What is Alexander Disease?
Alexander disease is an extremely rare brain disorder that usually starts in infancy, but can sometimes occur later in life. It’s named after W. Stewart Alexander, who first identified it in 1949, and is part of a group of genetically inherited conditions known as leukodystrophies. These rare diseases progressively affect the white matter – the part of the brain and spinal cord that contains nerve fibers – causing it to either develop abnormally or break down over time.
The disease is caused by a mutation in a specific gene, the GFAP gene, which is responsible for a protein in certain types of brain cells known as astrocytes. This makes Alexander disease a unique example of a genetic disorder that primarily impacts astrocytes. The effects and severity of the disease can vary greatly, usually becoming more severe the earlier it starts. Over time, as scientists have gained a better understanding of the disease’s genetic characteristics, it’s been referred to by several different names, but these are not commonly used anymore.
To diagnose Alexander disease, doctors look for specific symptoms and characteristics in brain scans. A diagnosis can then be confirmed with a genetic test. Unfortunately, treatment options are limited and generally focused on managing symptoms, such as using anticonvulsants to control seizures. The outlook for people with the disease can vary widely. Those with a type of the disease that starts at birth typically face severe disability or death within the first two years of life. Children affected by the infant form (which starts between 2-4 years of age) have a life expectancy ranging from weeks to a few years. However, when the disease starts later in childhood or adulthood, people can live up to 30 years or more.
This article provides detailed information about the causes, diagnosis process, and treatment options for Alexander disease. Furthermore, it emphasizes the crucial role of a team of healthcare professionals in enhancing the quality of life for those affected by this inherited condition.
What Causes Alexander Disease?
Alexander disease is usually caused by a mutation in the GFAP gene. This gene abnormality is passed down in families, meaning it is genetically inherited. It’s found on a specific region of chromosome 17. The GFAP gene is responsible for producing a protein made up of 432 amino acids. This protein plays a key role in controlling the shape and movement of astrocytes, a type of brain cell, as well as the interaction between astrocytes and another type of brain cell known as oligodendrocytes.
This protein is produced at a high rate when the brain is injured. However, the exact way this process works is not fully known. Scientists believe these GFAP gene mutations disrupt this protein production process, leading to abnormal protein build-up and the collapse of cellular structures.
Some researchers suggest that accumulation of GFAP protein can disturb the assembly of cellular fibers. The most common mutations occur on different sections of the gene, known as exons. These mutations can affect the creation of different kinds of RNA molecules.
Despite these mutations all being in the same gene, the disease can present differently in different individuals, meaning different people may experience different symptoms.
Risk Factors and Frequency for Alexander Disease
Alexander disease is an extremely rare illness and we don’t know exactly how common it is. So far, only about 550 cases have been recorded since the disease was first identified. A study from Japan suggested that the disease might occur in about 1 out of every 2.7 million people. It’s also important to note that among all leukodystrophies, a group of disorders affecting the white matter of the brain, Alexander disease only accounts for around 1.6 percent of cases.
Signs and Symptoms of Alexander Disease
Alexander disease typically impacts infants and children who often experience symptoms such as a large head (macrocephaly), developmental delays, severe muscle weakness (progressive quadriparesis), and seizures. This illness has traditionally been classified into four categories based on the age of onset: neonatal, infantile, juvenile, and adult.
- Neonatal form: Most common in newborns, it includes symptoms such as seizures, increased pressure in the brain, and severe motor dysfunction. It often results in death within the first weeks to years of life.
- Infantile form: This begins before the age of two and includes symptoms such as seizures, trouble with balance (ataxia), overactive reflexes (hyperreflexia), fluid in the brain (hydrocephalus), a large brain (megalencephaly), difficulties in eating, and muscle stiffness (spasticity). Children also show a decline in mental development and often pass away within weeks or several years of life.
