Seasonal variation in night blindness incidence among Union soldiers in the US Civil War.

BACKGROUND: During the US Civil War, medical officers typically attributed night blindness among soldiers to malingering. A dietary basis was not generally suspected or appreciated. DESIGN/METHODS: Incident cases of night blindness, scurvy, and diarrheal diseases, as well as mean troop strength among Union troops, were abstracted by month and race from tabulations of the US Surgeon General for the period from July 1861 through June 1866. Monthly incidence rates and annual incidence rates are presented as time series by race. RESULTS: Night blindness incidence was seasonal. Seasonal patterns of night blindness incidence were similar for white and black soldiers, although the peak incidence rates were approximately 2-3 times higher in black soldiers. The seasonal effect for white Union soldiers increased progressively to 1864. The seasonal pattern for night blindness roughly parallels that for scurvy and for diarrheal diseases. The peak season for night blindness incidence was summer, and the next highest season was spring. The mode of monthly incidence rates for diarrheal diseases slightly anticipated that for night blindness and scurvy. In addition, there was greater relative variation in monthly incidence for night blindness and scurvy than for diarrheal diseases. CONCLUSIONS: Nutritional night blindness occurred in a seasonal pattern among soldiers forced to subsist on nutritionally inadequate diets. The seasonal pattern is consistent with seasonal variations in the availability of foodstuffs with high vitamin A or provitamin A content, superimposed on marginal vitamin A reserves, and possibly exacerbated by co-occurring seasonal patterns of diarrheal disease.

Fundus albipunctatus: novel mutations and phenotypic description of Israeli patients.

PURPOSE: To characterize the genetic defects associated with fundus albipunctatus (FAP) in patients in Israel. METHODS: Twenty patients with FAP from diverse ethnicities underwent ophthalmic and electroretinogram tests following the International Society for Clinical Electrophysiology of Vision protocol. Genomic DNA was extracted from peripheral blood. Mutation analysis of the 11-cis retinol dehydrogenase (RDH5) gene was performed with direct sequencing of PCR-amplified exons. RESULTS: Four novel RDH5 gene mutations were identified. Of them, the null mutations c.343C>T (p.R54X) and c.242delTGCC were most prevalent. Macular involvement was present in two patients who carry different mutation types. CONCLUSIONS: Mutation analysis of the RDH5 gene in the present series revealed four novel mutations and a previously reported one. No significant genotype-phenotype correlation was found.

A variant form of Oguchi disease mapped to 13q34 associated with partial deletion of GRK1 gene.

PURPOSE: The purpose of this paper is to map the locus for a variant form of Oguchi disease in a Pakistani family and to identify the causative mutation. METHODS: Family 61029 was ascertained in the Punjab province of Pakistan. It includes three 13- to 19-year-old patients with night blindness and 12 unaffected family members. A complete ophthalmological examination including fundus photography and electroretinography (ERG) was performed on each family member. A genome-wide scan was performed using microsatellite markers at about 10 cM intervals, and two-point lod scores were calculated. Polymerase chain reaction (PCR) cycle dideoxynucleotide sequencing was used to screen candidate genes inside the linked region for mutations and to delineate the deletion. Multiplex PCR and long template PCR were used to detect deletions and to define the size of deletions. Evaluation of fundus changes and ERG, lod score estimation, and identification of a mutation in the GRK1 gene were carried out. RESULTS: All patients had night blindness since early childhood. Irregular coarse pigmentation was observed in the peripheral retina of each patient. The fundus appearance before and after 4 h of dark adaptation was similar except that the peripheral retinal pigmentary changes were slightly less evident after extended dark adaptation. Minimal or no rod function with normal cone function on ERG recordings were detected in all three affected members. The rod showed slow recovery to nearly normal amplitude after 4 h in the dark ERG in one individual but not in two other patients. A genome-wide scan showed linkage only to D13S285. Fine mapping defined a region from D13S1315 to 13qter, with a lod score of 2.89 at theta=0 shown by D13S285 and 2.90 at theta=0 by the D13S261-D13S285-D13S1295-D13S293 haplotype. Analysis of the GRK1 gene, which is included in this interval, identified a c.827+623_883del mutation. This intragenic deletion cosegregates with the disease in the family and is only homozygous in affected individuals. This mutation was not detected in 96 controls. CONCLUSIONS: The retinal disease in the family reported here has several features differing from typical Oguchi disease, including an atypical Mizuo-Nakamura phenomenon and a non-recordable rod ERG even after 4 h of dark adaptation. Normal visual acuity, normal caliber of retinal blood vessels, and normal cone response on ERG recording suggest retinal dysfunction rather than degeneration (i.e., a variant form of Oguchi disease but unlikely to be retinitis pigmentosa). The disease in the Pakistani family localizes to 13q34 and is caused by a novel deletion including Exon 3 of the GRK1 gene.

