Designing a muon scattering scanner for nuclear debris measurement.

Removal of fuel debris is planned to start at Unit 2 of the Fukushima Daiichi Nuclear Power Plant. During the removal, it is desirable to distinguish fuel debris from radioactive wastes and to sort the fuel debris accordingly to the amounts of nuclear material contained. Muon scattering tomography invented at Los Alamos in the early 2000s is highly sensitivity to high-atomic-number materials such as uranium. A muon scanner to sort the debris is designed and currently in production. One of the challenges is to operate the muon scanner in the presence of high γ-ray radiations from the debris: muon-event-identification electronics and a muon-tracking algorithm in the presence of high γ-ray radiations were developed.

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

LRRTM4-C538Y novel gene mutation is associated with hereditary macular degeneration with novel dysfunction of ON-type bipolar cells.

The macula is a unique structure in higher primates, where cone and rod photoreceptors show highest density in the fovea and the surrounding area, respectively. The hereditary macular dystrophies represent a heterozygous group of rare disorders characterized by central visual loss and atrophy of the macula and surrounding retina. Here we report an atypical absence of ON-type bipolar cell response in a Japanese patient with autosomal dominant macular dystrophy (adMD). To identify a causal genetic mutation for the adMD, we performed whole-exome sequencing (WES) on four affected and four-non affected members of the family for three generations, and identified a novel p.C538Y mutation in a post-synaptic gene, LRRTM4. WES analysis revealed seven rare genetic variations in patients. We further referred to our in-house WES data from 1360 families with inherited retinal diseases, and found that only p.C538Y mutation in LRRTM4 was associated with adMD-affected patients. Combinatorial filtration using public database of single-nucleotide polymorphism frequency and genotype-phenotype annotated database identified novel mutation in atypical adMD.

Hidden Genetic Variation in LCA9-Associated Congenital Blindness Explained by 5'UTR Mutations and Copy-Number Variations of NMNAT1.

Leber congenital amaurosis (LCA) is a severe autosomal-recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden noncoding defects or structural variations (SVs). The starting point of this study was an LCA9-associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the untranslated regions of NMNAT1 revealed a novel homozygous 5'UTR variant, c.-70A>T. Moreover, an adjacent 5'UTR variant, c.-69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5'UTR variants resulted in decreased NMNAT1 mRNA abundance in patients' lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE-1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu-rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1-associated LCA and emphasized a shift from coding to noncoding regulatory mutations and repeat-mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness.

A novel mutation (967-970+2)delAAAGGT in the choroideremia gene found in a Japanese family and related clinical findings.

PURPOSE: To investigate the choroideremia (CHM) gene of one affected male and one obligate carrier in a Japanese family with choroideremia, and to characterize the related clinical features. METHODS: We examined one affected man and one carrier woman from a Japanese family. Genomic DNA was extracted from leukocytes of peripheral blood collected from the affected man and his daughter, who is an obligate carrier of choroideremia. Exons 1-15 of the CHM gene were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations including best-corrected visual acuity, slit-lamp examination, fundus examination, electroretinography, and Goldmann perimetry. RESULTS: A novel (967-970+2)delAAAGGT mutation was detected in the CHM gene. The affected man was hemizygous and had night-blindness, chorioretinal atrophy spreading from the posterior pole to the mid-periphery, and bareness of the sclera. His daughter was a heterozygous carrier who had chorioretinal atrophy and mottled appearance of the retinal pigment epithelium. CONCLUSION: A novel (967-970+2)delAAAGGT mutation existed in the CHM gene of a Japanese family with choroideremia.

A novel mutation in the cornea-specific keratin 12 gene in Meesmann corneal dystrophy.

