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early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia 1 (EAOH/AOA1)

EAOH/AOA1 is characterized by early‑onset slowly progressive ataxia, ocular motor apraxia, peripheral neuropathy and hypoalbuminemia.
AOA1 is an autosomal recessive spinocerebellar ataxia syndrome that resembles Friedreich's ataxia and A-T (ataxia telangiectasia) neurologically, but which lacks extraneurological features such as immunodeficiency and telangiectasia. Ataxia with oculomotor apraxia is a condition characterized by progressive problems with movement. The hallmark of this condition is difficulty coordinating movements (ataxia), which is often the first symptom. About half of affected people have trouble moving their eyes to look side-to-side (oculomotor apraxia). People with oculomotor apraxia have to turn their head to see things in their side (peripheral) vision.
A recent study of 14 French, Italian and Algerian AOA1 patients from nine families supports the likelihood that, although cerebellar atrophy, ataxia and sensorimotor axonal neuropathy are common to most AOA1 patients, the presence and severity of other features is more variable (~85% of patients in the case of oculomotor apraxia). Variation in clinical impact and/or severity of AOA1 is suggested further by reported clinical overlap with other neurological diseases/conditions, such as MSA (multiple system atrophy) and ataxia with coenzyme Q10 deficiency. AOA1 accounts for 5-10% of all autosomal recessive cerebellar ataxias and has variable age of onset (typically 1-18 years), with a mean of ~5 years. Unlike A-T cells, AOA1 cells are only mildly sensitive, if at all, to ionizing radiation and other genotoxins, and exhibit normal cell-cycle-checkpoint control and chromosome stability following ionizing radiation. Consistent with these observations, elevated cancer incidence has not been reported in AOA1 patients. The gene mutated in AOA1 is designated APTX, and the protein product of APTX is designated aprataxin.

There are two types of ataxia with oculomotor apraxia. The two types are very similar but are caused by mutations in different genes, (APTX in EAOH/AOA1 and SETX in AOA2/SCAR1). Shared features, in addition to ataxia and oculomotor apraxia, are involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). Type 1 typically has an earlier onset of symptoms (around age 7) than type 2 (around age 15). Chorea and myoclonus tend to disappear gradually in type 1 whereas these movement problems are persistent in type 2. Neuropathy is more severe in type 1 and can lead to impaired mobility, muscle and nerve degeneration (atrophy), and occasionally, limb deformities. Individuals with type 1 typically require wheelchair assistance about 10 years after the start of movement problems; those with type 2 tend to be mobile for a longer period of time. Intellectual functioning is usually not affected by either type of the disorder, but some people may have mild cognitive problems, such as difficulty concentrating or performing multi-step activities.
People with ataxia with oculomotor apraxia type 1 tend to have decreased amounts of a protein called albumin, which transports molecules in the blood, and increased amounts of cholesterol circulating in their bloodstream. Increased cholesterol levels may raise a person's risk of developing heart disease. The effects of abnormal levels of albumin are unknown. People with ataxia with oculomotor apraxia type 2 tend to have high amounts of a protein called alpha-fetoprotein (AFP) in their blood. The level of this protein is usually increased in the bloodstream of pregnant women. Affected individuals may also have high amounts of a protein called creatine phosphokinase (CPK) in their blood. This protein is found mainly in muscle tissue. The effect of abnormally high levels of AFP or CPK in people with ataxia with oculomotor apraxia is unknown.

DNA single‑strand breaks (SSBs) are non‑overlapping discontinuities in strands of a DNA duplex. Significant attention has been given on the DNA SSB repair (SSBR) system in neurons, because the impairment of the SSBR causes human neurodegenerative disorders, including early‑onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), also known as ataxia‑oculomotor apraxia Type 1 (AOA1).
Neuropathological examination reveals severe loss of Purkinje cells and moderate neuronal loss in the anterior horn and dorsal root ganglia. EAOH/AOA1 is caused by the mutation in the APTX gene encoding the aprataxin (APTX) protein. APTX interacts with X‑ray repair cross complementing group 1 protein, which is a scaffold protein in SSBR. In addition, APTX‑defective cells show increased sensitivity to genotoxic agents, which result in SSBs. These results indicate an important role of APTX in SSBR. SSBs are usually accompanied by modified or damaged 5′‑ and 3′‑ends at the break site. Because these modified or damaged ends are not suitable for DNA ligation, they need to be restored to conventional ends prior to subsequent repair processes. APTX restores the 5′‑adenylate monophosphate, 3′‑phosphates and 3′‑phosphoglycolate ends. The loss of function of APTX results in the accumulation of SSBs, consequently leading to neuronal cell dysfunction and death.

ataxia-oculomotor apraxia 1



TYPE: neurodegenerative disease, psychomotor impairment, NO CANCER development, eye or vision problem, immunodeficiency

DNAtraffic protein(s) related to disease: APTX

OMIM: 208920

Last modification date: Aug. 17, 2011