Alexander disease

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at January 6, 2017
StartDiseasesAlexander disease

Most people have never heard of Alexander disease also known as fibrinoid leukodystrophy. This is because it is an extremely rare genetic disorder. It is both a progressive and fatal neurodegenerative disease affecting infants and children. Delays in development as well as changes in physical characteristics of a child suffering from this disease are results of this neurodegenerative disease. 

Contents

Definition & Facts

Surrounding nerve fibers is a fatty covering of white matter also known as the myelin sheath that acts as an insulator. A patient suffering from Alexander disease which is a type of leukodystrophy is characterized by this myelin sheath being destroyed and having protein deposits called Rosenthal fibers that are abnormal.

Cases of the infantile form of Alexander disease begin as early as two years of age. The infantile form of the disease includes:

Although it is less frequent, the onset of the disease can occur late in childhood or adulthood. Problems common in both the juvenile and adult forms of the disease are poor coordination, abnormalities of speech, and difficulties in swallowing.

Mutations of the GFAP gene are the cause of Alexander disease. Although the condition is inherited most of the time in a fashion that is autosomal dominant, new mutations of the gene cause most cases. 

Symptoms & Complaints

There are various symptoms of Alexander disease. There are different forms of the condition and its symptoms vary in severity and type. The form of the disease is determined by when the disease becomes apparent. The earlier the onset, the more severe the symptoms and results.

The disease forms and their symptoms are as follows:

  • Neonatal. A newborn baby having this form will suffer from severe disabilities or die within two years. Symptoms include both severe intellectual disabilities and motor disabilities, hydrocephalus which is a condition of a buildup of fluid in the brain and seizures.
  • Infantile. During the first two years of life, this most common type of Alexander disease begins. Delays in physical and mental development are usual for this form. Delayed milestones in development occur and the infant's head size increases abnormally. Seizures are also a symptom of this form of the disease. 
  • Juvenile. Between the ages of two and 13, this type of Alexander disease has its onset. It is less common than the other forms of the disease. Symptoms of this form of the disease include difficulty with speaking and swallowing, vomiting excessively, a loss of motor control and poor coordination.
  • Adult. This form of Alexander disease is the mildest of the different forms and also quite rare. Its onset may occur anytime from the late teens to sometime late in life. Some of the cases of the disease have symptoms that are primarily the same as those of multiple sclerosis or Parkinson's disease

Causes

Approximately 95 percent of the cases of Alexander disease have been found to be caused by mutations of a structural protein. This GFAP protein is known as a glial fibrillary acidic protein. The mutation causes this protein to become abnormal. The abnormal protein then accumulates in astroglial cells and forms Rosenthal fibers.

The mutations of the GFAP are dominant genes. A new mutation is the cause of Alexander disease in most cases. The disease can be passed from one generation to the next generation. Each pregnancy of a genetic carrier has a 50 percent chance of transmitting the disease to offspring.

Diagnosis & Tests

For years, the diagnosis for Alexander disease has been dependent on a brain biopsy in order to establish whether there is the presence of Rosenthal fibers. However, these fibers are also present in tumors and other disorders, so this is not a definitive diagnostic criterion.

Imaging studies such as computed tomography (CT) scans and magnetic resonance imaging (MRI) scans as well as an ultrasound of the patient’s head have been used. Recently, criteria based on MRI's have been found to be accurate in the diagnosis of the early onset type I (neonatal) disease. In Type II cases, atrophy of the brainstem, spinal cord, or cerebellum is shown.

As part of the diagnostic process, the presence of GFAP mutations may be identified. This can be done by using a swab from the patient's inside cheek or a blood sample. From these, a DNA analysis can be made. However, in about 5 percent of known cases of Alexander disease, the mutation in the GFAP is absent.

Treatment and Therapy

Since the disease has no cure, the only therapies and treatment available presently reduce symptoms. Included in this are anticonvulsant medications, antibiotics, speech therapy, occupational therapy, and surgery. Surgery may take the form of cerebral shunt to treat hydrocephalus. Clinical trials are also available.

Prevention & Prophylaxis

Patients and their families may gain a better understanding of the disease through genetic counseling. A couple who have had a child affected by this disease may choose to undergo a fetal diagnosis.