PURPOSE: To report a novel mutation in the keratin 12 gene (KRT12) found in a Japanese family in association with Meesmann corneal dystrophy (MECD). METHODS: After informed consent was obtained, genomic DNA was extracted from the leukocytes of the peripheral blood of the proband, her affected father, normal mother, and 50 normal unrelated volunteers. Exons 1-8 of the KRT12 gene were amplified by polymerase chain reaction and directly sequenced. RESULTS: A novel heterozygous T to G transversion at the second nucleotide position of codon 433 (CTG>CGG), resulting in the replacement of leucine by arginine at codon 433 of the KRT12 gene (L433R), was detected in the proband and her affected father but not in her normal mother or the 50 controls. CONCLUSIONS: The novel L433R mutation of the KRT12 gene found in two members of this Japanese family caused MECD.

In vivo laser confocal microscopic findings of corneal stromal dystrophies.

OBJECTIVE: To investigate in vivo laser confocal microscopic findings of genetically mapped corneal stromal dystrophies and their relationship to histopathologic findings. METHODS: Seven patients with Avellino corneal dystrophy, 2 patients with lattice corneal dystrophy, and 2 patients with macular corneal dystrophy were examined genetically and using slitlamp biomicroscopy and in vivo laser confocal microscopy. Corneal specimens obtained after surgery in selected patients were histopathologically studied. RESULTS: In Avellino corneal dystrophy (Arg124His mutation of human transforming growth factor beta-induced gene [TGFBI]), highly reflective granular materials with irregular edges were observed in the superficial stroma. In lattice corneal dystrophy (Arg124Cys and Leu527Arg mutations of TGFBI), highly reflective branching filaments of variable width were observed in the stroma. In macular corneal dystrophy (Ala217Thr mutation of the carbohydrate sulfotransferase gene [CHST6]), homogeneous reflective materials with dark striaelike images were observed throughout the stroma. All confocal findings correlated well with histopathologic findings. CONCLUSIONS: In vivo laser confocal microscopy is capable of high-resolution visualization of characteristic corneal microstructural changes related to 3 types of genetically mapped corneal stromal dystrophies. The use of laser confocal microscopy may be valuable in the differential diagnosis of corneal stromal dystrophies, especially when diagnosis is otherwise uncertain.

Mitochondrial DNA mutations with Leber's hereditary optic neuropathy in Japanese patients with open-angle glaucoma.

PURPOSE: Abnormal optic disc excavations are found in patients with Leber's hereditary optic neuropathy (LHON). The purpose of this study was to determine whether heteroplasmy for the major three LHON mutations or for the rare LHON mutations are risk factors for open-angle glaucoma. METHODS: Blood samples from 835 Japanese subjects were screened with the Invader assay for ten LHON-associated mutations: three major mutations (G3460A, G11778A, T14484C) and seven rare mutations (T9101C, G9804A, C14482A, C14482G, G14459A, T14498C, and A14510G). Of the 835 subjects, 241 were patients with primary open-angle glaucoma (POAG), 310 were patients with normal-tension glaucoma (NTG), and 284 were healthy controls. RESULTS: Five POAG patients and three NTG patients had one of five mutations, C9099A, T9101G, T9101C, G9804A, or G11778A, but none of these patients had LHON. The C9099A (Ile191Met) and T9101G (Ile192Ser) mutations were novel and identified within the probes by lack of signal in the assay. Two patients with the G11778A mutation showed heteroplasmy, with 15% mutant mtDNA in the male patient and 80% in the female patient. The remaining LHON-associated mutations were not detected in any of the subjects. A case-control study did not show a significant difference (P = 0.099): eight potentially disease-associated variants in 551 patients versus zero variants in the 284 controls. CONCLUSIONS: Rare LHON-associated mitochondrial DNA mutations were found in Japanese patients with open-angle glaucoma (OAG). However, whether mitochondrial DNA mutations are risk factors for OAG is still open to question.

Central retinal vein occlusion caused by human herpesvirus 6.

We describe a 1-year-old girl with central retinal vein occlusion caused by human herpesvirus 6. She received systemic corticosteroid therapy. Although there was retinal recovery after the therapy, the visual acuity in her left eye still could not be measured.

