AOA Fact Sheet
Ataxia:
Ataxia with Oculomotor Apraxia (AOA1, AOA2)
RELATED GENES:
APTX (AOA1), SETX (AOA2)
LOCATION:
Chromosome 9 (APTX 9p21.1), (SETX 9q34.13 )
MUTATION TYPE:
APTX, SETX -> Pathogenic variants
LAST UPDATE:
September 22, 2025 by Marcio Galvão
HERITAGE:
Autosomal Recessive
Content generated with the support of Generative AI, reviewed by the author.
1. ABOUT AOA
Ataxias with oculomotor apraxia (AOA) are rare, inherited neurological conditions with autosomal recessive inheritance that affect the central nervous system. In addition to ataxia, people affected by AOA also develop oculomotor apraxia and other symptoms (see Section 2. Typical Symptoms ).
There are several types of ataxia with oculomotor apraxia (AOA) caused by mutations in different genes, with types 1, 2, and 4 (AOA1, AOA2, and AOA4) being the most common. There is also an ataxia in the "AOA" group called XRCC1-AOA [8] . These types are similar in symptoms, which in all of them typically manifest in childhood or adolescence.
About AOA1 (Ataxias with oculomotor apraxia type 1)
In the case of AOA1, the disease is caused by mutations in the APTX gene, which provides instructions for creating the aprataxin protein. Dozens of different mutations in the APTX gene that can cause AOA1 have been identified. Most are point mutations, such as single nucleotide substitutions, insertions, or deletions. Depending on the type of mutation, there may be a reduction in aprataxin synthesis, or amino acid modifications may occur, resulting in nonfunctional or unstable proteins that break down easily in cells [6] . These mutations interfere with aprataxin's ability to repair damaged DNA , leading to the characteristic symptoms of AOA1.
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The protein aprataxin (APTX) is involved in the repair of damaged DNA within cells ( single-stranded DNA repair [8] ). DNA can be damaged by various causes, such as exposure to damaging agents such as certain types of reactive oxygen species (ROS), exposure to ionizing radiation, or other environmental factors. DNA breaks can also occur when chromosomes exchange genetic material in preparation for cell division.
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Due to the reduced or less functional amount of the aprataxin protein and the accumulation of DNA damage within the mitochondria, mitochondrial dysfunctions may also occur in AOA1 to which muscle and brain tissues are especially sensitive due to their greater need for energy [6, 7] .
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The aprataxin protein plays an important role in regulating the transcription process (the conversion of DNA into messenger RNA or mRNA - see Figure 1), interacting directly with other proteins involved in transcription. If aprataxin is defective or dysfunctional due to a mutation in the APTX gene, it may impact the transcription process, resulting in the deficiency of other proteins essential for life, and also causing cell death [6] .
Figure 1 - Role of aprataxin in the process of DNA transcription into mRNA - image reproduced from [6] .
In summary, in individuals with AOA1, the amount of the aprataxin protein encoded by the APTX gene is reduced, or unstable or defective proteins may be synthesized, which affects efficient DNA repair in cells. Without adequate DNA repair, the cell becomes unstable and may die. In the case of nerve cells (neurons) in the central nervous system, cell death is especially impactful, as regeneration does not occur, resulting in cumulative neuronal loss , which can result, for example, in atrophy of the cerebellum , responsible for coordinating our movements, and thus the symptoms of ataxia ( Figure 2 - Image generated by the author with the support of Artificial Intelligence).
About AOA2 (Ataxias with oculomotor apraxia type 2)
Ataxia with oculomotor apraxia type 2 (AOA2) is also referred to in some sources as SCAR1 and SCAN2. It combines typical symptoms of ataxia (poor coordination, balance problems, and others) with chronic axonal neuropathy, and in about half of cases, oculomotor apraxia [10] .
