Ataxia with oculomotor apraxia type 1

Other Names: EAOH; Ataxia-oculomotor apraxia 1; AOA1; Ataxia-telangiectasia-like syndrome; Early-onset cerebellar ataxia with hypoalbuminemia; EOCA-HA; Early-onset ataxia with oculomotor apraxia and hypoalbuminemia; Ataxia-oculomotor apraxia type 1

A rare autosomal recessive cerebellar ataxia, characterized by progressive cerebellar ataxia associated with oculomotor apraxia, severe neuropathy, and hypoalbuminemia.

Epidemiology

Ataxia-oculomotor apraxia type 1 (AOA1) represents 3.6% of all autosomal recessive cerebellar ataxia (ARCA) in Portugal; in Japan, AOA1 seems to be the most frequent cause of ARCA. In a cohort of 227 patients mostly of French origin with progressive cerebellar ataxia selected after exclusion of Friedreich ataxia, the relative frequency of AOA1 was of 5%.

Cause

AOA1 results from mutations in APTX gene (9p13.3) encoding aprataxin which plays a role in DNA-single-strand break repair. Most mutations identified so far are localized in exons 5, 6 and 7. Some correlations between genotype and phenotype have been established: for example severe and persistent choreic phenotype is associated with mutations A198V; truncating mutations are associated with earlier onset and deletions with more severe phenotype and intellectual disability.

Inheritance

Autosomal recessive inheritance, a 25% chance

Transmission of AOA1 is autosomal recessive. Genetic counseling is recommended as each sib of an affected individual has 25% chance of being affected, 50% chance of being an asymptomatic carrier, and 25% chance of being neither affected nor a carrier.

Signs and symptoms

Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy.

The first manifestation is progressive gait imbalance (mean age of onset: 4.3 years; range: 2-10 years), followed by dysarthria, then upper-limb dysmetria with mild intention tremor.

Oculomotor apraxia, usually noticed a few years after the onset of ataxia, progresses to external ophthalmoplegia. All affected individuals have generalized areflexia followed by a peripheral neuropathy and quadriplegia with loss of ambulation about seven to ten years after onset. Hands and feet are short and atrophic. Chorea and upper-limb dystonia are common. Intellect remains normal in some individuals; in others, different degrees of cognitive impairment have been observed.

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

• Ataxia
• Gait disturbance(Abnormal gait)
• Medial flaring of the eyebrow
• Peripheral neuropathy

5%-29% of people have these symptoms

• Mental deterioration(Cognitive decline)

1%-4% of people have these symptoms

• Choreoathetosis

Diagnosis

Diagnosis of ataxia with oculomotor apraxia type 1 (AOA1) should be suspected in individuals with the following combination of clinical features and test results.

Clinical features

• Cerebellar ataxia, oculomotor apraxia, and areflexia followed by signs of severe peripheral neuropathy
• Childhood onset
• Slow progression leading to severe motor handicap
• Long survival
• Absence of extraneurologic findings common in ataxia-telangiectasia (telangiectasias and immunodeficiency).
• Family history consistent with autosomal recessive inheritance

Test results

• MRI. Cerebellar atrophy is present in all affected individuals. A very few individuals also have brain stem atrophy.
• EMG. Signs of axonal neuropathy are found in 100% of individuals with AOA1. Note: Normal EMG results may be observed only in those investigated in the very early stages of the disease.

Laboratory findings that can be used to confirm the diagnosis of AOA1 in a symptomatic person include :

• Serum concentration of albumin. Serum concentration of albumin is decreased (<3.8 g/L) in 83% of individuals with disease duration of more than ten to 15 years.
• Serum concentration of total cholesterol. Serum concentration of total cholesterol is increased (>5.6 mmol) in 68% of individuals with disease duration of more than ten to 15 years.
• Normal serum concentration of alpha-fetoprotein
• Neuropathology. Nerve biopsy confirms axonal neuropathy.

Treatment

• Physical therapy may be helpful, particularly for disabilities resulting from peripheral neuropathy.
• A wheelchair is usually necessary for mobility by age 15-20 years.
• Educational support should be provided to compensate for difficulties in speaking (dysarthria), in reading (oculomotor apraxia), and in writing (upper-limb ataxia and weakness).

NIH genetic and rare disease info

• NIH info on Ataxia with oculomotor apraxia type 1

Ataxia with oculomotor apraxia type 1 is a rare disease.