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.

Gene analysis and evaluation of the single founder effect in Japanese patients with Oguchi disease.

PURPOSE: To analyze mutations of the arrestin/S-antigen (SAG) gene in nine newly identified Oguchi disease patients, and to examine whether the 926delA (formerly called 1147delA) mutation in the SAG gene is inherited from a single founder. METHODS: DNA samples were assayed for mutations around nucleotide 926 of the SAG gene by direct sequencing, and analyzed for polymorphisms at codon 403 and IVS6-18 of the SAG gene by restriction analysis of polymerase chain reaction products. RESULTS: All nine newly identified patients were homozygous for the 926delA mutation and had the same haplotype at codon 403 and IVS6-18. These findings are identical to those of previous reports of four Japanese Oguchi disease patients. CONCLUSIONS: Mutation 926delA of the SAG gene is the main cause of Oguchi disease in Japanese. This mutation appears to have been inherited from a single founder.

Macular dystrophy in a Japanese family with fundus albipunctatus.

PURPOSE: To report a Japanese family with fundus albipunctatus and macular dystrophy associated with a mutation in the 11-cis retinol dehydrogenase (RDH5) gene. DESIGN: Observational case report. METHOD: Ophthalmic examinations and DNA analysis were performed. RESULTS: The fundi of a 56-year-old man and his 51-year-old sister showed numerous yellow-white punctata. He also had bull's-eye maculopathy and prepappillary arterial loops, whereas she did not, and his best-corrected visual acuity was impaired, whereas hers was normal. Their kinetic visual fields did, however, show central or paracentral scotoma, and both had tritanomalous color vision. Their scotopic electroretinograms were typical of fundus albipunctatus, and photopic electroretinograms were significantly reduced. A homozygous Gly107Arg mutation in the RDH5 gene was detected in both siblings. CONCLUSIONS: We suggest that the macular dystrophy is caused by the RDH5 gene mutation as a phenotype variation in fundus albipunctatus.

A novel Gly35Ser mutation in the RDH5 gene in a Japanese family with fundus albipunctatus associated with cone dystrophy.

OBJECTIVE: To assess the clinical and genetic characteristics of a Japanese family with fundus albipunctatus with progressive cone dystrophy associated with a mutation in the RDH5 gene. DESIGN: Case report with clinical findings and results of fluorescein angiography, electroretinograms, kinetic visual field testing, dark adaptometry, and DNA analysis. SETTING: University medical center. PATIENTS: We studied the ocular findings in 6 members of a Japanese family with fundus albipunctatus with cone dystrophy and a guanine-to-adenine transversion at the first nucleotide in codon 35 of the RDH5 gene. The mutation resulted in a substitution of serine for glycine in amino acid 35 (Gly35Ser) of the RDH5 gene. RESULTS: Characteristic features included poor night vision, white dots in the retina, cone dystrophy, and a mottled appearance of the retinal pigment epithelium. Electroretinograms showed greater impairment of the rod-mediated responses than the cone-mediated responses. After 3 hours of dark adaptation, the a and b waves and scotopic b waves recovered. CONCLUSIONS: Although the mutation of the RDH5 gene has been known as a causative gene of fundus albipunctatus, the Gly35Ser mutation in the RDH5 gene may be related to the pathogenesis of progressive retinal degeneration. This phenomenon may provide evidence of gene phenotype caused by a mutation in the RDH5 gene. CLINICAL RELEVANCE: The Gly35Ser mutation causes fundus albipunctatus with cone dystrophy. This finding provides evidence that some kinds of mutations in the RDH5 gene are related, in part at least, to the pathogenesis of progressive retinal degeneration.

Novel CACNA1F mutations in Japanese patients with incomplete congenital stationary night blindness.

PURPOSE: Although it was reported that congenital stationary night blindness (CSNB) could be divided into complete and incomplete CSNB clinically in 1986, it was not until 1998 that the two types were found to be distinct clinical diseases by molecular genetic analysis. The purpose of this article is to report mutations in the retina-specific calcium channel alpha1-subunit gene (CACNA1F) in Japanese patients with incomplete CSNB and to describe the clinical features of these patients. METHODS: Seven patients from five separate Japanese families with incomplete CSNB were examined. Genomic DNA was extracted from leukocytes of the peripheral blood, and all 48 exons of the CACNA1F were amplified by polymerase chain reaction and directly sequenced. A complete ophthalmic examination was performed, including best corrected visual acuity, slit lamp and fundus examinations, fundus photography, and electroretinography. RESULTS: A mutation in the CACNA1F was identified in all the patients. The identified mutations were a missense mutation (Gly609Asp); a nonsense mutation (Arg913stop); a splice donor site mutation of G to C at nucleotide 2571+1; a G insertion at nucleotide 709, resulting in a frame shift with a predicted stop codon at codon 247; and a 4-bp deletion at nucleotides 271 to 274, with a replacement by an abnormal 34-bp sequence. Clinically, each patient had essentially normal fundi, mildly reduced corrected visual acuity, and slight myopia or hyperopia with astigmatism. Electrophysiologically, the mixed rod-cone ERG showed a negative configuration with recordable oscillatory potentials. The rod ERG was recordable but subnormal, and the cone and 30-Hz flicker ERGs were markedly depressed. CONCLUSIONS: Five novel mutations were identified in the CACNA1F in five Japanese families with incomplete CSNB, leading to the conclusion that in most Japanese patients, incomplete CSNB is caused by a CACNA1F mutation.