In the case of AOA2, the disease is caused by mutations in the SETX gene, which synthesizes the protein senatexin (SETX), a DNA/RNA helicase (see Note 1) located in the cell nucleus that is involved in DNA repair. More than one hundred different mutations in the SETX gene that can cause AOA2 (and other diseases) have been identified. Most are nonsense, missense, and splice site mutations , as well as small deletions and insertions. [10, 6] . Depending on the type of mutation, there may be a reduction in senataxin synthesis, or amino acid modifications may occur, resulting in nonfunctional or unstable proteins that break down easily in cells . These mutations may interfere with senataxin's ability to repair damaged DNA, as well as interfering in other important cellular processes (regulation of DNA transcription into mRNA, autophagy and removal of toxic proteins, regulation of R-loops and others) , which can cause neuronal loss (nerve cell death) leading to the emergence of the characteristic symptoms of AOA2 [6] ,
Note 1: A DNA/RNA helicase is an enzyme that plays a crucial role in the replication, transcription, and repair of DNA and RNA. These enzymes are responsible for unwinding the DNA or RNA double helix, separating the two complementary strands to allow processes such as replication and transcription to occur. During DNA replication, for example, helicase unwinds the double helix, allowing other enzymes, such as DNA polymerase, to copy the DNA strands. Similarly, during the transcription of DNA into RNA, helicase unwinds the double helix to allow RNA polymerase to synthesize messenger RNA.
Note 2: In addition to AOA2 ataxia, which is recessively inherited (see Section 5. Inheritance ), mutations in the senataxin (SETX) gene can also cause amyotrophic lateral sclerosis type 4 (ALS4), an autosomal dominant form of juvenile-onset amyotrophic lateral sclerosis [10].
2. TYPICAL SYMPTOMS
Symptoms of AOA can vary from person to person, even within the same family. Some people may develop more symptoms than others, and when they do occur, they can be mild, moderate, or severe. Below, we present just a brief overview of the typical symptoms of AOA1 and AOA2.
Symptoms of AOA1
According to sources [1,2] , patients with AOA1 initially present with typical symptoms of ataxia with slow progression, such as problems with motor coordination and balance (difficulty walking), difficulties with speech (dysarthria) and swallowing (dysphagia), as well as intention tremors and muscle spasms.
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Some years after the onset of ataxia symptoms, all individuals with AOA1 also develop symptoms of oculomotor apraxia , such as difficulty focusing on objects and voluntarily moving their eyes from side to side. When asked to look to one side (left or right), or up and down, patients with AOA1 first turn their head, with counter-inversion in their gaze, and only then do their eyes follow the same direction in small, slow saccades. Many individuals with AOA1 blink excessively.
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Other symptoms of AOA1 are loss of muscle mass (atrophy) in the hands and feet.
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About 30% of patients studied with AOA1 had Pes cavus , and a few others developed scoliosis (symptoms that also occur in Friedreich's Ataxia - see Differential Diagnosis in Section 7. Additional Information ).
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Involuntary movements (chorea) and dystonia of the upper limbs may occur.
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In more advanced stages, axonal peripheral neuropathies dominate the clinical picture of AOA1, which can cause muscle weakness in the limbs. After many years with the disease, patients may experience problems with reflexes and the ability to sense vibrations. The senses of pain, light, and touch are preserved.
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Intelligence is not usually affected by ataxia with oculomotor apraxia type 1 (AOA1), although some people with this condition may have cognitive impairments.
Some individuals with AOA1 may require the use of a wheelchair, typically 10 to 15 years after the onset of symptoms (or between 15 and 20 years of age on average).
Symptoms of AOA2
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Ataxia is the first symptom of AOA2, and also the main disabling cause at the onset of the disease.
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Subsequently, sensorimotor peripheral neuropathy (particularly in the lower limbs) plays an important role in the progression of the disease, affecting between 90% and 100% of individuals (reduction or absence of reflexes and sensory losses (e.g., feeling vibrations).
