What is Alexander Disease?
Alexander disease (AD) is a neurological disorder that affects the brain and spinal cord. It is one of a group of conditions called leukodystrophies, genetic disorders that affect parts of the nervous system called white matter. White matter consists of cells surrounded by a protective coating called myelin. Myelin aids in the transmission of signals between nerve cells and protects the cells from damage.
In AD, abnormal structures called Rosenthal fibers develop in brain cells. Although scientists don’t understand exactly why, these fibers interfere with the production and function of myelin, leading to the neurological dysfunction that causes the disease’s symptoms.
Types of Alexander Disease
Until recently, Alexander disease was grouped into three different types: an infantile form, a juvenile form that affects older children, and an adult form. Now scientists believe that there are actually two broad forms of the disease, each of them accounting for about half of all cases.
- Type I. This form of the disease occurs in children under the age of four and is the more severe type of AD.
- Type II. This form of the disease occurs in people over the age of four, including adults. Symptoms in this type are often less severe than those of Type I.
A rare neonatal form of AD appears soon after birth. This is the most severe type of the disease and is usually fatal before the age of two.
Symptoms of Alexander Disease
Symptoms of Type I Alexander disease include:
- Enlarged head
- Muscle stiffness and impaired movement (spasticity)
- Slow growth
- Delays in motor development
- Delays in intellectual development
- Difficulties swallowing or breathing
Symptoms of Type II Alexander disease include:
- Swallowing difficulty
- Poor coordination or balance
- Speech difficulties
- Abnormal spine development
What Causes Alexander Disease?
In most cases, AD is caused by an abnormal change (mutation) in the GFAP gene. This gene is responsible for the production of a compound called glial fibrillary acidic protein. Scientists don’t yet understand how the GFAP mutations cause the disease. They know that the mutations cause a buildup of GFAP and the production of abnormal structures called Rosenthal fibers in brain cells. These abnormalities somehow interfere with the production and function of myelin, leading to a progressive deterioration of brain cells.
About five percent of people with AD do not have a GFAP mutation. Scientists do not know what causes the disease in these cases.
Is Alexander Disease Hereditary?
Most of the time, the GFAP mutations that cause AD occur spontaneously during the development of egg or sperm cells or during the early development of the fetus. In these cases, the person with AD does not have a family history of the disease, and the mutation is not inherited from either parent.
In cases where the mutation is passed from parent to child, it is inherited in an autosomal dominant pattern. This means that the disease will develop if the child inherits a single copy of the mutated gene from either parent.
How Is Alexander Disease Detected?
Diagnosis of AD can be challenging because some of the disease’s symptoms are similar to those of other disorders. This can be especially true in Type II cases in which deterioration of the brain’s white matter is less pronounced. Other conditions that may sometimes be confused with Alexander disease include:
- Canavan’s disease
- Glutaric Aciduria
- Krabbe leukodystrophy
- Leigh syndrome
- Metachromatic leukodystrophy
- Pelizaeus-Merzbacher disease
- Tay-Sachs disease
How Is Alexander Disease Diagnosed?
At one time, AD diagnosis was based on a biopsy of brain tissue to look for the presence of Rosenthal fibers in the cells. This approach has fallen out of favor because the fibers are sometimes present in other disorders. The current diagnostic process relies on the presence of more distinctive features of the disease.
Diagnostic steps often include:
- Magnetic resonance imaging (MRI) to look for deterioration of white matter in the brain. This procedure may not be effective at diagnosing Type II cases in which there is little or no loss of white matter.
- Genetic testing to look for GFAP gene mutations
PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.
How Is Alexander Disease Treated?
Alexander disease has no cure, and no treatment will stop or reverse its symptoms. Treatments and therapies are meant to prevent complications and improve the child’s quality of life.
Common treatment options include:
- Feeding assistance
- Anti-seizure medications
- Antibiotics to treat infections
- Physical therapy
- Occupational therapy
- Speech therapy
How Does Alexander Disease Progress?
The symptoms of Alexander disease worsen over time, and complications from the symptoms are almost always fatal. In general, the progression of symptoms is faster in early-onset cases, but that is not always true. Babies with the neonatal form of the disease often don’t survive infancy. The median life expectancy in Type I cases is 14 years and 25 years in Type II cases.
