Azorean Disease

Azorean disease causes progressive degeneration of the central nervous system. Affected individuals experience deterioration in muscle coordination and other physical symptoms, but intelligence and mental function remain unaffected by the disease.

Description

Azorean disease is an inherited disorder that causes impaired brain functioning, vision problems, and loss of muscle control. It is named for the Azores, the group of nine Portuguese islands where the disease is prevalent.

Many of the reported cases have been found in the direct descendants of William Machado, an Azorean native who immigrated to the New England area of the United States, and Atone Joseph, a Portuguese sailor from the island of Flores who came to California in 1845. Other names for Azorean disease include Machado-Joseph disease, Joseph disease, and spinocerebellar ataxia type III.

Azorean disease is classified into three types depending on the age of onset and the specific physical symptoms. In type I, the age of onset is usually before age 25 and the affected individuals experience extreme muscle stiffness and rigidity. In type II, the age of onset is typically in the mid-30s, and progressive loss of muscle coordination (ataxia) occurs, resulting in the inability to walk. In type III, the average age of onset is 40 or later, and the main symptoms are weakness and loss of sensation in the legs.

The symptoms of Azorean disease result from the loss of brain cells and the impairment of neurological connections in the brain and spinal cord. This degradation of the central nervous system is believed to be caused by the production of a destructive protein from a mutated gene .

Genetic profile

Azorean disease is inherited as an autosomal dominant trait. This means that only one parent has to pass on the gene mutation in order for the child to be affected with the syndrome.

Each gene in the human body is made up of units called nucleotides, abbreviated C (cytosine), A (adenine), T (thymine), and G (guanine). A sequence of three nucleotides is called a trinucleotide. Azorean syndrome is caused by a genetic mutation that results in the over-duplication of a CAG trinucleotide sequence.

The location of the mutant gene in Azorean disease is 14q32, on the long arm of chromosome 14. This gene normally encodes the formation of a cellular protein called ataxin- 3. In the general population, there are between 13 and 36 repeats of the CAG sequence, but in those individuals with Azorean disease, there may be between 61 and 84 repeats. The increased number of repetitions causes the gene to encode an abnormal protein product that is believed to cause cell death in the brain and spinal cord.

In successive generations, the number of the repetitions may increase, a phenomenon known as genetic anticipation. In addition, there appears to be a strong relationship between the number of repetitions and the age at onset of Azorean disease: the more repetitions, the sooner the disease presents and the more serious the symptoms are. Also, if the individual is homozygous for the mutated gene, meaning he or she inherits the gene from both parents, Azorean disease is more severe and the age of onset is as early as 16 years.

Demographics

Azorean disease is primarily found in people of Portuguese ancestry, particularly people from the Azores islands. In the Azores islands the incidence of Azorean disease is approximately one in every 4,000, while among those of Azorean descent, it is one in every 6,000. Azorean disease has also been identified in other ethnic groups, including Japanese, Brazilians, Chinese, Indians, Israelis, and Australian aborigines.

Signs and symptoms

The age of onset of Azorean disease is typically from the late teens to the 50s, although onset as late as the 70s has been reported. The first observable symptoms are difficulty in walking and slurred speech. There is wide variation in the range of observed symptoms, but they typically include problems with muscular coordination, eyes and vision, and other physical bodily functions such as speech and urination. Mental ability is not impaired by Azorean disease.

Muscular symptoms

Muscular symptoms observed in people with Azorean disease include:

• difficulty in walking, including staggering or stumbling,
• weakness in arms or legs,
• involuntary jerking or spastic motions,
• cramping or twisting of the hands and feet,
• facial tics and grimaces,
• twitching or rippling of the muscles in the face.

Eyes and vision

People with Azorean disease may experience double vision, bulging eyes, difficulty in looking upward, difficulty in opening the eyes, a fixed or staring gaze, or involuntary eye movements from side to side.

Other symptoms

Other symptoms reported in people with Azorean disease include difficulty in speech such as slurring, loss of feeling in arms or legs, frequent urination, infections of the lungs, diabetes, weight loss, and difficulty sleeping.

Diagnosis

Azorean disease can be diagnosed after observation of typical symptoms and a medical history that establishes a familial pattern to the disease. Brain imaging studies such as computerized tomography (CT) and magnetic resonance imaging (MRI) may be employed. Blood tests can show increased levels of blood sugar and uric acid. Genetic studies that reveal the presence of the increased number of CAG trinucleotide repeats in the affected individual will provide definite confirmation of the diagnosis of Azorean disease.

The symptoms of Azorean disease are similar to other degenerative neurological conditions such as Parkinson disease , Huntington disease , and multiple sclerosis. Careful diagnosis is required in order to distinguish Azorean disease from these other conditions.

Treatment and Management

Treatment for Azorean disease is based on management of the symptoms. As of 2001 there is no treatment that stops or reverses the effects of the disease itself. A multidisciplinary team of specialists in neurology, ophthalmology, and endocrinology is often called for. Medications that specifically treat movement disorders, such as dopamine agonists, may help alleviate some of the symptoms of Azorean disease. Some experimental drugs and treatments under development for other neurological disorders may also benefit patients with Azorean disease.

Since Azorean disease is an inherited disorder, genetic counseling is recommended for people with a family history of the disease.

Prognosis

The prognosis for individuals with Azorean disease varies depending on the age of onset and severity of the symptoms. The muscular degeneration caused by the disease usually results in eventual confinement to a wheelchair. After onset of the symptoms, life expectancy ranges from 10 to 30 years.

Clinical Characteristics

Ocular Features: 

External ophthalmoplegia in some form is usually present and there may be a supranuclear component.  Smooth horizontal movements are impaired and saccades are dysmetric.  Gaze-evoked nystagmus is a common finding.  The eyes are often described as ‘bulging’ and this has been attributed to eyelid retraction.  With time the abnormal saccadic movements slow resulting in ophthalmoparesis with restriction of upgaze.

Systemic Features: 

This form of spinocerebellar ataxia is considered to be the most frequent.  It is a progressive disease in all aspects which accounts for some of the considerable clinical heterogeneity reported.  Onset is likewise highly variable depending upon the number of repeats but usually sometime between the second to fifth decades.  In a large cohort of Azorean individuals the mean age of onset was reported to be 37 years.

An unsteady gait, dysarthric speech, general clumsiness, and diplopia are among the early symptoms.  Nystagmus, spasticity, and various autonomic signs including reduced bladder control may also be noted.  Chronic pain, sleep disturbances, impaired mental functioning, and memory deficits are often present and some authors have labelled these as indicative of dementia.

Virtually all clinical signs progress with ambulation difficulties requiring the need for assistive devices about a decade after the onset of disease.  Eventually signs of brain stem involvement appear with facial atrophy, perioral twitching, tongue fasciculations and atrophy, and dysphagia. Some degree of peripheral polyneuropathy with muscle wasting and loss of sensation are often present.  Tremors and other signs of Parkinsonism may be present.  Dystonic movements are often seen.

Imagining of the brain has revealed pontocerebellar atrophy and enlargement of the 4th ventricle but this is variable.  Nerve conduction studies documents involvement of the sensory nerves.  Neuropathologic studies show widespread neuronal loss in the CNS and spinal cord.

Genetics

This is considered to be an autosomal dominant disorder caused by an excess of heterozygous trinucleotide repeats in the ataxin3 gene (14q32) encoding glutamine.  The number in normal individuals is up to 44 repeats whereas patients with SCA3 have 52-86 repeats.  However, clinical signs of SCA3 have been found in patients with as few as 45 glutamine repeats.

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