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Oculomotor apraxia is present in about half (51%) of individuals. This condition results in difficulty fixing one's gaze on objects and voluntarily moving the eyes from side to side. When asked to look to one side (left or right), or up and down, patients with AOA2 first turn their head, with counter-gaze, and only then do their eyes follow the same direction as the head turned in small, slow saccades.
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Other ocular changes (e.g., nystagmus, corvergent strabismus) are observed in some individuals with AOA2.
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Other movement disorders (e.g., hand dystonia, chorea, head tremors, and postural tremors) may also occur in some cases.
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Cognitive problems (not severe) are present in some individuals, which can affect some executive functions, speech, short-term memory, and hinder learning.
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Other less common symptoms (including non-neurological symptoms) are described in [10] .
Some individuals with AOA2 may require the use of a wheelchair for improved mobility, typically around age 30 [10] .
3. ONSET
AOA1
The onset of symptoms of AOA1 typically occurs around 4 years of age [2] .
Notes
1. The GeneReviews portal [1] indicates the age range between 2 and 10 years for the onset of symptoms, with an average of 4.3 years.
2. The NEUROMUSCULAR portal [3] indicates the range between 1 and 16 years, with an average of 4.7 years.
3. Source [8] indicates a range between 2 and 12 years, with an average of 5 years.
AOA2
The age at which symptoms of AOA2 ataxia appear varies between 3 and 30 years (average 20.3 years), that is, symptoms can manifest in children, adolescents or adults [10] .
The NEUROMUSCULAR portal [11] indicates the onset of AOA2 symptoms between 2 and 22 years of age, with an average of 15 years.
While AOA1 ataxia typically manifests in childhood, the source [12] characterizes AOA2 as a "typically adolescent" disorder with symptom onset between 10 and 25 years of age, with a mean of 14-15 years,
4. ANTICIPATION
Anticipation is not observed in AOA, given that the disease "skips generations".
5. INHERITANCE
As we have seen, AOA1 is associated with mutations (pathogenic variants) in the APTX gene, while AOA2 is associated with mutations in the SETX gene. Both types can be passed from parents to children.
All types of AOA have an autosomal recessive inheritance pattern. This means that children of any sex have an equal chance of inheriting the mutation that may cause the disease. An individual will only develop symptoms if they inherit two copies (alleles) of the mutated gene—one from each parent. If they inherit only one copy of the mutated gene (from either the mother or the father), they will not develop the disease but will be a carrier of the mutated gene. In carriers (i.e., individuals who have only one allele with the mutation), the "normal" copy of the gene takes precedence over the faulty one, so they do not develop symptoms. However, individuals who inherit two defective copies of the gene will develop the disease at some point in their life (see Section 3. Onset).
Unless they have undergone genetic testing due to a family history of the disease, most carriers are unaware that they carry a mutated gene, since they show no symptoms. It is common for parents to discover they are carriers only when one of their children is diagnosed with a condition such as AOA1 (which means both biological parents are carriers).
Probability of Children Inheriting the Disease
Statistically, if both parents are carriers:
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Each child has a 25% chance of developing the disease (i.e., inheriting one mutated gene from each parent).
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Each child has a 50% chance of being a carrier without developing the disease (i.e., inheriting only one mutated gene, from either parent).
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Each child has a 25% chance of not inheriting any mutated gene (i.e., not developing the disease and not being a carrier).
Genetic Counseling
Since the condition is hereditary (can be passed on to future generations), once a pathogenic variant of the gene causing any AOA subtype is identified in a family member, genetic counseling is recommended for adult carriers who plan to have children.
Notes: "Autosomal" means the gene is located on any chromosome except the sex chromosomes (X and Y). Genes, like chromosomes, normally exist in pairs (one copy inherited from the mother, the other from the father). Therefore, males and females have equal chances of inheriting a mutated gene that can cause a hereditary ataxia. "Recessive" means that two mutated copies (alleles) of the gene—one from each biological parent—are necessary for the person to develop the disease.
Figure 3 – Source: MedlinePlus, U.S. National Library of Medicine.
