About dysmyelogenic leukodystrophy-megalobare
What is dysmyelogenic leukodystrophy-megalobare?
Alexander disease is named after the physician who first described the condition in 1949 (WS Alexander). It is an extremely rare, usually progressive and fatal, neurological disorder. Initially it was detected most often during infancy or early childhood, but as better diagnostic tools have become available has been found to occur with similar frequency at all stages of life. Alexander disease has historically been included among the leukodystrophies--diseases of the white matter of the brain. These diseases affect the fatty material (myelin) that forms an insulating wrapping (sheath) around certain nerve fibers (axons). Myelin enables the efficient transmission of nerve impulses and provides the "whitish" appearance of the so-called white matter of the brain. There is a marked deficit in myelin formation in most early onset cases of Alexander disease, and sometimes in later onset cases, particularly in the front (frontal lobes) of the brain's two hemispheres (cerebrum). However, white matter defects are sometimes not observed in later onset cases. Instead, the unifying feature among all Alexander disease cases is the presence of abnormal protein aggregates known as "Rosenthal fibers" throughout certain regions of the brain and spinal cord (central nervous system [CNS]). These aggregates occur in astrocytes, a particular cell type in the CNS that helps maintain a normal CNS environment. Accordingly, it is more appropriate to consider Alexander disease a disease of astrocytes (an astrogliopathy) than a white matter disease (leukodystrophy).
What are the symptoms for dysmyelogenic leukodystrophy-megalobare?
Each form of metachromatic leukodystrophy occurs at a different age and can have different initial signs and symptoms and rates of progression:
- Late infantile form. This is the most common form of metachromatic leukodystrophy, starting around 2 years of age or younger. Progressive loss of speech and muscle function occurs rapidly. Children with this form often do not survive beyond childhood.
- Juvenile form. This is the second most common form and starts in children between 3 and 16 years of age. Early signs are behavior and cognitive problems and increasing difficulty in school. Loss of the ability to walk may occur. Although the juvenile form doesn't progress as fast as the late infantile form, survival is generally less than 20 years after symptoms begin.
- Adult form. This form is less common and typically starts after age 16. Signs progress slowly and may begin with behavior and psychiatric problems, drug and alcohol misuse, and issues with school and work. Psychotic symptoms such as delusions and hallucinations may occur. The course of this form varies, with periods of stable symptoms and periods of rapid decline in functioning. Adults may survive for several decades after initial symptoms.
What are the causes for dysmyelogenic leukodystrophy-megalobare?
Metachromatic leukodystrophy is an inherited disorder caused by an abnormal (mutated) gene. The condition is inherited in an autosomal recessive pattern. The abnormal recessive gene is located on one of the nonsex chromosomes (autosomes). To inherit an autosomal recessive disorder, both parents must be carriers, but they do not typically show signs of the condition. The affected child inherits two copies of the abnormal gene — one from each parent.
The most common cause of metachromatic leukodystrophy is a mutation in the ARSA gene. This mutation results in a lack of the enzyme that breaks down lipids called sulfatides that build up in the myelin.
Rarely, metachromatic leukodystrophy is caused by a deficiency in another kind of protein (activator protein) that breaks down sulfatides. This is caused by a mutation in the PSAP gene.
The buildup of sulfatides is toxic, destroying the myelin-producing cells ― also called white matter ― that protect the nerves. This results in damage to the function of nerve cells in the brain, spinal cord and peripheral nerves.
What are the treatments for dysmyelogenic leukodystrophy-megalobare?
Metachromatic leukodystrophy can't be cured yet, but clinical trials hold some promise for future treatment. Current treatment is aimed at preventing nerve damage, slowing progression of the disorder, preventing complications and providing supportive care. Early recognition and intervention may improve outcomes for some people with the disorder.
As the disorder progresses, the level of care required to meet daily needs increases. Your health care team will work with you to help manage signs and symptoms and try to improve quality of life. Talk to your doctor about the possibility of participating in a clinical trial.
Metachromatic leukodystrophy can be managed with several treatment approaches:
- Medications. Medications may reduce signs and symptoms, such as behavioral problems, seizures, difficulty with sleeping, gastrointestinal issues, infection and pain.
- Physical, occupational and speech therapy. Physical therapy to promote muscle and joint flexibility and maintain range of motion may be helpful. Occupational and speech therapy can help maintain functioning.
- Nutritional assistance. Working with a nutrition specialist (dietitian) can help provide proper nutrition. Eventually, it may become difficult to swallow food or liquid. This may require assistive feeding devices as the condition progresses.
- Other treatments. Other treatments may be needed as the condition progresses. Examples include a wheelchair, walker or other assistive devices; mechanical ventilation to assist with breathing; treatments to prevent or address complications; and long-term care or hospitalization.
Care for metachromatic leukodystrophy can be complex and change over time. Regular follow-up appointments with a team of medical professionals experienced in managing this disorder may help prevent certain complications and link you with appropriate support at home, school or work.
Potential future treatments
Potential treatments for metachromatic leukodystrophy that are being studied include:
- Gene therapy and other types of cell therapy that introduce healthy genes to replace diseased ones
- Enzyme replacement or enhancement therapy to decrease buildup of fatty substances
- Substrate reduction therapy, which reduces the production of fatty substances
What are the risk factors for dysmyelogenic leukodystrophy-megalobare?
Dysmyelogenic leukodystrophy-megalobare or Alexander disease is an extremely rare, usually progressive and fatal, neurological disorder. Initially, it was detected most often during infancy or early childhood.
Alexander disease has historically been included among the leukodystrophies–diseases of the white matter of the brain. These diseases affect the fatty material (myelin) that forms an insulating sheath around certain nerve fibers (axons).
Myelin enables the efficient transmission of nerve impulses and provides the “whitish” appearance of the so-called white matter of the brain.
1. About 95% of Alexander's disease cases are caused by mutations in a gene called GFAP for a structural protein called glial fibrillary acidic protein that is found exclusively in astrocytes in the CNS.
2. The cause of the other 5% of cases is not known.
3. The GFAP mutations are dominant. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease.
4. Thus, Alexander patients have one mutant copy and one normal copy of the GFAP gene. The abnormal gene can be inherited from either parent or can be the result of a new mutation
5. Alexander disease has been estimated to occur at a frequency of about 1 in 1 million births.
6. No racial, ethnic, geographic, or sex preference has been observed, nor is any expected given the de novo (new) nature of the mutations responsible for most cases.
7. Although initially diagnosed primarily in young children, it is now being observed with similar frequency at all ages.
Floppiness,A loss of previously acquired mental and motor skills,Poor head control,An abnormally enlarged head (megalencephaly) and/or blindness
Leukodystrophies–diseases of the white matter of the brain,These diseases affect the fatty material (myelin) that forms an insulating sheath around certain nerve fibers (axons)
Symptomatic and supportive therapy