How Is Alexander Disease Prevented?
There is no known way to prevent Alexander disease when the disease-causing gene mutations are present. Parents with a family history of the disorder or who have had another child with AD are advised to consult a genetic counselor to assess their risk if they plan to have another child. Prenatal testing may be able to detect these gene mutations during pregnancy.
Alexander Disease Caregiver Tips
- Take time to process your grief. The process of coping with a diagnosis of Alexander disease is different for everyone. Don’t feel rushed to make sense of your emotion. Go at your own pace, and ask for help from a professional counselor if you need it.
- Don’t go it alone. As a caregiver, your health is at risk when you neglect your needs. Accept help from family, friends, and others, and take time away from caregiving when you can.
- Find support from other families who share your experiences. Hunter’s Hope has compiled a list of organizations and foundations dedicated to helping families living with leukodystrophies. These organizations provide education, support, equipment-sharing, and financial assistance to families who need it.
Alexander Disease Brain Science
Scientists don’t yet understand how mutations in the GFAP gene lead to the symptoms of Alexander disease. All cases of AD feature the accumulation of Rosenthal fibers in non-nerve brain cells called astrocytes. Some scientists believe that AD is thus more accurately considered an astrocyte disease (astrogliopathy) than a white matter disease (leukodystrophy).
However, white matter does contain astrocytes, and the cells containing Rosenthal fibers do accumulate there. They also commonly occur in other parts of the brain, including the brain stem, the spinal cord, the protective covering of the brain (meninges), the fluid-filled cavities inside the brain (ventricles), and the blood vessels of the central nervous system.
Animal studies have suggested the GFAP mutations somehow produce a toxic effect that is harmful to otherwise healthy cells.
Alexander Disease Research
Title: Evaluation of Outcome Metrics in Alexander Disease (AxD Outcomes)
Principal investigator: Amy T. Waldman, MD, MSCE
Children’s Hospital of Philadelphia
The purpose of this study is to define the natural history of Alexander Disease, a leukodystrophy that causes neurological dysfunction. Investigators will obtain clinical outcome assessments to measure how the disease affects a patient’s gross motor, fine motor, speech and language function, swallowing, and quality of life. The data obtained from this study will be used for the design of future treatment trials.
Participants will be asked to complete physical examinations including physical therapy, occupational therapy, speech and language therapy, and swallowing assessments. Patients (or caretakers) may be asked to complete questionnaires as well. The study asks for participants to return at least once yearly to repeat assessments.
Title: A Study to Evaluate the Safety and Efficacy of ION373 in Patients With Alexander Disease (AxD)
Joanne Kurtzberg, MD
Lucile Packard Children’s Hospital Stanford
Palo Alto, CA
The purpose of this study is to evaluate the safety and efficacy of ION373 in improving or stabilizing gross motor function across the full range of affected domains in patients with AxD.
This is a Phase 1-3, multi-center, double-blind, placebo-controlled, multiple-ascending dose (MAD) study in up to 58 patients with AxD. Participants will be randomized in a 2:1 ratio to receive ION373 or matching placebo for a 60-week double-blind treatment period; then, all participants will receive ION373 for a 60-week open-label treatment period. Multiple-dose cohorts will be evaluated in the study. Cohorts will be enrolled sequentially. The initial participants in each dose cohort must be at least (8) years of age at screening.
Title: Natural History, Diagnosis, and Outcomes for Leukodystrophies
Contact: Josh Bonkowsky, MD, PhD
Primary Children’s Hospital
Salt Lake City, UT
Inherited leukodystrophies affect close to 1 in 7500 children with mortality greater than 30%. Affected patients face additional serious medical complications, including epilepsy, developmental regression, and intellectual disabilities. Diagnosis is difficult and requires the assistance of a specialist. Finally, identifying treatments and improving outcomes is complex.
The Western Leukodystrophy Project, a part of the University of Utah and Primary Children’s Hospital, a certified Leukodystrophy Care Network Center, provides a specialized resource for patients with leukodystrophies.
This clinical study assists with diagnosis of leukodystrophies; suggesting treatment options and implementing care guidelines, and improving outcomes for all patients by understanding the clinical histories and outcomes of affected patients.