[Clinical phenotype of a Japanese family with primary open-angle glaucoma caused by a Ala 363 Thr mutation in the MYOC gene].

BACKGROUND: Myocilin is a gene that causes primary open-angle glaucoma (POAG). We report a family whose members had an Ala 363 Thr mutation in the myocilin gene. We present the clinical phenotype of this family. CASE: The proband was a 57-year-old man diagnosed with POAG. His younger sister (50 years old) was also diagnosed with POAG. Visual field impairment did not worsen and ocular pressure decreased with eyedrop treatment. Although two of their children in their 30s had ocular hypertension, they did not have any sign of glaucomatous optic neuropathy. Genetic analysis revealed that all four family members had an Ala 363 Thr mutation in myocilin gene. CONCLUSION: Ala 363 Thr mutation was considered to be the cause of open-angle glaucoma. In this family, age at onset was comparatively high The two patients in their 30s had high intraocular pressure but no loss in visual acuity. The family members who had POAG and those who did not have POAG were not different from each other in the results of standard ocular examinations, only in age. Patients with this mutation will develop high intraocular pressure after 30 years of age and glaucomatous neuropathy after 50 years of age. When this gene mutation is detected in juvenile patients, careful follow-up and early therapy are necessary.

Genetic polymorphisms in the angiotensin II receptor gene and their association with open-angle glaucoma in a Japanese population.

PURPOSE: The local renin-angiotensin system (RAS) is present in the ciliary body and plays a role in regulating aqueous humor dynamics and thus intraocular pressure (IOP). The purpose of this study was to determine whether gene polymorphisms in the RAS increase the risk of development of glaucoma in the Japanese. METHODS: A case-control study was performed in 698 Japanese subjects: 190 patients with primary open-angle glaucoma (POAG), 268 patients with normal-tension glaucoma (NTG), and 240 normal subjects. Ten polymorphisms in seven genes-AGT/Thr174Met and AGT/Met235Thr; REN/I8-83G-->A; ACE/insertion(I)-deletion(D); CMA/-1930A-->G; AGTR1/-731T-->G, AGTR1/-521C-->T, and AGTR1/1166A-->C; AGTR2/3123C-->A; and CYP11B2/-344T-->C were examined. The age, IOP, and visual field defects, all at diagnosis, were examined to determine whether they were associated with the polymorphisms. The effects of oral angiotensin II receptor blocker (ARB) on IOP were examined in association with the AGTR1 and AGTR2 polymorphisms in 20 normal subjects. RESULTS: Of the 10 polymorphisms, the AGTR2/3123C-->A polymorphisms had a significantly different distribution in female patients with NTG; the frequency of the CA+AA genotypes was significantly higher than in female control subjects (P = 0.0095 for CC versus CA+AA). Although no significant difference was seen in the clinical characteristics of female patients with NTG who carried the AGTR2/3123C-->A genotype, patients with CC in the AGTR2 gene had significantly worse visual field scores if they carried ACE/ID+DD (i.e., D carriers; P = 0.012). ARB significantly lowered IOP in normal subjects, but the male subjects with the AGTR2/3123A genotype had significantly less lowering of IOP than those with the C genotype (P = 0.014). CONCLUSIONS: Angiotensin II receptor gene polymorphisms may be associated with the risk of glaucoma in the Japanese population.

Association between glaucoma and gene polymorphism of endothelin type A receptor.