6. PREVALENCE
AOA1
Ataxia with oculomotor apraxia type 1 is a rare disease, and its exact prevalence is unknown. It is estimated that AOA1 affects a few hundred people worldwide, with the highest prevalence appearing in Portugal, Japan, Italy, and France [8].
There are also cases identified in Tunisia, Germany, the United States, Brazil and other countries.
AOA2
Ataxia with oculomotor apraxia type 2 is a rare disease, and its exact prevalence is unknown. It is estimated that fewer than 5,000 people in the United States have this disease [13] . The estimated incidence of AOA2 is probably higher than that of ataxia telangiectasia, which is about 3 cases per million. The prevalence of AOA2 in France is estimated at 1/900,000 [12] .
Studies conducted in Portugal since 1993 suggest that, after Friedreich's ataxia, AOA (considering all subtypes!) is the most prevalent autosomal recessive ataxia (12.6%). While types 1 and 4 are more common in Portugal, type 1 appears to be the leading cause of autosomal recessive ataxia in Japan, where AOA1 is called "early-onset ataxia with oculomotor apraxia and hypoalbuminemia," referring to the fact that patients with AOA1 have a deficiency in albumin production.
Due to its rarity, awareness of the different types of AOA and the level of information about the disease is still very limited, which brings challenges to diagnosis (see Section 7. Additional Information ).
7. ADDITIONAL INFORMATION
Diagnosis of AOA (Any Type with Identified Gene)
The diagnosis of AOA (any type with an identified gene) can be established through a combination of clinical evaluation, family history, physical examination, and laboratory findings, and it can be confirmed by molecular genetic testing (DNA testing), which may also be used to identify asymptomatic carriers of gene mutations that can cause certain subtypes of AOA.
Diagnosis of AOA1
It is important to obtain an accurate diagnosis of AOA1, as other neurological disorders may produce similar symptoms (see Differential Diagnosis below). Early diagnosis allows for timely initiation of appropriate treatment to manage symptoms. However, diagnosing AOA1 in very young children can be difficult, as the disorder's symptoms may not yet be fully apparent.
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During clinical evaluation, the physician may identify signs of ataxia (motor coordination, reflexes, muscle strength, etc.) and other neurological signs associated with oculomotor apraxia.
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MRI scans show cerebellar atrophy in all affected individuals. Some may also show atrophy in other central nervous system structures (e.g., brainstem).
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Signs of axonal neuropathy are found in 100% of individuals with AOA1. These signs can be detected by EMG (electromyography).
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To support diagnosis, the neurologist will ask detailed questions about the patient's medical history and family history (e.g., whether others in the family have been diagnosed with or show symptoms of AOA1), as well as other relevant factors that might help identify possible risks or underlying causes.
Laboratory Tests and Indicators for AOA1
Individuals with certain types of ataxia with oculomotor apraxia may have specific blood abnormalities. People with type 1 (AOA1) tend to have reduced levels of a protein called albumin, which transports molecules in the blood. Albumin deficiency (hypoalbuminemia) generally results in elevated cholesterol in the bloodstream, which in turn increases the risk of heart disease [2]. For more detailed information on lab findings useful in diagnosing AOA1, see sources [1, 8]. According to sources [3, 6], Coenzyme Q10 levels may be reduced in patients with AOA1.
Diagnosis of AOA2
Main clinical features of AOA2:
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Slowly progressive cerebellar ataxia
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Absent or diminished tendon reflexes and peripheral axonal neuropathy (>90% of individuals)
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Oculomotor apraxia (~51% of individuals)
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Pyramidal signs (plantar reflex is flexor or neutral)
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Dystonic hand posture, choreic movements, head or postural tremors
Laboratory Tests and Indicators for AOA2:
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Cerebellar atrophy can be detected by MRI (especially in the cerebellar hemispheres and vermis).
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EMG shows signs of axonal neuropathy in 90–100% of individuals with AOA2.
