Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene.

Autosomal dominant optic atrophy (ADOA) is genetically heterogeneous, with OPA1 on 3q28 being the most prevalently mutated gene. Additional loci are OPA3, OPA4, and OPA5, located at 19q13.2, 18q12.2, and 22q12.1-q13.1, respectively. Mutations in the WFS1 gene, at 4p16.3, are associated with either optic atrophy (OA) as part of the autosomal recessive Wolfram syndrome or with autosomal dominant progressive low frequency sensorineural hearing loss (LFSNHL) without any ophthalmological abnormalities. Linkage and sequence mutation analyses of the ADOA candidate genes OPA1, OPA3, OPA4, and OPA5, including the genes WFS1, GJB2, and GJB6 associated with recessive inherited OA or dominant LFSNHL, were performed. We identified one novel WFS1 missense mutation E864K, c.2590G-->A in exon 8 that co-segregates with ADOA combined with hearing impairment and impaired glucose regulation. This is the first example of autosomal dominant optic atrophy and hearing loss associated with a WFS1 mutation, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to ADOA combined with impaired hearing.

A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect.

Dominant optic atrophy (DOA) is a hereditary optic neuropathy characterised by decreased visual acuity, colour vision deficits, centro-coecal scotoma and optic nerve pallor. The gene OPA1, encoding a dynamin-related GTPase, has recently been identified within the genetic linkage interval for the major locus for DOA on chromosome 3q28 and shown to harbour genetic aberrations segregating with disease in DOA families. The prevalence of the disorder in Denmark is reported to be the highest of any geographical location, suggestive of a founder effect. In order to establish the genetic basis of disease in a sample of 33 apparently unrelated Danish families, we screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. A novel identical mutation in exon 28 (2826delT) was associated with DOA in 14 pedigrees and led to a frameshift and abnormal OPA1 protein -COOH terminus. Haplotype analysis of a region of approximately 1 Mb flanking the OPA1 gene using eight polymorphic markers revealed a common haplotype shared by all 14 patients; this haplotype was markedly over-represented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with DOA over approximately 600 kb encompassing the disease mutation. We have therefore demonstrated that the relatively high frequency of DOA in Denmark is attributable to a founder mutation responsible for approximately 42% of the examined families and suggest that presymptomatic screening for the (2826delT) mutation may facilitate diagnosis and genetic counselling in a significant proportion of DOA patients of Danish ancestry.

Retinopathy of prematurity in a Copenhagen high-risk sample 1997-98. The allover surveillance for ROP appears more and more complete.

PURPOSE: From two recent materials to describe the present clinical status regarding retinopathy of prematurity in Denmark, and to outline trends over time. METHODS: A) Results of regular ophthalmic surveillance of 201 clinically selected (higher risk of ROP than average) pre-term infants of birth year 1997-98 taken care of in the two greater Copenhagen tertiary neonatal units, in an intended prospective design. Gestational age range was 24-32 weeks at delivery; birth weights 490-2200 g. Median values 28 weeks and 1090 g. B) A brief account of the latest ROP-associated registrations of visual impairment in Danish children aged 0-17 years (n=138). RESULTS: A) ROP was observed in 31.3% (n=201). Retinal cryotherapy was given to eleven 'own' cases and to two from elsewhere (n=13, gestational age at delivery 25-31 weeks). Five had cryotherapy twice. Four of the 13 were later registered for visual impairment. B) Comparing the first and the latest third of the registrations, visual impairment has dropped in frequency and severity over the period from 1981 till now. CONCLUSIONS: Compared to previous data the present clinical profile of ROP in Denmark indicates a relatively lower overall frequency of ROP and a decrease in eventual severe visual impairment. Undoubtedly, the continued refinement of neonatal care has been of relevance, but the definite decline in visual impairment further reflects a more complete ophthalmic surveillance, on a national basis. The advanced cases are generally detected in time and retinal ablation therapy offered.

Metastatic bacterial endophthalmitis. A report of four cases all leading to blindness.

PURPOSE: To draw attention to the rare but severe entity of endophthalmitis as encountered due to metastatic spread of bacteria. METHODS: We report our experience from four cases of metastatic bacterial endophthalmitis. RESULTS: Systemic infection (Pneumococcus meningitis) was evident in two cases, but in the other two there was no early clue to systemic infection. Eventually, however, endocardial vegetations were disclosed as the source of bacterial emboli (E.coli, peptostreptococcus). In the most atypical patient, magnetic resonance scanning had indicated disseminated brain tumours, and only autopsy revealed the infectious nature of the disease. Ocular ultrasonography being part of the work-up, the four eyes under study all showed marked morphological intraocular changes, including 'solid tumour' in the presumed neoplastic case. CONCLUSION: Our cases stress the severity of metastatic bacterial endophthalmitis and the easily missed early diagnosis, even where experienced clinicians are involved. The role of diagnostic ultrasound is discussed.

Refinement of the dominant optic atrophy locus (OPA1) to a 1.4-cM interval on chromosome 3q28-3q29, within a 3-Mb YAC contig.

