SO...WHAT IS ADOA?

ADOA, also known as Autosomal Dominant Optic Atrophy, is a genetically inherited disease that affects the optic nerves.

CLINICAL DETAILS

FAQ'S

GLOSSARY OF TERMS

Portrait of little positive boy with eye
 

CLINICAL

DETAILS.

ADOA causes reduced visual acuity and is a contributing factor of blindness, vision loss or impairment, beginning in childhood. This condition is due to mitochondrial dysfunction mediating the death of optic nerve fibers.

 

Dominant Optic Atrophy is associated with mutation of the OPA1 gene (3) found on chromosome 3, region q28-qter. Also, five other chromosomal genes are described as causing optic atrophy: OPA2 (x-linked), OPA3 (dominant), OPA4 (dominant), OPA5 (dominant), OPA6 (recessive) (4), OPA7 & OPA8 (recessive). (9)

 

In complicated cases of Autosomal Dominant Optic Atrophy, in addition to bilateral optic neuropathy, several other neurological signs of neurological involvement can be observed: peripheral neuropathy, deafness, cerebellar ataxiaspastic paraparesis and myopathy(2)

CLINICAL OVERVIEW

Autosomal Dominant Optic Atrophy can present clinically as an isolated bilateral optic neuropathy (non-syndromic form) or rather as a complicated phenotype with extra-ocular signs (syndromic form) peripheral neuropathy, deafness, cerebellar ataxia, spastic paraparesis and myopathy. (2) Dominant optic atrophy usually affects both eyes roughly symmetrically in a slowly progressive pattern of vision loss beginning in childhood and therefore is a contributor to childhood blindness. Vision testing will reveal scotomas (areas of impaired visual acuity) in the central visual fields with peripheral vision sparing and impaired color vision (color blindness). Visual acuity loss varies from mild to severe.

 

First signs of ADOA are typically present between four to six years of age, though presentation as early as one year of age has been reported. In some cases, Dominant Optic Atrophy may remain subclinical until early adulthood. Generally, the severity of the condition by adolescence reflects the overall level of visual function to be expected throughout most of the patient’s adult life. (5)

AUTOSOMAL DOMINANT OPTIC ATROPHY PLUS SYNDROME (ADOA PLUS)

Autosomal Dominant Optic Atrophy Plus Syndrome (ADOA Plus) is a variant of ADOA and accounts for approximately 20 percent of all ADOA cases. ADOA Plus is caused by mutations in the OPA1 gene. (10) Symptoms of ADOA Plus Syndrome typically start to occur within the first decade of life and are characterized by bilateral and symmetric progressive visual loss. Sensorineural deafness along with other extra-ocular manifestations may appear, such as chronic progressive external ophthalmoplegiaproximal myopathy, ataxia and axonal sensory motor polyneuropathy beginning in the second to third decades of life. 

OPA1 GENE MUTATION

Optic atrophy type 1 (ADOA & ADOA Plus) is caused by mutations in the OPA1 gene. The protein produced from this gene is made in many types of cells and tissues throughout the body. The OPA1 protein is found inside mitochondria, which are the energy-producing centers of cells.

 

The vision problems experienced by people with optic atrophy type 1 are due to mitochondrial dysfunction, leading to the breakdown of structures that transmit visual information from the eyes to the brain. Affected individuals first experience a progressive loss of nerve cells within the retina, called retinal ganglion cells. The loss of these cells is followed by the degeneration (atrophy) of the optic nerve. The optic nerve is partly made up of specialized extensions of retinal ganglion cells called axons. When the retinal ganglion cells die, the optic nerve cannot transmit visual information to the brain normally. (6)

OTHER AUTOSOMAL DOMINANT OPTIC ATROPHY DISORDERS

Less common than OPA1 are two other Autosomal Dominant Disorders, OPA4 and OPA5. As with OPA1, vision loss in OPA4 and OPA5 generally starts in the first decade of life, however, it may not be evident until the third decade of life in some people. No systemic findings or abnormalities have been found in OPA4 or OPA5. (9)

 

AUTOSOMAL RECESSIVE OPTIC ATROPHY DISORDERS

OPA2 X-Linked (only affects males)

OPA3, OPA6, OPA7 and OPA8 (9)

 

INHERITANCE

Dominant optic atrophy is inherited in an autosomal dominant manner. That is, a heterozygous patient with the disease has a 50 percent chance of passing on the disease to offspring, assuming his/her partner does not have the disease.

