finally diagnosed with cone-rod dystrophy (CRD), which was confirmed by 2CTP. Patients presented with variability in progression, nystagmus, and nyctalopia. Most of the patients were hyperopic. Electroretinography recordings showed residual rod and mixed cone-rod responses in 2 of the subjects. Age-dependent VF losses followed funduscopic changes of progressive atrophy of the retinal pigment epithelium and neuroretina in the macula and midperiphery marked by disturbed FA. Optical coherence tomography showed decreased central retinal thickness. Comparative analysis of the 131 published data sets revealed 2 groups: patients with early and late onset. CONCLUSIONS: We described a 2-generation family with a novel mutation in CRX. The resulting phenotype is that of CRD with variable age at onset and progression. The phenotype description of previously published cases is conclusive only for CRD.