Relative frequencies of inherited retinal dystrophies and optic neuropathies in Southern France: assessment of 21-year data management.

PURPOSE: Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are rare diseases defined by specific clinical and molecular features. The relative prevalence of these conditions was determined in Southern France. METHODS: Patients recruited from a specialized outpatient clinic over a 21-year period underwent extensive clinical investigations and 107 genes were screened by polymerase chain reaction/sequencing. RESULTS: There were 1957 IRD cases (1481 families) distributed in 70% of pigmentary retinopathy cases (56% non-syndromic, 14% syndromic), 20% maculopathies and 7% stationary conditions. Patients with retinitis pigmentosa were the most frequent (47%) followed by Usher syndrome (10.8%). Among non-syndromic pigmentary retinopathy patients, 84% had rod-cone dystrophy, 8% cone-rod dystrophy and 5% Leber congenital amaurosis. Macular dystrophies were encountered in 398 cases (30% had Stargardt disease and 11% had Best disease). There were 184 ION cases (127 families) distributed in 51% with dominant optic neuropathies, 33% with recessive/sporadic forms and 16% with Leber hereditary optic neuropathy. Positive molecular results were obtained in 417/609 families with IRDs (68.5%) and in 27/58 with IONs (46.5%). The sequencing of 5 genes (ABCA4, USH2A, MYO7A, RPGR and PRPH2) provided a positive molecular result in 48% of 417 families with IRDs. Except for autosomal retinitis pigmentosa, in which less than half the families had positive molecular results, about 75% of families with other forms of retinal conditions had a positive molecular diagnosis. CONCLUSIONS: Although gene discovery considerably improved molecular diagnosis in many subgroups of IRDs and IONs, retinitis pigmentosa, accounting for almost half of IRDs, remains only partly molecularly defined.

Screening genes of the retinoid metabolism: novel LRAT mutation in leber congenital amaurosis.

PURPOSE: To evaluate the mutation prevalence and phenotype in genes involved in the ocular retinoid metabolism. DESIGN: We analyzed LRAT, encoding the lecithin retinol acyltransferase, and RDH10, a retinal pigment epithelium-specific retinol dehydrogenase. METHODS: We screened by denaturing-high performance liquid chromatography (D-HPLC) and direct sequencing all coding exons of LRAT and RDH10 in 216 patients, including 134 with simplex or multiplex retinitis pigmentosa and 82 with various types of flecked retinal dystrophies. RESULTS: Only nonpathogenic variants were found in this series. In an additional 2.5-year-old patient presenting with an "RPE65" phenotype (night blindness, photoattractivity, and visual improvement several months after birth), we discovered a homozygous deletion in LRAT (c.217_218delAT) leading to a premature stop at codon 120. CONCLUSIONS: The phenotype of patients with mutations in LRAT is similar to that of patients with mutations in RPE65, suggesting the need to systematically screen both genes in case of typical phenotype.

Gene structure, chromosomal localization, and mutation screening of the human gene for the inner ear protein otospiralin.

Otospiralin is a novel protein of unknown function that is produced by non-sensory cells (fibrocytes) of the inner ear (cochlea and vestibule). We showed that downregulation of otospiralin in guinea pigs leads to deafness and we therefore hypothesized that genetic defects in the otospiralin gene could also cause deafness in humans. In this study, we cloned and localized OTOSP, the human gene for otospiralin. OTOSP spans 1630 nucleotides, contains four exons and codes for a 567-nucleotide cDNA. By fluorescence in situ hybridization and hybrid panel mapping we localized OTOSP on chromosome 2 at position q37.3. There is currently no deafness family linked to this region. We screened OTOSP for mutations in 410 unrelated patients exhibiting various levels of hearing loss. Beside intronic polymorphisms, a rare variant (Pro7Leu) was found in 4 deafness patients and 3 control individuals, indicating that this change is not involved in this condition and excluding OTOSP as a major gene for genetic deafness.

Phenotypic diversity and mutation spectrum in hypotrichosis with juvenile macular dystrophy.

Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by abnormal growth of scalp hair during infancy, and by the later occurrence of macular degeneration leading to blindness during the first to third decade of life. Hypotrichosis with juvenile macular dystrophy was recently shown to result from mutations in CDH3 encoding P-cadherin. In this study, we assessed 27 individuals, including nine patients, belonging to five families in an attempt to characterize further the CDH3 mutation spectrum and delineate possible phenotype-genotype correlations. Deleterious biallelic mutations, predicted to lead to the translation of a dysfunctional protein, were found in all affected individuals. Four of these mutations are novel. Affected individuals of two large separate apparently unrelated families of Arab Israeli origin were found to carry the same homozygous mis-sense mutation (R503H) in exon 11 of the CDH3 gene. This mutation, which alters a Ca2+-binding site in the fourth extracellular domain of P-cadherin, was previously described in a third unrelated Arab Israeli family. Using haplotype analysis for a series of polymorphic markers encompassing the CDH3 gene, we obtained evidence suggesting a founder effect for R503H in the Arab Israeli population. We also compared the dermatologic and ophthalmologic features of 22 hypotrichosis with juvenile macular dystrophy patients with known recessive mutations in CDH3. Whereas hair paucity and macular degeneration were found in all patients, we noticed significant interfamilial and intrafamilial differences in hair morphology, associated skin findings as well as severity and age of onset of visual disability. Altogether, our results obtained in a series of families of various ethnic origins firmly establish mutations in CDH3 as the proximal cause of hypotrichosis with juvenile macular dystrophy and demonstrate genetic homogeneity as well as phenotypic heterogeneity in this disorder.

Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy.

The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.