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Disease Profile

Autosomal dominant optic atrophy plus syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

Adolescent

ICD-10

H47.2

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

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;

Categories

Congenital and Genetic Diseases; Eye diseases; Metabolic disorders;

Summary

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.[1]

ADOA plus is caused by changes (mutations) in the OPA1 gene. The syndrome is inherited in an autosomal dominant manner. A diagnosis of ADOA plus is suspected when an eye exam finds degeneration of the optic nerve (optic atrophy). The diagnosis can be confirmed with a muscle biopsy and genetic testing of the OPA1 gene. Treatment options include visual and hearing aids. Certain medications have been found to help improve vision loss in some people.[1][2]

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).[1]

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.[1]

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.[3][4]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Impaired pain sensation
Decreased pain sensation
0007328
Optic atrophy
0000648
Sensorineural hearing impairment
0000407
30%-79% of people have these symptoms
Color vision defect
Abnormal color vision
Abnormality of color vision

[ more ]

0000551
Reduced tendon reflexes
0001315
Visual impairment
Impaired vision
Loss of eyesight
Poor vision

[ more ]

0000505
5%-29% of people have these symptoms
Abnormality of visual evoked potentials
0000649
Ataxia
0001251
Decreased nerve conduction velocity
0000762
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

0001288
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Strabismus
Cross-eyed
Squint
Squint eyes

[ more ]

0000486
Percent of people who have these symptoms is not available through HPO
Abnormal amplitude of pattern reversal visual evoked potentials
0000650
Abnormal auditory evoked potentials
0006958
Autosomal dominant inheritance
0000006
Central scotoma
Central blind spot
0000603
Centrocecal scotoma
0000576
Horizontal nystagmus
0000666
Increased variability in muscle fiber diameter
0003557
Myopathy
Muscle tissue disease
0003198
Ophthalmoplegia
Eye muscle paralysis
0000602
Peripheral neuropathy
0009830
Polyneuropathy
Peripheral nerve disease
0001271
Progressive
Worsens with time
0003676
Progressive sensorineural hearing impairment
0000408
Ptosis
Drooping upper eyelid
0000508
Red-green dyschromatopsia
Red green color blindness
0000642
Reduced visual acuity
Decreased clarity of vision
0007663
Tritanomaly
Blue yellow color blindness
0000552

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.[4] 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.[1][5] 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.[1]

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.[3][6]

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:

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.[1]

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:[1]

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.[1][2] However, this medication may not be appropriate for everyone with ADOA plus, and it may only be available through research studies. 

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Organizations Providing General Support

      Learn more

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      In-Depth Information

      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Autosomal dominant optic atrophy plus syndrome. Click on the link to view a sample search on this topic.

        References

        1. Milea D and Procaccio V. Autosomal dominant optic atrophy plus syndrome. Orphanet. April 2015; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=1215.
        2. Barboni P. et al. Idebenone treatment in patients with OPA1-mutant dominant optic atrophy. Brain. February 2013; 136(Pt 2):e231. https://www.ncbi.nlm.nih.gov/pubmed/23388408.
        3. Optic Atrophy With Or Without Deafness, Ophthalmoplegia, Myopathy, Ataxia, And Neuropathy. Online Mendelian Inheritance in Man (OMIM). April 7, 2016; https://www.omim.org/entry/125250:
        4. Skidd PM, Lessell S, and Cestari DM. Autosomal dominant hereditary optic neuropathy (ADOA): a review of the genetics and clinical manifestations of ADOA and ADOA+. Seminars in Ophthalmology. September-November 2013; 28(5-6):422-426. https://www.ncbi.nlm.nih.gov/pubmed/24138050.
        5. Bonifert T, Karle KN, Tonagel F, Batra M, Wilhelm C, Theurer Y, Schoenfeld C, Kluba T, Kamenisch Y, Carelli V, Wolf J, Gonzalez MA, Speziani F, Schule R, Zuchner S, Schols L, Wissinger B, and Synofzik M. Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier. Brain. August 2014; 137(Pt. 8):2164-2177. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24970096/.
        6. Delettre-Cribaillet C, Hamel CP, and Lenaers G. Optic Atrophy Type 1. GeneReviews. November 12, 2015; https://www.ncbi.nlm.nih.gov/books/NBK1248/.

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