PURPOSE: Endothelin 1 (ET-1), a potent vasoconstrictor, may affect regulation of intraocular pressure and ocular vessel tone. Thus, ET-1 and its receptors may contribute to development of glaucoma. We investigated whether gene polymorphisms of ET-1 (EDN1) and its receptors ETA (EDNRA) and ETB (EDNRB) were associated with glaucoma phenotypes and clinical features. METHODS: We studied 224 normal Japanese controls and 426 open angle glaucoma (OAG) patients including 176 with primary open angle glaucoma (POAG) and 250 with normal tension glaucoma (NTG). Nine single nucleotide polymorphisms were detected among the participants using the Invader assay; four for EDN1 (T-1370G, +138/ex1 del/ins, G8002A, K198N), four for EDNRA (G-231A, H323H, C+70G, C+1222T), and one for EDNRB (L277L). Genotype distributions were compared between normal controls and OAG. Age at diagnosis, untreated maximum intraocular pressure (IOP), and visual field defects at diagnosis were examined for association with polymorphisms. RESULTS: Of the 9 polymorphisms, genotype distributions showed no significant differences between OAG patients and controls adjusted by age. The GG genotype of EDNRA/C+70G was associated with worse visual field defects in NTG patients (p=0.014; Mann-Whitney U test, and p=0.027; logistic regression analysis). CONCLUSIONS: The polymorphism of EDNRA/C+70G may be related to NTG risk factors.

Epilepsy phenotypes in siblings with Norrie disease.

Norrie disease is an X-linked recessive disorder that is characterized by congenital blindness. Although epileptic seizures are observed in some patients with Norrie disease, little is known about this phenomenon. Here, we report the manifestation of epilepsy in siblings with Norrie disease to increase our knowledge of epilepsy in this condition. Three brothers with congenital blindness were diagnosed with Norrie disease after genetic analyses indicated the deletion of exon 2 of the NDP gene. The eldest brother had suffered from epileptic seizures since the age of 11years, and his seizures were resistant to antiepileptic drugs. Although the second brother had no epileptic seizures, the youngest sibling had experiences epileptic seizures since the age of 8years. His seizures were controlled using lamotrigine and levetiracetam. An electroencephalography (EEG) revealed epileptiform discharges in the occipital areas in all three brothers. A study of these patients will increase our knowledge of epilepsy in patients with Norrie disease.

Truncation and mutagenesis analysis of the human X-arrestin gene promoter.

X-arrestin (arrestin-3) is an arrestin present specifically in the outer segments of red-, green-, and blue-cone photoreceptors. The X-arrestin gene is on Xcen-q22, and consists of 17 exons with a promoter containing a TATA box and elements important for photoreceptor expression, including three CRX and one PCE-1-like element. In order to delineate the promoter structure necessary for the pan-cone-specific expression of X-arrestin, the expression of the gene in retinoblastoma cell lines was investigated, and a structure-function analysis of the promoter was conducted in the appropriate cellular substrate. Expression of X-arrestin was detected at a low level in the Y79 retinoblastoma cell line but not in the WERI retinoblastoma cell line. Truncation and expression analysis of the X-arrestin promoter in Y79 showed maximal activity in the proximal 378-bp region containing the CRX and PCE-1-like elements upstream of the TATA and CAAT boxes and a negative regulator in the distal 1-2-kbp region. Mutagenesis of the three CRX and PCE-1-like elements and expression analysis demonstrated complete elimination of the promoter activity. Mutagenesis of the TATA box and PCE-1-like element individually resulted in similar decrease in promoter activity, but the decrease in the promoter activity was greater when the CRX elements were mutagenized with a 5' to 3' spatial gradient in the negative effect, suggesting a cooperative effect of the three CRX elements. The regulation of expression from this promoter may involve the binding of a multi-protein enhanceosome complex at the CRX triplet and the PCE-1-like element, resulting in the recruitment and activation of the RNA polymerase II complex at the downstream TATA box.

Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma.