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People with AOA2 present elevated alpha-fetoprotein (AFP) levels, a glycoprotein synthesized by the liver—above 20 ng/mL (normal range: 0–20 ng/mL) in over 95% of affected individuals.
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Total blood cholesterol is also elevated (>5.6 mmol/L; normal range: 3.5–5.8 mmol/L) in about 50% of affected individuals.
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Elevated levels of immunoglobulins (IgG and IgA) have been reported in some families.
Differential Diagnosis of AOAs
In children, AOA2 is the disorder most likely to be confused with AOA1.
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While AOA1 presents with low serum albumin (and high cholesterol), AOA2 is marked by elevated alpha-fetoprotein levels.
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In addition to AOA2, it is also important to differentiate AOA1 from AOA3 (caused by mutations in the PIK3R5 gene) and AOA4 (PNKP gene). For more information, see Table 2 in [1].
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During the diagnostic process in adolescents, it is important to rule out other autosomal recessive ataxias such as Friedreich’s ataxia and Vitamin E deficiency ataxia (AVED). Note that oculomotor apraxia does not occur in Friedreich’s ataxia, which can help in differential diagnosis. It is also important to distinguish AOA2 from Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS). Since Coenzyme Q10 levels may be reduced in AOA1, differential diagnosis should also include SCAR9 (primary CoQ10 deficiency ataxia).
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In adult patients without a known family history (so-called “simplex” cases), AOA1 and AOA2 can be mistaken for Spinocerebellar Ataxia Type 2 (SCA2), which has an autosomal dominant inheritance pattern and also features cerebellar ataxia with slow eye movements. Diagnosis of SCA2 can be confirmed (or ruled out) by molecular genetic testing for mutations in the ATXN2 gene [1, 10].
8. THERAPIES AND DRUGS IN TRIALS FOR AOA
There are still no medications and therapies approved by the FDA (United States) and ANVISA (Brazil) specifically to cure or modify the course of AOA, although it is possible to treat symptoms (see Section 9. Treatments ).
Comments for AOA1
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Mitochondrial dysfunction caused by AOA1 was already treated in a 2015 study with a diabetes drug called Rosiglitazone [7] . Note that the study cited here was not a clinical trial with human patients, but rather a study conducted on cells.
Comments for AOA2
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Drugs to improve the cellular autophagy process or the R-Loops regulation process are candidates for new therapies for AOA2.
9. TREATMENTS
AOA ataxia currently has no cure, but its symptoms can be managed to improve quality of life and provide continuous support for the patient. It is important that patients with any subtype of AOA are followed by a neurologist and a specialized multidisciplinary medical team, with the gradual inclusion of other healthcare professionals as needed depending on the symptoms (e.g., geneticist, neuro-ophthalmologist, neurofunctional physical therapist, occupational therapist, speech therapist, nutritionist, etc.).
Specific Recommendations for AOA1
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To prevent secondary complications in patients with AOA1, a high-protein diet is recommended to prevent edema and restore serum albumin levels, while also maintaining a low-cholesterol diet [1].
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Since Coenzyme Q10 (CoQ10) levels may be reduced in the cells of some patients with AOA1 [3,6], CoQ10 supplementation (prescribed by a physician) may help increase energy levels (some patients respond positively) [6].
Specific Recommendations for AOA2
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A low-cholesterol diet is recommended for individuals with AOA2, and cholesterol levels in these patients should be monitored regularly.
General Symptom Management Recommendations for AOAs [1]:
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The doctor may prescribe different medications for specific symptoms.
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Exercise and neurofunctional physical therapy are recommended to improve motor coordination, balance, muscle strength, and reduce the risk of falls.
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Occupational therapy can help patients maintain independence in daily activities.
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For balance difficulties caused by ataxia, canes, walkers, or wheelchairs may be adopted depending on disease progression. Home modifications are also recommended (e.g., grab bars in bathrooms).
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Weight control is advisable to avoid worsening mobility.
