Toshitaka Itabashi

Identifying Pathogenic Genetic Background of Simplex or Multiplex Retinitis Pigmentosa Patients: A Large-Scale Mutation Screening Study

Background and purpose: More than half of the retinitis pigmentosa (RP) cases are genetically simplex or multiplex. To date, 37 causative genes of RP have been identified; however, the elucidation of gene defects in simplex or multiplex RP patients/families remains problematic. The aim of our study was to identify the genetic causes of RP in patients with unknown or non-Mendelian inheritance. Methods and results: Since 2003, 52 simplex RP patients, 151 patients from 141 multiplex RP families, and six sporadic patients with retinal degeneration were studied. A total of 108 exons of 30 RP-causing genes that harboured the reported mutations were screened by an efficient denaturing high performance liquid chromatography (dHPLC) based assay. Aberrant fragments were subsequently analysed by automatic sequencing. Twenty-six mutations, including two frameshift mutations, one single amino acid deletion, and 23 missense mutations, were identified in 28 probands (14.07%). Eighteen mutations have not been reported to date. Three pairs of combined mutations in different genes were identified in two sporadic cases and one multiplex family, indicating the possibility of novel digenic patterns. Of the 23 missense mutations, 21 were predicted as deleterious mutations by computational methods using PolyPhen, SIFT, PANTHER, and PMut programs. Conclusion: We elucidated the mutation spectrum in Japanese RP patients and demonstrated the validity of the mutation detection system using dHPLC sequencing for genetic diagnosis in RP patients independent of familial incidence, which may provide a model strategy for identifying genetic causes in other diseases linked to a wide range of genes.

Adult-onset Foveomacular Vitelliform Dystrophy with Retinal Folds

BACKGROUND Adult-onset foveomacular vitelliform dystrophy is characterized by a solitary, oval, slightly elevated, yellowish subretinal lesion of the fovea. We examined a patient with adult-onset foveomacular vitelliform dystrophy with stellate retinal folds by optical coherence tomography and scanning laser ophthalomoscopy. CASE A 58-year-old Japanese woman with a complaint of decreased vision in her right eye was diagnosed as having adult-onset foveomacular vitelliform dystrophy. OBSERVATIONS Ophthalmoscopic examination revealed a yellowish lesion of one-third disc diameter in size at the fovea in the right eye. Fluorescein angiography demonstrated an irregular block of choroidal fluorescence corresponding to the yellowish lesion, which was surrounded by stellate retinal folds. Optical coherence tomography images showed a steep elevation of the retinal pigment epithelium (RPE) as a focally protruded reflective band over an optically clear space. Scanning laser ophthalmoscopy provided morphologic enhancement in the specifically affected layers of the macula. Using an argon green laser, band-shaped bright reflexes were seen in the right fovea. The helium-neon laser revealed a bright patch corresponding to the yellowish lesion over the fovea, which was surrounded by stellate retinal folds. The diode laser revealed a bright patch corresponding to the yellowish lesion. CONCLUSION The stellate retinal folds of this patient were considered to be caused by the steep elevation of the RPE with an extracellular accumulation of the vitelliform deposits.

Clinical features of a Japanese family with autosomal dominant retinitis pigmentosa associated with a Thr494Met mutation in the HPRP3 gene

AbstractPurposeTo determine the clinical features of a Japanese family with autosomal dominant retinitis pigmentosa (ADRP) associated with a Thr494Met mutation in the HPRP3 gene.MethodsMutational screening by direct sequencing was performed on 96 unrelated patients with ADRP. The clinical features were determined by visual acuity, slit-lamp biomicroscopy, electroretinography, fluorescein angiography, and kinetic visual field testing.ResultsA Thr494Met mutation in the HPRP3 gene was found in one family and it cosegregated with ADRP in the three affected members. The ophthalmic findings were those of typical retinitis pigmentosa with rapid progression after 40-years-of-age. One patient also had retinoblastoma as a child.ConclusionWe conclude that the Thr494Met mutation in the HPRP3 gene causes ADRP in Japanese patients. This mutation was found in 1% of patients with ADRP in Japan.

Clinical features of Japanese families with a 402delT or a 555-556delAG mutation in choroideremia gene.

Purpose: To characterize the clinical features of two Japanese families with choroideremia associated with a 402delT and a 555–556delAG mutation in the choroideremia gene (CHM). Methods: Four affected members and one obligate carrier from two Japanese families with choroideremia were studied. To detect mutations of the CHM gene, the products of polymerase chain reaction were directly sequenced in both directions. The ophthalmologic examination included best-corrected visual acuity, slit-lamp examination, fundus examination, kinetic perimetry, electroretinography, and fluorescein angiography. Results: A 402delT and a 555–556delAG mutation were found in two Japanese families with choroideremia. All affected members had night-blindness, progressive constriction of the visual field, chorioretinal atrophy, and mottled appearance of the retinal pigment epithelium. The obligate carrier had mild patchy areas of retinal pigment epithelial atrophy with no visual symptoms. Conclusion: The authors found a 402delT and a 555–556delAG mutation in the CHM gene, one of which (402delT) is a novel mutation. They conclude that these mutations cause choroideremia in Japanese families.

Ocular findings in a Japanese family with an Arg41Trp mutation of the CRX gene

PurposeTo characterize the ophthalmological features and clinical course of an autosomal dominant cone–rod dystrophy (CORD2) in a Japanese family with an Arg41Trp mutation in the CRX gene.MethodsMutation screening by direct sequencing was performed on 42 patients with cone–rod dystrophy. The clinical features of the patients were characterized by the visual acuity and by the findings of slit-lamp biomicroscopy, electroretinography, fluorescein angiography, and kinetic visual field testing.ResultsAn Arg41Trp mutation in the CRX gene was identified in three members from three generations of one family with cone–rod dystrophy. Fundus examination demonstrated that the retinal dystrophy worsened with increasing age.ConclusionsA heterozygous Arg41Trp mutation in the CRX gene can produce cone–rod dystrophy in Japanese patients. Clinical examination of patients of different ages demonstrated that there was a rapid progressive worsening of the disease with increasing age.

Macular degeneration in a Japanese patient with aceruloplasminemia.

PURPOSE To characterize the clinical features of a Japanese patient with macular degeneration in aceruloplasminemia. METHODS The clinical features were evaluated by visual acuity measurements, fluorescein angiography, electroretinography, and kinetic visual field testing. RESULTS We observed a Japanese patient with macular degeneration in aceruloplasminemia. This patient also had diabetes mellitus and neurodegeneration. Ocular examination showed macular degeneration, which included yellow deposits around the macula area and no foveal reflex. CONCLUSION It has been reported that Japanese patients with aceruloplasminemia have atrophy of the retinal pigment epithelium in the midperipheral area and yellowish discoloration of the fundus. However, the retinal findings and results of fluorescein angiography in our case were very similar to those for a white patient. We suggest that retinal degenerations in Japanese patients with aceruloplasminemia have clinical variability. We believe that impairment of iron metabolism caused by iron overload in the retina led to retinal degeneration in this case.