 

Dominant Optic Atrophy has been estimated to be 1:50,000 with prevalence as high as 1:10,000 in the Danish population. (5)

FAQ's.

WHEN DO YOU TYPICALLY SEE SIGNS OF ADOA?

Autosomal Dominant Optic Atrophy is usually diagnosed between the ages of 4-6 but signs have been reported as early as 1 year of age. For some, it has been reported as late as 14-15 years of age. It is primarily a pediatric disease and those affected will typically show signs of nerve deterioration slowing by the age of 15.

 

CAN YOU COMPLETELY LOSE ALL VISION?

It is not likely to lose all vision from ADOA. However, vision can be severely impacted, causing children to become legally blind and there have been cases where people affected have gone completely blind. It is one's central vision that is more heavily impacted, sparing some of the peripheral vision.

 

CAN GLASSES OR CONTACTS HELP IMPROVE THE VISION THAT'S BEEN LOST?

While glasses or contacts lenses may correct coexisting farsightedness, nearsightedness and astigmatism, they will not repair or correct the vision loss caused by ADOA. ADOA deteriorates the optic nerve, which transmits the signal from the eye to the brain. Once that nerve is damaged, the signal to the brain, and therefore vision, will be disrupted. However, people with ADOA may find improvement in visual functioning with magnifiers, telescopes, tinted lenses, electronic magnifiers, or other adaptive devices. These types of visual devices are available from a low vision rehabilitation optometrist.

 

IS THERE A TREATMENT OR CURE?

There currently is no treatment or cure ADOA.  The supplement, Idebenone, according to one study, showed some improvement in visual acuity in patients with ADOA.

 

DOES ADOA HAVE OTHER AFFECTS ON THE BODY OTHER THAN VISION LOSS?

Other affects on the body depends on the mutation of the gene. Some show only vision loss while others who have Dominant Optic Atrophy-Plus Syndrome experience nerve deterioration in other nervous systems throughout the body.

GLOSSARY.

Atrophy

The deterioration of cells.

Autosomal

Pertaining to a chromosome that is not a sex chromosome. People normally have 22 pairs of autosomes (44 autosomes) in each cell, together with 2 sex chromosomes, X and Y in a male and X and X in a female.

Axonal Sensory Motor Polyneuropathy

 A condition that causes a decreased ability to move or feel (sensation) due to nerve damage.

Cerebellar Ataxia

The cerebellum is the area of the brain responsible for controlling muscle coordination. Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements. Cerebellar ataxia is a form of ataxia originating in the cerebellum. 

Heterozygous

Humans contain two copies of each gene, one from the father and one from the mother, which sometimes are referred to as the alleles of a gene. If a mutation occurs in just one copy of the gene then that individual is considered heterozygous.

Mitochondria

Mitochondria are known as the powerhouses of the cell. They are organelles that act like a digestive system which takes in nutrients, breaks them down, and creates energy rich molecules for the cell. The biochemical processes of the cell are known as cellular respiration. Many of the reactions involved in cellular respiration happen in the mitochondria. Mitochondria are the working organelles that keep the cell full of energy. 


 

Mitochondrial Disease

A group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell. Mitochondria are found in every cell of the human body except red blood cells, and convert the energy of food molecules into the ATP that powers most cell functions.

Myopathy

A muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness.