Dominant optic atrophy, type Kjer, is an autosomal dominant eye disease that is characterized by progressive optic atrophy with onset in early childhood, decrease of visual acuity, colour vision defects and centrocecal scotoma. By examination of 5 Danish families and the use of polymorphic markers, we have refined the localization of the OPA1 locus and assigned it to a 1.4-cM interval on chromosome 3q28-3q29, between markers D3S3669 and D3S3562. This localizes the gene on a 3-Mb YAC contig covering the disease locus. We have also located a possible candidate gene HRY to this contig.

Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects.

Sixty-two patients from three large Danish families with autosomal dominant optic atrophy were clinically examined, and retrospective follow-up was made on 30 patients. We found great inter-and intrafamiliar variation in visual acuity and visual decline. One hundred and seventy-five chromosomal markers were analyzed in 118 family members. Linkage was demonstrated between the disease gene (OPA1) and the microsatellite markers D3S1314, D3S1262, D3S1265 and D3S1601, with the highest Lod score to D3S1601 Z=11.75. All markers are located on chromosome 3q in the telomeric area, the most probable location for the OPA1 gene being D3S1601-OPA1-D3S1265. Using data from the Danish Family Register of Hereditary Eye Diseases, the minimum prevalence rate was estimated to 1:12.301, making DOA the most common hereditary optic atrophy.

Dominant optic atrophy (OPA1) mapped to chromosome 3q region. I. Linkage analysis.

Dominant optic atrophy, type Kjer (McKusick no. 165500) is an autosomal dominant eye disease. The disease is characterized by moderate to severe visual impairment with an insidious onset during the first decade of life, blue-yellow dyschromatopsia and centrocecal scotoma of varying density. We examined three extended Danish pedigrees using highly informative short tandem repeat polymorphisms and found linkage of the disease gene (OPA1) to a (CA)n dinucleotide repeat polymorphism at locus D3S1314 (Zmax = 10.34 at theta M = F = 0.075). Using two additional chromosome 3 markers we were able to map the OPA1 gene in the region between D3S1314 and D3S1265 (3q28-qter).

Trabeculotomy in juvenile primary open-angle glaucoma.

Long-term results of trabeculotomy in juvenile primary open-angle glaucoma (JPOAG) were investigated based on a follow-up study of 16 eyes in 11 patients, diagnosed when they were between 10 and 45 years old. Preoperative visual field defects were found in 75% (12/16) of the eyes. After a mean follow up of 7 years (range, 1 to 18 years), 88% (14/16) of the eyes had an intraocular pressure (IOP) of 21 mm Hg or less (peak pressure at diurnal curves). Nine of these were receiving no medical treatment and five were being treated with beta-blockers and/or dipivefrin. The best results were in the younger patients; the success rate of those under age 40 years was 100%. After normalization of IOP, visual field testing showed no progression in defects. We conclude that trabeculotomy rather than filtering surgery should be used to treat JPOAG, because the success rate of filtering surgery decreases with decreasing age. Also, the good functional results achieved in these patients after normalization of IOP may indicate that ocular hypertension is the only risk factor in JPOAG.

Lens fluorescence in relation to nephropathy in insulin-dependent diabetes mellitus.

The relationship between diabetic nephropathy and blue-green lens fluorescence, lens transmittance, and other lens fluorometry parameters was studied in patients with long-term insulin-dependent diabetes mellitus. The findings in 10 patients who presented with diabetic nephropathy were compared with those of 11 patients of comparable age and duration of diabetes but without nephropathy. Diabetic nephropathy was associated with increased lens fluorescence (P = 0.04) and decreased lens transmittance (P = 0.045). We propose that lens changes may be responsible for various psychophysical abnormalities in diabetic patients and that our results explain the correlation of these abnormalities with the degree of microangiopathy.

Lens fluorescence in relation to metabolic control of insulin-dependent diabetes mellitus.

The correlation of blue-green lens fluorescence to the metabolic control of insulin-dependent diabetes mellitus was studied in 36 patients in whom the level of glycosylated hemoglobin A1c (HbA1c) had been followed from the onset of diabetes. Good metabolic control (22 patients, all with mean HbA1c levels, less than 7.0% and, thus, low blood glucose concentrations) was associated with less lens fluorescence and a higher lens transmittance than poor metabolic control (14 patients, all with mean HbA1c levels, greater than 9.7%). It appears that in diabetes, an increase in lens fluorescence and a decrease in lens transmittance are delayed by good metabolic control, and that the determination of lens fluorescence provides information about the long-term control of diabetes.

Lens autofluorescence in diabetes compared with the level of glycosylated hemoglobin A1c.

The autofluorescence of the crystalline lens has been measured by an ocular fluorophotometer in two comparable groups of patients with insulin-dependent diabetes mellitus. One group has had a high level of HbA1c since the onset of diabetes (mean 10.1 per cent) and the other group a very low level (mean 6.5 per cent). The group with low HbA1c during the disease period showed a significantly lower lens fluorescence than the group with high HbA1c.