Alexander disease
Alexander disease is a rare and progressive neurological condition classified as a leukodystrophy, affecting the white matter of the brain due to a genetic mutation in the glial fibrillary acidic protein (GFAP) gene. While it can manifest at various life stages—infancy, childhood, or adulthood—the disease typically leads to severe health complications, particularly in its infantile form, which is the most common and most severe. Symptoms can include developmental delays, seizures, increased head size, and coordination difficulties in infants, while older children may experience swallowing and speech issues, seizures, and cognitive decline. Adult cases are less common and may exhibit a range of symptoms such as speech problems, incontinence, and abnormal movement.
Genetic predisposition is the primary risk factor, with sporadic new mutations often occurring in the father's sperm or mother's egg. While the condition is generally fatal for infantile and juvenile-onset cases—with a life expectancy of about ten years—individuals with later-onset forms may have a more variable prognosis. Diagnostic methods include brain MRI and genetic testing, which can identify GFAP mutations; however, there is currently no cure, and treatment is largely supportive, focused on managing symptoms.
Alexander disease
ALSO KNOWN AS: Leukodystrophy with Rosenthal fibers
DEFINITION Alexander disease is a type of leukodystrophy, or disorder of the white matter of the brain, caused by a genetic mutation. This rare progressive neurological condition may develop in infancy, childhood, or adulthood. It is variable in severity yet typically fatal and was first described by W. Stewart Alexander in 1949.
Risk Factors
The only risk factor is a known familial mutation. Because variability in symptoms and age of onset exists even within the same family, other unknown genes and environmental factors must play a role in how the disease is expressed. Alexander disease has been reported across many different ethnicities and does not appear to occur more commonly in any one ethnic group. Men and women are equally likely to be affected. As of 2023, only 550 cases of Alexander disease had been reported, although not all have had confirmatory genetic testing.
Etiology and Genetics
Alexander disease typically occurs as a result of a sporadic new mutation, meaning one that is not inherited from a parent, in the glial fibrillary acidic protein (GFAP) gene on chromosome 17q21. The mutation most likely occurs in the father’s sperm but may occur in the mother’s egg. Rarely, individuals are suspected to have Alexander disease but do not have a detectable GFAP mutation. Mutations are typically missense, where one is changed to another, and may cause abnormal formation of the glial acidic fibrillary protein, which is necessary for proper myelination of nerve cells. Myelin acts as insulation for these cells. If myelination is disrupted, then the nervous system may not work properly. Abnormal protein may accumulate as Rosenthal fibers, which may be detected in certain brain cells.
Parents of one affected infant or child are not typically at risk of having another child with Alexander disease, since neither parent commonly has the mutation. Alexander disease is inherited in an autosomal dominant manner, meaning offspring of an individual with a mutation are at a 50 percent risk to inherit the same mutation. Individuals with a GFAP mutation known to cause earlier onset forms of the disease will likely develop the condition. Current research shows that 90 percent of individuals with the disease have a mutation in the gene that makes GFAP although it is unclear how the mutations in the gene cause the disease There are reports of adults with a GFAP mutation that have yet to show signs of the condition, meaning that onset may occur relatively late in life or not at all.
Symptoms
The infantile form is the most common and most severe, while the adult-onset form is least common and most variable. In infancy (the first two years of life), symptoms progress rapidly and can include delay in developmental milestones, loss of developmental skills, seizures, extra fluid in the brain, increase in head size, and coordination difficulties. Children with juvenile onset (two to thirteen years of age) may have problems with coordination, swallowing, and speech; frequent vomiting; seizures; intellectual decline; and loss of motor skills. Symptoms of the adult form (late teens through adulthood) may include problems with speech, swallowing, and walking; eye movement abnormalities; abnormal movement of the palate; incontinence; constipation; sweating and blood pressure abnormalities; sleep apnea; and seizures. Abnormal spinal curvature, diabetes, and problems with growth may occur. Brain biopsy or autopsy may show Rosenthal fibers, which are common with Alexander disease but are also known to occur with other conditions. Routine medical examinations are recommended to monitor for disease progression and medical complications.
Screening and Diagnosis
Diagnostic criteria for brain MRI have been developed and may be helpful in reaching a diagnosis. Brain biopsy and autopsy are available to identify Rosenthal fibers. Genetic testing has replaced the need for biopsy for diagnosis, however. Other clinical studies may be beneficial to detect medical problems and complications.
Treatment and Therapy
There is no cure for this disease, and treatment is supportive. Medications may be available to alleviate some neurologic symptoms, but individual response varies. Assistive devices and therapy may be beneficial.
Prevention and Outcomes
Diagnostic genetic testing can provide an accurate diagnosis in affected individuals. With a known familial mutation, predictive genetic testing is available to determine whether an unaffected adult has inherited the gene mutation and may be at risk to develop the adult-onset form of Alexander disease.
There is no known prevention for developing Alexander disease once an individual is known to have a GFAP mutation. Routine medical care and therapies may help to prevent other complications. Prenatal diagnosis and preimplantation genetic diagnosis may be possible with identified familial mutations.
Alexander disease is typically fatal for infantile and juvenile-onset forms. Life expectancy is usually up to about ten years, although those with juvenile or adult onset may survive longer.
Bibliography
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Kumar, Jagadish, et al. “Infantile Alexander Disease: A Rare Leukodystrophy.” Journal of Pediatric Neurosciences vol. 7, no. 2, 2012, 117–19, doi: 10.4103/1817-1745.102573. Accessed 4 Sept. 2024.
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Parker, James N., and Philip M. Parker. The Official Parent’s Sourcebook on Alexander Disease: Updated Directory for the Internet Age. Rev. ed. San Diego: Icon Group International, 2003.
Schmidt, Holger, et al. “Acute Onset of Adult Alexander Disease.” Journal of the Neurological Sciences, vol. 331, nos. 1–2, 2013, 152–54, DOI: 10.1016/j.jns.2013.05.006. Accessed 4 Sept. 2024.
Singh, Navneet, et al. “Alexander’s Disease: Reassessment Of A Neonatal Form.” Child’s Nervous System: Official Journal of the International Society for Pediatric Neurosurgery vol. 28, no. 12, 2012, 2029–31, DOI: 10.1007/s00381-012-1868-8. Accessed 4 Sept. 2024.
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