Alexander disease

December 31, 2014

Synonyms

Overview

Alexander disease is a progressive and fatal neurodegenerative disease. It is a rare genetic disorder and mostly affects infants and children, causing developmental delay and changes in physical characteristics. It is a type of leukodystrophy characterized by the destruction of the myelin sheath (the fatty covering that acts as an insulator around nerve fiber) and abnormal protein deposits known as Rosenthal fibers. Most cases of Alexander disease begin before age 2 years (the infantile form).

Symptoms

The symptoms of Alexander disease vary depending on the form of the condition (neonatal, infantile, juvenile, and adult). Even within the different forms there may be huge differences in respect to symptoms and severity:

Neonatal form - Leads to severe disability or death within two years. Characteristics include seizures, hydrocephalus, severe motor and intellectual disability.
Infantile form - The most common type of Alexander disease. It has an onset during the first two years of life. Usually there are both mental and physical developmental delays, followed by the loss of developmental milestones, an abnormal increase in head size, and seizures.
Juvenile form - Less common and has an onset between the ages of two and thirteen. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control.
Adult form - Rare and is generally the most mild. Onset can be anywhere from the late teens to very late in life. In some cases the symptoms mimic those of Parkinson disease or multiple sclerosis.

In the infantile form of the disease, average age of onset is six months, with a range of birth to two years. Affected children tend to have progressive physical and mental retardation with loss of previously attained milestones. Head size becomes increasingly large and the forehead appears prominent as a result of megalencephaly (enlarged head and brain). Other disease manifestations include seizures, spasticity (stiffness of the arms and legs), quadriparesis, feeding problems, and ataxia (poor coordination). Hydrocephalus may also occur, especially in children with early onset of symptoms.

The juvenile form of ALX usually presents between age four and the early teens. Patients may develop some or all of the following symptoms: speech problems, difficulty swallowing, frequent vomiting, spasticity of the legs, ataxia, gradual intellectual decline, seizures, megalencephaly, or breathing problems. White matter abnormalities in the juvenile form are less prominent than in the infantile form.

The adult form of ALX represents the most variable and least common form of the disorder. Patients with the adult variant may have symptoms that mimic multiple sclerosis, or may display symptoms similar to the juvenile form of the disease, except with later onset and slower progression. White matter changes may or may not be present. Some adult cases have been discovered by chance when an autopsy reveals Rosenthal fibers, a characteristic finding of this disease.

Causes

The disease is caused by changes (mutations in the GFAP gene in about 90% of cases. This gene provides the instructions for making a protein called glial fibrillary acidic protein (GFAP). GFAP is a normal part of the brain, but it is not clear how mutations in the gene cause the disease. In most cases, the mutations are new in the family (de novo) and are not inherited from the parents. A small number of people who are thought to have Alexander disease are not found to have a mutation in the GFAP gene, which suggests that there may be other causes of Alexander disease that have yet to be identified.

It is inherited in an autosomal dominant manner, such that the child of a parent with the disease has a 50% chance of inheriting the condition, if the parent is heterozygotic. However, most cases arise de novo as the result of sporadic mutations.

Alexander disease belongs to leukodystrophies, a group of diseases that affect the growth or development of the myelin sheath. The destruction of white matter in the brain is accompanied by the formation of fibrous, eosinophilic deposits known as Rosenthal fibers. Rosenthal fibers appear not to be present in healthy people, but occur in specific diseases, like some forms of cancer. The Rosenthal fibers found in Alexander disease do not share the distribution or concentration of other diseases and disorders.

Prevention

Not known.

Diagnosis

A diagnosis of Alexander disease is usually based on radiologic findings and/or genetic test results in an individual who has symptoms suggestive of this condition. 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 fetus can be tested using cells obtained from chorionic villus sampling (CVS) or amniocentesis.

Prior to the discovery of the gene responsible for the disease, diagnosis of ALX was made by demonstration of Rosenthal fibers in a biopsy or autopsy sample from the brain. Though genetic testing has largely replaced these histologic studies, a brain biopsy or autopsy may be indicated in select cases if the diagnosis cannot be made through other means.

Prognosis

The prognosis for individuals with Alexander disease is generally poor and typically depends of the specific form. People with the neonatal form usually have the worst prognosis. Most children with the infantile form do not survive past the age of 6. The juvenile and adult forms of the disorder have a slower, more lengthy course. The adult form varies greatly and, in some cases, there are no symptoms. With early onset, death usually occurs within 10 years from the onset of symptoms. Usually, the later the disease occurs, the slower its course is.

Treatment

No specific therapy is currently available for Alexander disease. Management is supportive and includes attention to general care, physical and occupational therapy, nutritional requirements, antibiotic treatment for any infection, and antiepileptic drugs (AED) for seizure control.

Physical and occupational therapy and speech therapy may be recommended depending on the specific signs and symptoms present. Physical and occupational therapy may be indicated in people with developmental and language delays.

A bone marrow transplant has been attempted on a child, but did not cause the patient's condition to improve.