A novel compound heterozygous mutation in the RDH5 gene in a patient with fundus albipunctatus.

PURPOSE: To report a novel compound heterozygous mutation in the 11-cis retinol dehydrogenase (RDH5) gene in a patient with fundus albipunctatus. METHOD: We examined the RDH5 gene genotype in members of a Japanese family. Clinical examination showed that the proband had fundus albipunctatus and his aunt had retinitis pigmentosa. The RDH5 gene was analyzed by direct genomic sequencing. RESULTS: The proband had a compound heterozygotic missense mutation of Val177Gly (GTC-->GGC) and Arg280His (CGC-->CAC) in his RDH5 gene. His mother had the Arg280His mutation and his father had the Val177Gly mutation, but his father's aunt who has typical retinitis pigmentosa had the wild type RDH5 gene. The occurrence of Val177Gly has not been reported in the RDH5 gene of fundus albipunctatus. CONCLUSION: A novel compound heterozygous missense mutation in the RDH5 gene was found in a patient with fundus albipunctatus.

Mutations in the 11-cis retinol dehydrogenase gene in Japanese patients with Fundus albipunctatus.

PURPOSE: To detect mutations in the RDH5 gene encoding 11-cis retinol dehydrogenase in patients from Japan with fundus albipunctatus. METHODS: Polymerase chain reaction and direct genomic sequencing techniques were used to detect mutations of the RDH5 coding exons (exons 2-5) in two unrelated patients with fundus albipunctatus. Selected alleles that altered the coding region or intron splice sites were evaluated further through segregation analysis in the families of the index cases. RESULTS: Two novel RDH5 mutations were identified. One of these was a missense mutation Val264Gly in exon 5, and the other was an in-frame insertion of 3 bp in exon 5. CONCLUSIONS: The data indicate that mutations in RDH5 are the primary cause of fundus albipunctatus.

A frequent 1085delC/insGAAG mutation in the RDH5 gene in Japanese patients with fundus albipunctatus.

PURPOSE: To identify the frequency of a mutation of the RDH5 gene in Japanese patients with hereditary retinal degeneration and to characterize clinical findings for the patients associated with a 1085delC/insGAAG mutation in the RDH5 gene. METHODS: Mutation screening by single-strand conformation polymorphism was performed on 6 patients with fundus albipunctatus and 150 patients with autosomal recessive retinitis pigmentosa. The DNA fragment that showed abnormal mobility on SSCP was then sequenced. Clinical features were characterized by visual acuity, slit-lamp biomicroscopy, electroretinography, fluorescein angiography, kinetic visual field testing, and dark adaptometry. RESULTS: A novel 1085delC/insGAAG mutation in the RDH5 gene was identified in all 6 patients, from 4 unrelated families with fundus albipunctatus. The ophthalmic findings of each affected member were very similar, which may provide the natural course of the phenotype produced by the 1085delC/insGAAG mutation. CONCLUSIONS: A homozygous1085delC/insGAAG mutation in the RDH5 gene produces fundus albipunctatus in Japanese patients. These findings suggest that this mutation was a founder effect in Japanese patients with fundus albipunctatus.

A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness.

More than 100 mutations within the rhodopsin gene have been found to be responsible for some forms of retinitis pigmentosa, a progressive retinal degeneration characterized by night blindness and subsequent disturbance of day vision that may eventually result in total blindness. Congenital stationary night blindness (CSNB) is an uncommon inherited retinal dysfunction in which patients complain of night vision difficulties of a nonprogressive nature only and in which generally there is no involvement of day vision. We report the results of molecular genetic analysis of an Irish family segregating an autosomal dominant form of CSNB in which a previously unreported threonine-to-isoleucine substitution at codon 94 in the rhodopsin gene was found to segregate with the disease. Computer modeling suggests that constitutive activation of transducin by the altered rhodopsin protein may be a mechanism for disease causation in this family. Only two mutations within the rhodopsin gene have been previously reported in patients with congenital stationary night blindness, constitutive activation also having been proposed as a possible disease mechanism.