PURPOSE: To investigate sequence variations in the optineurin (OPTN) gene and their association with TNF-alpha polymorphisms in Japanese patients with glaucoma. METHODS: The OPTN gene was analyzed in blood samples from 629 Japanese subjects. There were 194 patients with primary open-angle glaucoma (POAG), 217 with normal-tension glaucoma (NTG), and 218 with no eye disease (control subjects). The gene was screened for mutations by denaturing high-performance liquid chromatography. Genotyping of three polymorphisms of -308G-->A, -857C-->T, and -863C-->A in the TNF-alpha promoter region was performed. The associations between the genotypes and age, intraocular pressure (IOP), and visual field defects at the time of diagnosis were examined. RESULTS: A possible glaucoma-causing mutation, His26Asp, was identified in 1 of the 411 Japanese patients with glaucoma. A c.412G-->A (Thr34Thr) polymorphism in the OPTN gene was significantly associated with POAG (genotype frequency, P = 0.011; allele frequency, P = 0.003). The frequency of TNF-alpha/-857T and optineurin/412A carriers was significantly higher (P = 0.006) in patients with POAG than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-857T, the optineurin/412A carriers had significantly worse (P = 0.020) visual field scores than the non-optineurin/412A ones. The frequency of TNF-alpha/-863A and optineurin/603A (or Lys98) carriers was significantly higher in patients with POAG (P = 0.008) or NTG (P = 0.027) than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-863A, the ones with optineurin/603A (or Lys98) had significantly worse (P = 0.026) visual field scores than did those with non-optineurin/603A (or Lys98). CONCLUSIONS: These findings demonstrated that the OPTN gene is associated with POAG rather than NTG in the Japanese. Statistical analysis showed a possible interaction between polymorphisms in the OPTN and the TNF-alpha genes that would increase the risk for glaucoma.

Novel MYOC gene mutation, Phe369Leu, in Japanese patients with primary open-angle glaucoma detected by denaturing high-performance liquid chromatography.

PURPOSE: To screen for mutations in the MYOC gene in Japanese patients with primary open-angle glaucoma (POAG) using denaturing high-performance liquid chromatography (DHPLC). PATIENTS AND METHODS: Blood samples were collected from 171 patients with POAG and 100 controls from seven institutions in Japan. For high-throughput analysis, seven exonic regions were amplified by polymerase chain reaction using DNA pooled from three patients; each DNA pool was then analyzed chromatographically. For analysis of a small number of samples, 7 exonic regions were amplified separately but simultaneously with annealing at 58 degrees C in each patient and then chromatographed, using 7 wells of the same 96-well plate per sample. When chromatographic patterns were abnormal by either method, the PCR products of the individual samples were sequenced. RESULTS: Four glaucoma-causing mutations were identified in five POAG patients (2.9%). One missense mutation, Phe369Leu, is new; and three others, Ile360Asn, Ala363Thr, and Thr448Pro, have been reported in Japanese patients. Phe369Leu was associated with adult onset POAG. CONCLUSIONS: Mutations in the MYOC gene were demonstrated chromatographically in 2.9% of our Japanese POAG patients. The use of pooled DNAs with DHPLC analysis is a time- and labor-saving technique. All mutations detected appear to be specific to Japanese patients.

Mutations in the membrane component, chromosome 1, surface marker 1 (M1S1) gene in gelatinous drop-like corneal dystrophy.

PURPOSE: To report mutations in the membrane component, chromosome 1, surface marker 1 ( M1S1) gene in two members of the same family who showed symptoms of gelatinous drop-like corneal dystrophy (GDLD). METHODS: DNA was extracted from leukocytes of peripheral blood of the two affected members of the family and from controls, and the coding region of M1S1 was amplified by polymerase chain reaction (PCR). The PCR products were analyzed by direct sequencing. Normal and mutant M1S1 expression vectors were constructed and transfected into CHO cells to identify the cellular location of the gene products. RESULTS: The affected members had compound heterozygous mutations consisting of a nonsense change at codon 84 (K84X) and a missense mutation resulting in a substitution of arginine for cysteine at codon 108 (C108R). Neither of these mutations was found in the 50 controls. Protein expression analysis showed that the C108R product was distributed diffusely in the cytoplasm, whereas the normal gene product accumulated at cell-to-cell adhesion borders. CONCLUSION: These data indicate that the K84X and C108R mutations in M1S1 cause GDLD.

A novel exon 17 deletion mutation of RPGRIP1 gene in two siblings with Leber congenital amaurosis.