- Juvenile form: This type has a slower onset than the infantile form. Symptoms include difficulty speaking and swallowing, muscle stiffness, and balance issues. Other signs include a decline in cognitive abilities and seizures. The survival period varies, patients may pass away in early adolescence or live into their 20-30s.
- Adult form: This is the least common type of the disease and has a variety of symptoms. Some include difficulty speaking and swallowing, progressive balance issues, severe muscle weakness, physical deformities, and autonomic dysfunction. Additional symptoms may include sleep disorders, posture changes like curve in the spine (scoliosis, kyphosis), abnormal palate formation, short neck, epilepsy, and seeing double vision (diplopia). The patient’s lifespan varies significantly and their death is usually due to other concurrent illnesses.
In 2011, a new classification model based on statistical analysis was introduced.
- Type 1: This type is generally more serious and is characterized by seizures, early onset, a large head, brain disease, motor delay, failure to thrive, and typical brain imaging features. The median survival is about 14 years.
- Type 2: Typically less severe than type 1, its symptoms include dysfunction in the automatic nervous system, bulbar symptoms, abnormalities in eye movement but lacks cognitive deficits, and atypical brain imaging features. The median survival for this type is about 25 years.
Testing for Alexander Disease
Alexander disease can be identified by signs visible on CT and MRI scans, with MRI being the preferred choice for its sensitivity. These scans often show changes and swelling in the brain’s white matter. The disease begins at the front of the brain and gradually extends towards the back. The subcortical U-fibers, located deep within the cerebral cortex, are generally unaffected in the early stages of the disease.
Typical MRI results for Alexander disease show abnormal signals in specific areas of the brain such as the symmetric bifrontal white matter, periventricular rim, and the head of the caudate. The changes could also be in the globus pallidus, thalamus, and brain stem, though this is less common. Interestingly, the disease tends to spare the temporal and occipital lobe white matter.
For an Alexander disease diagnosis using MRI, patients need to exhibit at least four out of five specific criteria which include more pronounced white matter changes in the front of the brain, abnormal periventricular rim, abnormalities in the basal ganglia and thalami, brainstem abnormalities, and contrast enhancement of specific structures within the brain.
Atypical MRI results might also show abnormal signals in the upper cervical cord and medulla, pons, superior/middle cerebellar peduncle, and ventricular garlands.
For further clarification, magnetic resonance spectroscopy might reveal an increase in choline in the basal ganglia, a reduction in N-acetylaspartylglutamate (NAAG) in the frontal white matter, and an increase in lactate in the frontal white matter.
The diagnosis is primarily based on the presentation of these imaging features and the patient’s clinical symptoms. If children present with typical symptoms of Alexander disease and at least four out of the five MRI criteria are met, a diagnosis can be made. However, if the imaging results are unclear or do not align with the typical appearance of the disease, genetic testing may be necessary to confirm a diagnosis. For this, tests to detect the most common gene mutations associated with Alexander disease are available and the entire gene can be sequenced if the mutation recurs. Genetic testing can also be applied for prenatal diagnosis.
Treatment Options for Alexander Disease
When it comes to treating Alexander disease, the focus is on providing supportive care with a variety of specialists working together. This approach can help increase the affected person’s quality of life. The care plan is focused on treating symptoms and continual monitoring. For example:
* Seizures can be kept in check with medication
* Stiff and tight muscles can be eased with physical therapy and a drug called baclofen
* Mobility can be enhanced by using equipment like ankle braces that fit properly
* A condition where fluids build up in the brain, known as obstructive hydrocephalus, can be addressed by surgically placing a special tube called a ventriculoperitoneal shunt
* Issues with nutrition can be tackled by working with a feeding specialist
* Acid reflux and vomiting can be managed with a specific group of medicines called proton pump inhibitors
* Problem with bladder control and accidental leakage can be handled with bladder training, inserting a tube to drain urine (catheterization), and certain medications
At present, the main aim of treating Alexander disease is providing support and managing symptoms. However, in the future, treatments could include strategies that work on reducing the function of a gene known as GFAP – this could be a promising option.