Neuropathy

The term used to describe a problem with the nerves, usually the peripheral nerves as opposed to the central nervous system (the brain and spinal cord). 

Ocular

Of or connected with the eyes or vision.

Ophthalmoplegia

Paralysis of the muscles within or surrounding the eye.

Optic Nerve

The optic nerve connects the eye to the brain. The optic nerve carries the impulses formed by the retina, the nerve layer that lines the back of the eye and senses light and creates impulses. These impulses are dispatched through the optic nerve to the brain, which interprets them as images.

Peripheral Neuropathy

The peripheral nervous system sends information from your brain and spinal cord (central nervous system) to the rest of your body. Peripheral neuropathy is a result of damage to your peripheral nerves. It often causes weakness, numbness and pain, usually in your hands and feet. It can also affect other areas of your body.

Proximal Myopathy

Symmetrical weakness of proximal upper and/or lower limbs.

 

Sensorineural Deafness

A type of hearing loss. It occurs from damage to the inner ear, the nerve that runs from the ear to the brain, (auditory nerve).

Spastic Paraparesis

A rare disorder where parts of the body develop spasticity and weakness. Usually the limbs are involved.

Syndromic

Occurring as a syndrome or part of a syndrome.

Systemic

Of or relating to a system, especially as opposed to a particular part. "The disease is localized rather than systemic."

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

REFERENCES

1. Kjer, P (1959). "Infantile optic atrophy with dominant mode of inheritance: a clinical and genetic study of 19 Danish families.". Acta ophthalmologica. Supplementum 164 (Supp 54): 1–147. PMID 13660776.

 

2. Yu-Wai-Man, P; Griffiths, PG; Gorman, GS; Lourenco, CM; Wright, AF; Auer-Grumbach, M; Toscano, A; Musumeci, O; Valentino, ML; Caporali, L; Lamperti, C; Tallaksen, CM; Duffey, P; Miller, J; Whittaker, RG; Baker, MR; Jackson, MJ; Clarke, MP; Dhillon, B; Czermin, B; Stewart, JD; Hudson, G; Reynier, P; Bonneau, D; Marques W, Jr; Lenaers, G; McFarland, R; Taylor, RW; Turnbull, DM; Votruba, M; Zeviani, M; Carelli, V; Bindoff, LA; Horvath, R; Amati-Bonneau, P; Chinnery, PF (March 2010). "Multi-system neurological disease is common in patients with OPA1 mutations". Brain : a journal of neurology 133 (Pt 3): 771–86. doi:10.1093/brain/awq007. PMC 2842512. PMID 20157015.

 

3. Delettre, C; Lenaers, G; Griffoin, JM; Gigarel, N; Lorenzo, C; Belenguer, P; Pelloquin, L; Grosgeorge, J; Turc-Carel, C; Perret, E; Astarie-Dequeker, C; Lasquellec, L; Arnaud, B; Ducommun, B; Kaplan, J; Hamel, CP (October 2000). "Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy". Nature genetics 26 (2): 207–10. doi:10.1038/79936. PMID 11017079.  Cite uses deprecated parameter |coauthors= (help)

 

4. OMIM: Optic Atrophy 1 OMIM 165500

 

5. Votruba, 1998.( Votruba; Moore, AT; Bhattacharya, SS (1998). "Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy". Journal of medical genetics 35 (10): 793–800. doi:10.1136/jmg.35.10.793. PMC 1051452. PMID 9783700.

 

6. Genetics Home Reference.com

 

7. Guy Lenaers et al. Dominant optic atrophy. Orphanet Journal of Rare Diseases. July 9, 2012; 7(46):http://www.ojrd.com/content/7/1/46. Accessed 11/13/2013.)

 

8. Barboni P. et al. Idebenone treatment in patients with OPA1-mutant dominant optic atrophy. Brain. 2013; 136(Pt 2):e231:Accessed 11/13/2013.

 

9.  http://disorders.eyes.arizona.edu/category/genes

 

10. www.orpha.net

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