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Autosomal dominant optic atrophy plus syndrome
A rare variant of autosomal dominant optic atrophy (ADOA) associating the typical optic atrophy with other extra-ocular manifestations such as sensorineural deafness, myopathy, chronic progressive external ophthalmoplegia, ataxia and peripheral neuropathy. More rarely, other manifestations have been associated with this condition, such as spastic paraplegia, multiple-sclerosis like illness.
ORPHA:1215Classification level: Disorder
Autosomal dominant optic atrophy plus syndrome (ADOA plus) accounts for approximately 20% of all ADOA cases.
ADOA plus is characterized by bilateral and symmetric progressive visual loss (visual acuities ranging from 20/30 to 20/200) and color vision deficiency, occurring typically during the first decade of life. Sensorineural deafness usually occurs later, during the second or third decade of life, although it may also be diagnosed, in rare instances, prior to the optic neuropathy. From the third decade onwards, other extra-ocular manifestations may appear, such as chronic progressive external ophthalmoplegia, proximal myopathy, ataxia and axonal sensory motor polyneuropathy. Other manifestations have been more rarely associated with ADOA plus, such as multiple sclerosis-like illness, migraine, cardiomyopathy, late-onset diabetes mellitus, and spastic paraplegia.
ADOA plus is caused by mutations in the OPA1 gene (3q29), encoding a dynamin-like GTPase involved in the fusion of the inner mitochondrial membrane. The phenotypes observed in ADOA plus are thus related to mitochondrial DNA instability resulting in multiple mitochondrial DNA deletions.
Ophthalmological examination is not specific and typically shows a moderate bilateral optic atrophy associated with bilateral central or paracentral scotomas. Diagnosis of ADOA plus relies both on the genetic screening of the OPA1 gene and on skeletal muscle biopsy to measure the enzymatic activity of the respiratory chain complexes, allowing histological examination (Gomori-modified trichrome and double cytochrome C oxidase/succinate dehydrogenase staining) which typically reveals features of mitochondrial myopathy (cytochrome C negative fibers and ragged red fibers). Laboratory findings may reveal hyperlactacidemia. Additional investigations may include an audiological work-up, peripheral nerve conduction studies, electromyography, electroencephalography, brain magnetic resonance imaging, according to the patient's symptoms.
Differential diagnosis includes several other hereditary optic neuropathies that may have bilateral manifestations associated with extra ocular features and that presents with a similar phenotype (such as Autosomal dominant Charcot-Marie-Tooth disease type 2A, Leber hereditary optic neuropathy, Wolfram syndrome and Wolfram-like syndrome (see these terms)).
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 variable penetrance and genetic counselling is recommended.
Management and treatment
There is currently no efficient treatment for ADOA plus. Low-vision aids may be recommended and cochlear implants have been shown to improve audition in patients with sensorineural deafness. The role of idebenone has been anecdotally reported in ADOA. Physiotherapy for the muscular symptoms programs can be warranted for patients with multiple sensory and motor handicaps. Avoiding tobacco and alcohol intake as well as medications interfering with mitochondrial metabolism (certain antibiotics, antivirals) is highly recommended.
Vision seems to be more severely affected in patients with ADOA plus than in patients with no extra ocular involvement. If associated, hearing loss can further impair social communication.
- Review article
- English (2012)