PURPOSE: To investigate mutations of causal genes in two affected male siblings of a Japanese family with suspected Leber congenital amaurosis (LCA) and to characterize the related clinical features. METHODS: After obtaining informed consent, genomic DNA was extracted from peripheral blood of the proband and his family members. Mutation screening was initially performed with microarrays. The PCR and direct sequencing were successively done for confirmation of mutation detected by microarray, and the two patients who are the subjects of this study were also clinically examined. RESULTS: Results of the microarray suggested deletion of exon 17 of RPGRIP1. Confirmation by PCR and direct sequencing following microarray analysis revealed that both siblings had homozygous deletion of exon 17 of the RPGRIP1 gene, while their unaffected parents were heterozygous carriers. Length of the deletion was 1339 bp including exon 17 at the position of c.2710+372_2895+76del1339. Clinical features of the two siblings showed nystagmus, poor visual acuity, hyperopia, and photophobia since early childhood; but there was no oculo-digital sign, vessel attenuation or RPE mottling from the mid-retina to the periphery. Full-field single flash ERG was recordable but 30 Hz flicker ERG was not detectable. CONCLUSIONS: Although the present patients did not show sufficient clinical findings as LCA, PCR findings and direct sequencing following microarray analysis confirmed that they were LCA. Genetic analyses are helpful for confirmation of clinical diagnosis.

Familial cases of Norrie disease detected by copy number analysis.

PURPOSE: Norrie disease (ND, MIM#310600) is an X-linked disorder characterized by severe vitreoretinal dysplasia at birth. We report the results of causative NDP gene analysis in three male siblings with Norrie disease and describe the associated phenotypes. METHODS: Three brothers with suspected Norrie disease and their mother presented for clinical examination. After obtaining informed consent, DNA was extracted from the peripheral blood of the proband, one of his brothers and his unaffected mother. Exons 1-3 of the NDP gene were amplified by polymerase chain reaction (PCR), and direct sequencing was performed. Multiplex ligation-dependent probe amplification (MLPA) was also performed to search for copy number variants in the NDP gene. RESULTS: The clinical findings of the three brothers included no light perception, corneal opacity, shallow anterior chamber, leukocoria, total retinal detachment and mental retardation. Exon 2 of the NDP gene was not amplified in the proband and one brother, even when the PCR primers for exon 2 were changed, whereas the other two exons showed no mutations by direct sequencing. MLPA analysis showed deletion of exon 2 of the NDP gene in the proband and one brother, while there was only one copy of exon 2 in the mother. CONCLUSION: Norrie disease was diagnosed in three patients from a Japanese family by clinical examination and was confirmed by genetic analysis. To localize the defect, confirmation of copy number variation by the MLPA method was useful in the present study.

OPA1 mutations in Japanese patients suspected to have autosomal dominant optic atrophy.

PURPOSE: To report three types of heterozygous mutations in the OPA1 gene in five patients from three families with autosomal dominant optic atrophy (ADOA, MIM#165500). METHODS: DNA was extracted from the leukocytes of the peripheral blood. For mtDNA, mutations were examined at positions 11778, 3460 and 14484. For the OPA1 gene, the exons were amplified by PCR and mutations were detected by restriction enzymes or the dye terminator method. RESULTS: We detected three types of OPA1 mutation but no mtDNA mutations. In the OPA1 gene, heterozygous frameshift mutations from codon 903 due to a four-base pair deletion in exon 27 were detected in three patients from one family (c.2708_2711delTTAG, p.V903GfsX905). A heterozygous mutation due to a three-base pair deletion in exon 17, leading to a one-amino acid deletion (c.1618_1620delACT, p.T540del), and a heterozygous mutation due to a one-base substitution in exon 11, leading to a stop codon (c.1084G>T, p.E362X), were detected in sporadic cases. CONCLUSION: OPA1 mutations existed in three Japanese families with ADOA. After a detailed clinical assessment of the proband, the screening of the OPA1 gene may be helpful for precise diagnosis of ADOA, provided the relevant information of the family members is limited.