Australasian Leukodystrophy Foundation | Incorporated No. IA41033

Alexanders Disease (ALX)

What is Alexanders?

Alexander disease is a progressive and usually fatal neurological disorder in which the destruction of white matter in the brain is accompanied by the formation of abnormal deposits known as Rosenthal fibres. Rosenthal fibres are aggregations of protein that occur in the astrocytes, which are non neuronal, supporting cells of the brain.

What causes ALX?

Recent discoveries show that most patients (~90%) with Alexander disease have a mutation on chromosome 17 in the gene for glial fibrillary acidic protein (GFAP). GFAP is a filamentous protein of astrocytes and also accumulates as part of the Rosenthal fibers. The site of the mutation on the gene varies, and it occurs on only one of the two copies of each gene that is present in every cell. For most of these mutations it is clear that they cause Alexander disease, but exactly how they do so is not presently understood. In general, there is not a good correlation between the particular mutation and the form or severity of the disease. Most of the mutations occur spontaneously and are not inherited from the parents. For some of the adult-onset cases, patients do live long enough to have children of their own and the disease can then be inherited through multiple generations in an autosomal dominant fashion. However, not every patient with proven Alexander disease (i.e. proven by biopsy or autopsy diagnosis) has an identified mutation in GFAP, so that there may be other genetic or perhaps even non-genetic causes that have yet to be identified.

Forms of ALX

Infantile (80% of cases approx)

The most common form of Alexander disease is the infantile form, which is typically defined as onset during the first two years of life. Usually there are several types of developmental delays (both mental and physical), followed by loss of milestones, an abnormal increase in head size, and often seizures. Some children die in the first year of life, a larger number live to be 5-10 years old.

The usual course of the disease is progressive, leading to eventual severe mental retardation and spastic quadriparesis (spasms that may involve all four limbs). However, in some children the degree of disability develops slowly over several years, and some children retain responsiveness and emotional contact until near the end of their lives. Feeding often becomes a problem, and assisted feeding may become necessary. Their head circumference is often enlarged. Children with hydrocephalus caused by Alexander disease usually have increased intracranial pressure and a more rapid progression of the disease. As with most Leukodystrophies, the earlier the age of onset of Alexander disease, the more severe and rapid the course.

Some of the symptoms and pathologies of Infantile Alexander Disease are:

Megalencephaly means that the head and brain is abnormally large; this can be associated with delayed development, convulsions, brain cortex and spinal cord dysfunction, and seizures.

Hydrocephaly characterized by the accumulation of fluid in the brain or between the brain and the skull. This can cause pressure on the brain, resulting in developmental defects. It also can lead to an abnormally large head size up to greater than 90% of normal.

Failure to thrive: A general term meaning the child is not growing and gaining weight at the expected rate.

Seizures: There are many types of seizures from small often unnoticed brain activity to major episodes that cause the body shake uncontrollably and often violently. It is essential that these are fully explained to you by your medical expert.

Spasticity/ spastic quadriparesis: This means that the child tends to suffer spasms, or involuntary contractions of muscles. Muscles are abnormally stiff and movement is restricted. Quadriparesis means that all four limbs are involved.

Progressive Psychomotor Retardation This can include difficulties with walking, speech difficulties, and mental regression. Eventually this can lead to loss of all meaningful contact with the environment.

Juvenile (14% of cases approx)

The juvenile form of Alexander disease is less common and is typically defined as onset between the ages of four and early teens. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control.

There may be difficulty with talking and the inability to cough. There can also be weakness and spasticity of the extremities, particularly the legs. Unlike in the infantile form of the disease, mental ability and head size may be normal but not always. Scoliosis can occur.

Pathologically, whereas the infantile form of Alexander disease generally affects the brain, the juvenile form generally leads to changes in the brain stem rather than in the brain. There are many Rosenthal fibers (as in infantile Alexander Disease), but the lack of myelin is less prominent than in the infantile form. Survival can extend several years following onset of symptoms, with occasional longer survival into middle age.

Adult (6% of cases approx)

Even rarer adult-onset forms of Alexander disease have been reported where the symptoms sometimes mimic those of Parkinson’s disease, tumour or multiple sclerosis. The disease occurs in both sexes, and there are no ethnic, racial, geographic, or cultural/economic differences in its distribution. Onset can be anywhere from the late teens to very late in life.
In older patients ataxia (impaired coordination) often occurs and difficulties in speech articulation, swallowing, and sleep disturbances may occur. Symptoms can be similar to those in juvenile disease, although the disease may also be so mild that symptoms are not even noticed until an autopsy reveals the presence of the Rosenthal fibres.

How do we diagnose ALX?

Because the genetic defect in Alexander disease is known, genetic testing on a blood sample can be used to diagnose most cases of Alexander Disease. A suggestive diagnosis can also be made from the clinical symptoms, including enlarged head size, combined with radiological studies and negative tests for other leukodystrophies. Radiologic studies that may aid in diagnosis include Magnetic Resonance Imaging (MRI) a computerized tomography (CT) scan, or a head ultrasound.

For example, an MRI of an individual with the infantile form typically reveals white matter loss that involves the frontal lobes of the brain, abnormalities of the basal ganglia and thalamus, and possibly, enlargement of the ventricles. Genetic testing is accomplished by looking for known or detectable mutations in the GFAP gene. In up to 94% of cases of ALX, a GFAP mutation is found. Prenatal diagnosis for couples with an affected child can be performed when the mutation responsible for ALX is known. The DNA of a foetus can be tested using cells obtained from chorionic villus sampling (CVS) or amniocentesis.

Incidence:

There are no known figures but it is very rare with the total affected thought to be well less than 1000.

Treatment:

There is no cure for Alexander disease, nor is there a standard course of treatment. Treatment of Alexander disease is symptomatic and supportive. Primary care would consist of attention to general care and nutritional needs antibiotic therapy for infections, and management of associated complications such as anti-epileptic drugs for seizures. Surgical interventions, including placement of a feeding tube and/or shunting for hydrocephalus as may Orthopaedic surgery for scoliosis.