Autosomal dominant optic atrophy plus syndrome

Other Names: Dominant optic atrophy, deafness, ptosis, ophthalmoplegia, dystaxia, and myopathy; OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY; DOMINANT OPTIC ATROPHY PLUS SYNDROME; Treft-Sanborn-Carey syndrome; Optic atrophy - deafness- polyneuropathy - myopathy; Optic atrophy-deafness-polyneuropathy-myopathy syndrome

Autosomal dominant optic atrophy plus syndrome (ADOA plus) is a rare syndrome that causes vision loss, hearing loss, and symptoms affecting the muscles. The syndrome is associated with degeneration of the optic nerve (optic atrophy). The optic nerve sends signals about what the eyes are seeing to the brain. When there is optic nerve damage, it causes vision loss. Other symptoms of ADOA plus include sensorineural hearing loss and symptoms affecting the muscles such as muscle pain and weakness.

Cause

Autosomal dominant optic atrophy plus syndrome (ADOA plus) is caused by mutations (changes) in the OPA1 gene. This gene provides instructions to make a protein that is present in many different parts of the body including the retina (part of the eye), muscles, and nervous system. The OPA1 protein is located in the mitochondria. Mitochondria are the parts of the cell that provide energy, and the OPA1 protein helps regulate the changing shapes of the mitochondria, so that the mitochondria can do its many jobs inside the cell.

When there are changes in the OPA1 gene, there is not enough protein working correctly to help maintain the mitochondria, especially in the eyes, muscles, and nervous system. Scientists believe these changes cause the signs and symptoms associated with ADOA plus.

In some cases, people with a mutation in the OPA1 gene have a different disease called optic atrophy type 1 that only causes vision loss without any other symptoms. It is not known exactly why some people with changes in OPA1 only have vision loss while others have additional symptoms, but it may be in part based on the location of the change in the OPA1 gene.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Autosomal dominant optic atrophy plus syndrome (ADOA plus) is inherited in an autosomal dominant manner. This means that people with ADOA plus have a disease-causing change in one copy of the OPA1 gene in every cell of their body. Of note, a disease-causing genetic change used to be called a mutation, but is now called a pathogenic variation on genetic testing reports. Most genes, including OPA1, come in pairs. We inherit one copy of each gene from our mother and the other from our father. When a person with ADOA plus has children, each child has a: 50% chance to have ADOA plus 50% chance not to have ADOA plus

ADOA plus shows features called variable expressivity and reduced penetrance. Variable expressivity means that people with the syndrome may have signs and symptoms that are different from each other, even among people in the same family. Reduced penetrance means that, in some cases, people in a family with ADOA plus may inherit a disease-causing change in the OPA1 gene without showing any signs or symptoms of the syndrome. However, anyone with a disease-causing change in the OPA1 gene, whether they have symptoms or not, can pass on the genetic change to their children, and those children could have symptoms of ADOA plus.

Signs and symptoms

Autosomal dominant optic atrophy plus syndrome (ADOA plus) is associated with vision loss, hearing loss, and symptoms affecting the muscles. Vision loss is frequently the first symptom that develops in people with ADOA plus, and it typically begins in childhood. Hearing loss that is caused by damage to the nerves of the inner ear (sensorineural hearing loss) typically develops during adolescence or young adulthood.

Other symptoms of ADOA plus may develop in adulthood and include muscle weakness (myopathy), weakness of the eye muscles

(ophthalmoplegia), trouble coordinating movements (ataxia), and pain and tingling in the arms and legs (peripheral neuropathy).

In general, the symptoms of ADOA plus are progressive. This means that symptoms of the syndrome may worsen over time. However, for some people with the syndrome, symptoms such as vision or hearing loss may stabilize. In rare cases, the symptoms of ADOA plus may progress to be similar to the symptoms of multiple sclerosis. ADOA plus is a syndrome that shows variable expressivity. This means that people with the syndrome may have signs and symptoms that are different from each other, even among people in the same family. For example, some people with ADOA plus may only have vision loss, while others may also have symptoms such as muscle weakness or hearing loss.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Impaired pain sensation(Decreased pain sensation)
• Optic atrophy
• Sensorineural hearing impairment

30%-79% of people have these symptoms

• Color vision defect(Abnormal color vision)
• Reduced tendon reflexes
• Visual impairment(Impaired vision)

5%-29% of people have these symptoms

• Abnormality of visual evoked potentials
• Ataxia
• Decreased nerve conduction velocity
• Gait disturbance(Abnormal gait)
• Spasticity(Involuntary muscle stiffness, contraction, or spasm)
• Strabismus(Cross-eyed)

Diagnosis

Autosomal dominant optic atrophy plus syndrome (ADOA plus) is typically suspected when a person has signs or symptoms consistent with the syndrome, such as evidence of degeneration of the optic nerve (optic atrophy) on an eye exam. If ADOA plus is suspected, other tests may be ordered including:

• Electromyography (EMG)
• Muscle biopsy
• Brain MRI

Genetic testing of the OPA1 gene may be ordered to confirm the diagnosis and to help identify other family members who are affected with the syndrome.

Treatment

Unfortunately, there is no cure for autosomal dominant optic atrophy plus syndrome (ADOA plus). Treatment options that may be recommended for people with ADOA plus include:

• Visual aids such as glasses and contact lenses
• Hearing aids or cochlear implants

Currently, there are no medications that are regularly used to relieve or reverse the symptoms associated with ADOA plus. In some clinical trials, people with a disease-causing genetic change in the OPA1 gene have found some improvement in vision using a medication called idebenone. However, this medication may not be appropriate for everyone with ADOA plus, and it may only be available through research studies.

Prognosis

In general, autosomal dominant optic atrophy plus syndrome (ADOA plus) is a progressive syndrome, meaning symptoms may continue to worsen over time. In some cases, symptoms of the syndrome such as vision or hearing loss may stabilize. Because the different symptoms of ADOA plus may begin at different ages, it may be difficult to know if other symptoms of the disease will develop over time. In general, it is thought that the vision loss associated with ADOA plus is more severe than in individuals who have other types of autosomal dominant optic atrophy.

NIH genetic and rare disease info

• NIH info on Autosomal dominant optic atrophy plus syndrome

Autosomal dominant optic atrophy plus syndrome is a rare disease.

Autosomal dominant optic atrophy plus syndrome Resources
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