What else can Alexander Disease be?
When doctors are trying to pinpoint a diagnosis for Alexander disease, they look at disorders that cause changes in the brain’s white matter or an enlarged head, called macrocephaly. For instance, in younger children, they have to consider conditions that result in an oversized head, developmental delays, and muscle stiffness, otherwise known as spasticity. For older children, the diagnosis must take into account disorders that lead to muscle stiffness, brain stem problems, macrocephaly, and seizures.
Alexander disease can generally be distinguished from other similar conditions through brain scans (MRI) and observing the patient’s symptoms. The following are diseases that doctors consider as possible alternate diagnoses to Alexander disease:
- Adrenoleukodystrophy: This brain disorder features lesions mostly in the back and upper parts of the brain and appears on both sides.
- Canavan disease: This genetic disorder is characterized by lesions at the front of the brain. It is also identified by increased N-acetylaspartic acid in an MRI scan, but with no contrast enhancement.
- Metachromatic leukodystrophy: This is a type of storage disease where cells can’t properly break down particular fats called lipids, causing lesions at the front of the brain. However, it doesn’t show any contrast enhancement.
- Megalencephalic leukodystrophy: This illness causes lesions in the front and temporal lobe of the brain.
- Classic congenital muscular dystrophy: This genetic disorder is characterized by extensive changes in the brain’s white matter, while the back of the brain remains relatively unaffected.
Many times, understanding the distribution of white matter lesions in the brain can aid in making a diagnosis. In Alexander disease, the changes typically start in the frontal lobe of the brain and move from the front to the back.
What to expect with Alexander Disease
The outlook for those with Alexander disease is typically not good.
Under traditional classifications, the disease is categorized into four main forms. In the newborn form, death may occur within weeks to years after birth. In the infant form, death usually happens within weeks to several years. In the juvenile form, death generally comes between early teenage years up to 20-30 years old. Lastly, for the adult form, the survival rate is usually the highest, with death occurring later on in life.
In a revised classification, the disease is split into two types. Type 1 tends to start earlier and is more severe, with a median survival time of 14 years. In contrast, Type 2 starts later and patients usually live longer, with a median survival time of 25 years.
Possible Complications When Diagnosed with Alexander Disease
The treatment for Alexander’s disease mainly focuses on providing long-term care to manage a variety of complications. Here’s a look at some of the potential long-term complications:
- Seizures
- Spasticity, or muscle stiffness
- Mobility problems
- Hypotonia, or poor muscle tone
- Scoliosis, a curvature of the spine
- Obstructive hydrocephalus, a buildup of fluid in the brain
- Dysphagia, or difficulty swallowing
- Gastrointestinal symptoms, like vomiting and reflux
- Failure to thrive, or not growing and developing normally
- Urinary retention, or difficulty emptying the bladder
What’s notable is that these symptoms can fluctuate, sometimes getting better or worse, throughout the treatment period.
Preventing Alexander Disease
Alexander disease is a type of inherited disease, known as a leukodystrophy, which mostly impacts the white matter in the central nervous system. It is unique as it’s the only known inherited disease that impacts astrocyte cells, which are a type of cell in the brain.
The disease is rare and can appear in different forms from birth to adulthood. Generally, the earlier the disease appears, the more severe it can be. Alexander disease usually comes from a random mutation in the GFAP gene, located on chromosome 17q21.
A clear sign of Alexander disease is the presence of rod-like structures, known as Rosenthal fibers, that cluster in astrocytes. The disease is categorized into four different types depending on when it appears: neonatal (at birth), infantile (in infancy), juvenile (in childhood), and adult.
To diagnose Alexander disease, doctors typically rely on clinical signs and imaging tests. Genetic testing is often done to confirm the diagnosis, if the disease is suspected. The current treatment for Alexander disease is supportive care aimed at easing symptoms. However, future therapy may involve reducing the production of GFAP, the protein linked to the disease.
