No abstract

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, 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).

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.

. Purpose:  This study set out to investigate retinal nerve fibre layer (RNFL) thickness and best corrected visual acuity (BCVA) in relation to age in healthy subjects and patients with OPA1 autosomal dominant optic atrophy (DOA). Methods:  We carried out a cross‐sectional investigation of RNFL thickness and ganglion cell layer density in 30 healthy subjects and 10 patients with OPA1 DOA using optical coherence tomography (OCT). We then performed a regression analysis of RNFL thickness and BCVA versus age. Results:  Both healthy subjects and DOA patients demonstrated a gradual reduction in RNFL thickness with age; the relationship was best described statistically by a model that assumed a constant offset between the two groups. Best corrected VA decreased significantly with age in DOA patients, in whom BCVA was correlated with peripapillary RNFL thickness in the inferior and superior peripapillary quadrants and with total macular thickness at eccentricities of 500–3000 μm. The observations were best described by a constant offset of 41.9 μm separating the two groups and an annual decrease in RNFL thickness of 0.48 μm (p < 0.0001). In patients with DOA, increasing age was associated with decreasing BCVA (p = 0.046). Conclusions:  This cross‐sectional study found evidence of comparable age‐related decreases in RNFL thickness in healthy subjects and in DOA patients, where the deficit in DOA patients is best described using a model that assumes the deficit between the groups does not vary with age. The gradual reduction of BCVA with age may be a consequence of a relative deficit in RNFL thickness that is established before the second decade of life.