Introduction:
Genetic diseases that exclusively affect the white matter of the central nervous system (CNS) are called leukodystrophy. White matter refers to tissues that contain bundles of nerve fibers called axons that connect nerve cells. The disease was first found in 1949. The condition is also known as Alexander's disease, ALX, AxD, demyelinogenic leukodystrophy, dysmyelinogenic leukodystrophy, fibrinoid degeneration of astrocytes, and leukodystrophy with Rosenthal fibers.
How Is Alexander’s Disease Caused?
A gene called the GFAP gene is responsible for instructing the synthesis of a protein called glial fibrillary acidic protein. Various molecules of glial fibrillary acidic protein join together to form intermediate filaments, providing strength and support to the cells. Mutations (changes in the basic genetic structure) in the GFAP gene cause structural alterations in glial fibrillary acidic protein. This alteration causes malformation of normal intermediate filaments. The abnormal glial fibrillary acidic protein aggregates in astroglial cells (a large, star-shaped cell that holds nerve cells in one place and helps them to develop and work) which leads to the formation of Rosenthal fibers that affects cell function. The Rosenthal fibers damage the myelin (a substance that covers the nerves and increases the speed of transmission of information).
What Are the Types of Alexander’s Disease?
Based on the stage at which the disease occurs, Alexander's Disease can be classified as follows:
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Neonatal: This type of Alexander's disease develops during the first month of life.
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Infantile: About 80 percent of the symptoms occur in the infantile period before the infant turns two years of age.
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Juvenile: This type is common in 14 percent of all diagnoses and usually appears between two to 13 years of age. The disease usually manifests between four and ten years old.
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Adult: Adult type of onset is present in six percent of the diagnoses and can manifest any time after the late teen and is usually associated with mild symptoms.
How Is Alexander’s Disease Inherited?
The majority of the cases are linked with fresh genetic mutations and are not associated with family history. In inherited cases, Alexander’s disease is inherited in an autosomal dominant pattern that is, one copy of the altered gene from one parent is enough to cause the genetic condition.
Who Are at Risk of Getting Alexander’s Disease?
Anyone is susceptible to acquiring Alexander's disease as it is based on gene mutations. If the condition is inherited, a gene from one parent is sufficient to cause the disease. But, the inherited pattern is rare.
What Are the Signs and Symptoms of Alexander’s Disease?
The signs and symptoms based on different stages are as follows:
Neonatal Type: The symptoms are:
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Hydrocephalus (collection of fluid in the child’s brain).
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Megalencephaly (enlarged brain and head).
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Seizures (sudden, uncontrolled electrical disturbance in the brain that causes changes in behavior, movements, feelings, and level of consciousness).
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Spasticity (a condition characterized by an abnormal increase in muscle tone or stiffness in the muscles which prevents normal movement).
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Developmental delays.
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Hindrance in normal growth.
Death occurs in babies within a couple of weeks to years.
Infantile Type: The majority of the symptoms coincide with the neonatal type. Other symptoms are:
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Delayed ability to learn new skills.
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Loss of fine or gross motor skills (movements that involve the large and small muscles of the body).
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A slow progression of disease that lasts for years.
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Language delay.
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Seizures, are triggered by illness but can be less severe than the neonatal type.
Death occurs in infants within weeks to several years.
Juvenile Type: The symptoms include:
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Difficulty in swallowing and talking.
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Ataxia (unbalanced movements, coordination, and stability).
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Muscle pain, muscle spasms, or muscle spasticity.
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Frequent episodes of vomiting.
Death can occur in early adolescence or between 20 to 30 years.
Adult-Onset Type: The symptoms are:
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Swallowing difficulties.
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Ataxia (unbalanced movements, coordination, and stability).
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Speech problems.
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Seizures.
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Sleep disturbances.
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Symptoms may mimic other conditions.
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Slowly progressive hemiparesis or hemiplegia (paralysis on one side of the body) or quadriparesis (paralysis in both arms and both legs) or quadriplegia (paralysis from the shoulders and below).
Death can occur after a few years or after a brief period of illness. In many cases, the disease can be identified only after death during an autopsy. Usually, in the adult-onset type of Alexander Disease, the symptoms are less severe. The size of the head and the mental development can be normal however, it may deteriorate later.
Does Alexander's Disease Affect Old Age?
It is uncommon for Alexander's disease to develop in old age. It may be confused with a brain tumor or multiple sclerosis (a condition in which the immune system destroys the protective covering of the nerves). Even if it occurs, it is least severe and the disease can be diagnosed in an autopsy report by the presence of abnormal protein deposits in the brain.
How Is Alexander’s Disease Diagnosed?
Based on the symptoms, doctors may suggest a blood test to conduct genetic testing (a test to find out the changes or mutations in genes that causes the disease). Imaging techniques like computed tomography (CT) and magnetic resonance imaging (MRI) may be required to study the changes in the brain’s white matter and to check for any swelling. The disease usually begins anteriorly and extends posteriorly. If four out of five of the following diagnosis is present in MRI, then the disease is confirmed:
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White matter changes are obvious in the front portion.
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Brainstem abnormalities.
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Abnormalities in the periventricular rim (part of the white matter of the brain).
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Abnormalities in the basal ganglia (a group of structures near the center of the brain that forms important connections) and the thalamus (transfers sensory impulses from receptors in the body to the cerebral cortex).
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Contrast appearance of the structures in the brain such as ventricular lining, frontal white matter, optic chiasm, basal ganglia, thalamus, fornix, dentate nucleus, and brainstem.
How Is Alexander’s Disease Treated?
Treatments are aimed at reducing the symptoms to retard the progression of the disease. Treatment modalities include:
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Anti-seizure medications (antiepileptic drugs).
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Shunt surgery (to drain excess fluid from the brain in case of hydrocephalus).
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Nutritional supplements.
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Antibiotics to treat infections.
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Physical and occupational therapy (therapies to improve the patient’s ability to move and carry out day-to-day activities).
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Increase mobility and movement with the use of equipment such as ankle braces.
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Control vomiting and acid reflux using proton-pump inhibitors (drugs that reduce acid produced by the glands in the lining of the stomach).
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Urinary retention and incontinence can be treated by bladder training, catheterization, and medications.
What Are The Complications Associated With Alexander's Disease?
The symptoms associated with the disease may worsen over time as a result of which a person may require:
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Wheelchairs or walkers to move around.
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Tube feedings are called enteral nutrition to get sufficient nutrition.
How Is Alexander’s Disease Managed?
The management includes a team of doctors such as neurologists (experts who treat nerve and related diseases), neurosurgeons (experts in surgery of the nervous system), feeding specialists, physical therapists, geneticists (experts in the study of genes and heredity), urologists (experts in diagnosing and treating diseases of urinary organs), radiologists (experts in creating and interpreting X-rays), and pathologists (experts who investigate diseases and illnesses). Regular follow-up with various healthcare professionals is necessary to evaluate the growth, neurological and nutritional status, and to prevent the progression of complications. Other treatments to improve communication skills in patients must also be considered.
Conclusion:
The outcome of the disease is usually poor and depends on the age of onset. The symptoms which occur in infants are severe while the symptoms in older individuals have less severity. The treatment is based on relieving the symptoms and there is no permanent cure for Alexander's disease. Researches are underway to study effective therapies to treat this rare disease.
