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Autosomal dominant optic atrophy, classic form
One of the most common forms of hereditary optic neuropathy characterized by progressive bilateral visual loss during the first decade of life, associated with optic disc pallor, visual field and color vision defects.
ORPHA:98673Classification level: Disorder
The prevalence of Autosomal dominant optic atrophy (ADOA) is variable, commonly varying between 1/10,000 in Denmark (due to a founder effect) to 1/35,000 in the UK.
ADOA is usually detected during the first decade of life, often by vision screening in school but later onset is possible. Visual impairment is usually moderate (visual acuity ranges from 20/80 to 20/120) but may range from mild to severe. Visual field defect is typically centrocecal, central, or paracentral. Color vision is often affected, usually but not always in the blue-yellow axis (tritanopia). Legal blindness is rare. Patients may also be asymptomatic, albeit bearing the mutation. In about 20% of cases, extra-ocular signs are present, such as sensorineural hearing loss or other more severe neurological signs, that occur typically later in life, such as myopathy, ataxia, peripheral neuropathy, chronic progressive external ophthalmoplegia (ADOA plus; see this term).
A majority, but not all ADOA patients harbor mutations in the gene OPA1 (3q29) which codes for an inner mitochondrial membrane protein intricately involved in mitochondrial biogenesis, mitochondrial DNA replication and network stability. Visual impairment is highly variable both within and between families, even when considering the same mutation.
The diagnosis of ADOA is suspected in children with visual loss in the presence of family history (which though, may be absent in 50% of cases). Fundus examination reveals bilateral and symmetrical pallor of the temporal side of the optic disk, atrophic optic nerve rim and presence of a temporal grey crescent, sometimes cupping of the disk. Visual evoked potentials (VEP) are usually delayed and pattern electroretinogram shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform suggesting alterations of the ganglion cells layer. Optical Coherence Tomography (OCT) discloses a global reduction of the peripapillary retinal nerve fiber layer thickness, mainly in the infero-temporal quadrant. The diagnosis is confirmed by the genetic screening of OPA1.
Differential diagnosis includes all the common causes of optic neuropathies: compressive, inflammatory, ischemic, toxic and metabolic causes. Other hereditary optic neuropathies such as leber hereditary optic neuropathy, Wolfram syndrome (see these terms) have different initial presentations (later in life, associated or not with other neurological or systemic signs), but the final clinical phenotype of optic neuropathy is not specific.
Prenatal identification of a mutation may be proposed in families with previously known mutations, with the understanding that not all the carriers will manifest the disease.
Transmission is autosomal dominant with a penetrance of 50%.
Management and treatment
There are currently no efficient treatments in ADOA. Low-vision aids may be recommended in patients with severely decreased visual acuity. Tobacco use, excessive alcohol intake and medications that may have mitochondrial toxicity should be avoided. Idebenone has been anecdotally reported as potentially efficient, but still requires randomized controlled clinical trials.
Visual impairment in ADOA is classically irreversible, and spontaneous recovery has been only exceptionally reported. Visual loss is usually mild, but can at times worsen later during lifetime. ADOA does not affect intellectual development or life span. Patients may have normal familial and social life although vocational integration may at times be problematic. Anxiety and depression are not uncommon.