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For dysarthria, speech therapy and assistive communication devices (available for computers, iPads, etc.) are recommended.
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In cases of dysphagia (swallowing difficulties), a speech therapist can provide appropriate management strategies to maintain proper nutrition and hydration and reduce the risk of choking and aspiration pneumonia (which can be fatal).
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If necessary, medications may be prescribed to manage anxiety, depression, or other mental health issues.
Note! Some patients with various types of cerebellar ataxia have reported benefits and symptom improvement after sessions of non-invasive cerebellar neuromodulation or stimulation, such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) with certified physical therapists. However, although this therapy is already being offered commercially, it has not yet been approved by the FDA in the United States or by ANVISA in Brazil for the treatment of ataxias—meaning it remains an experimental treatment with no guaranteed results.
See information about medications for ataxia symptoms.
See information about treatments and care for patients.
See information about those with a recent diagnosis.
See information about Support Groups for patients and caregivers.
10. REFERENCES
The references below include academic sources and materials from specialized organizations that support the information in this technical factsheet, including peer-reviewed articles, genetic repositories – such as OMIM, literature summaries – such as GeneReviews, and educational materials from ataxia foundations. For more information, please consult the References list on ataxia.info.
Ref #1
Source:
Paula Coutinho, MD, PhD, Clara Barbot, MD, PhD, and Paula Coutinho, MD, PhD
Copyright © GeneReviews. GeneReviews ® is a registered trademark of the University of Washington, Seattle.
Language:
Inglês
Date:
Last Update: March 19, 2015.
Ref #2
Source:
MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US)
An official website of the United States government
Language:
Inglês
Date:
Last updated June 1, 2018
Ref #3
Source:
NEUROMUSCULAR DISEASE CENTER (Alan Pestronk, MD)
Washington University, St. Louis, MO - USA
Language:
Inglês
Date:
Last Updated: Please see https://neuromuscular.wustl.edu/rev.htm
Ref #4
Source:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
Inglês
Date:
Last Updated: January 2024
Ref #5
Source:
OMIM ® - An Online Catalog of Human Genes and Genetic Disorders.
Copyright © Johns Hopkins University.
Language:
Inglês
Date:
Edit History: carol: 11/13/2017
Ref #6
Source:
Webinar presented by Julie Greenfield about AOA1 and AOA2 hosted by Ataxia UK and the AT Society.
YouTube
Language:
Inglês
Date:
May 21, 2021
Ref #7
Source:
Beatriz Garcia-Diaz et al
PubMed Central ® Hum Mol Genet. 2015 Aug 15 PMID: 25976310; PMCID: PMC4512623.
Language:
Inglês
Date:
Published online 2015 May 14
Ref #8
Source:
NAF Webinar presented by Dr. Brent Fogel
YouTube
Language:
Inglês
Date:
Published online 2024 June 14
Ref #9
Source:
NAF (National Ataxia Foundation)
website
Language:
Inglês (a página pode ser traduzida para Português através do botão TRANSLATE)
Date:
2024
Ref #10
Source:
Maria-Ceu Moreira, MSc, PhD and Michel Koenig, MD, PhD.
Copyright © GeneReviews. GeneReviews ® is a registered trademark of the University of Washington, Seattle.
Language:
Inglês
Date:
Last Update: July 12, 2018
Ref #11
Source:
NEUROMUSCULAR DISEASE CENTER (Alan Pestronk, MD)
Washington University, St. Louis, MO - USA
Language:
Inglês
Date:
Last Updated: Please see https://neuromuscular.wustl.edu/rev.htm
Ref #12
Source:
Expert reviewer(s): Dr Perrine CHARLES
© Orphanet - The portal for rare diseases and orphan drugs (ORPHA:64753)
Language:
Inglês
Date:
Last Updated: Please see https://neuromuscular.wustl.edu/rev.htm
Ref #13
Source:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English
Date:
Last Updated: February 2025