THE INCURABLE ALEXANDER DISEASE

ALEXANDER DISEASE

      What is Alexander disease?

          Alexander disease is named after the physician who first described the condition in 1949 (WS Alexander). It is an extremely rare, progressive, neurological disorder that most often presents during infancy or early childhood, but can also occur as late as the sixth decade 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.

              Most cases of Alexander disease begin before age 2 and are described as the infantile form. Signs and symptoms of the infantile form typically include an enlarged brain and head size (megalencephaly), seizures, stiffness in the arms and/or legs (spasticity), intellectual disability, and developmental delay. Less frequently, onset occurs later in childhood (the juvenile form) or in adulthood. Common problems in juvenile and adult forms of Alexander disease include speech abnormalities, swallowing difficulties, seizures, and poor coordination (ataxia). Rarely, a neonatal form of Alexander disease occurs within the first month of life and is associated with severe intellectual disability and developmental delay, a buildup of fluid in the brain (hydrocephalus), and seizures.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). 

Synonyms

• ALX
• AxD
• Dysmyelogenic Leukodystrophy
• Dysmyelogenic Leukodystrophy-Megalobare
• Fibrinoid Degeneration of Astrocytes
• Fibrinoid Leukodystrophy
• Hyaline Panneuropathy
• Leukodystrophy with Rosenthal Fibers
• Megalencephaly with Hyaline Inclusion
• Megalencephaly with Hyaline Panneuropathy

      How do people inherit Alexander disease?

              This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.Most cases result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. Rarely, an affected person inherits the mutation from one affected parent. 

      What genes are related to Alexander disease?

             Mutations in the GFAP gene cause Alexander disease. GFAP, which encodes glial fibrillary acidic protein, is the only gene currently known to be associated with Alexander disease. The GFAP gene provides instructions for making a protein called glial fibrillary acidic protein. Several molecules of this protein bind together to form intermediate filaments, which provide support and strength to cells. Mutations in the GFAP gene lead to the production of a structurally altered glial fibrillary acidic protein. The altered protein is thought to impair the formation of normal intermediate filaments. As a result, the abnormal glial fibrillary acidic protein likely accumulates in astroglial cells, leading to the formation of Rosenthal fibers, which impair cell function. It is not well understood how impaired astroglial cells contribute to the abnormal formation or maintenance of myelin, leading to the signs and symptoms of Alexander disease.

       Diagnosis/testing of ALX: 

         Diagnosis of Alexander disease is based on MRI findings. Prior to the availability of molecular genetic testing the diagnosis was confirmed by the detection of astrocytic inclusion bodies (Rosenthal fibers) on brain histology. Molecular genetic testing is available on a clinical basis.

      Management of ALX:

         No specific therapy is currently available for Alexander disease. Treatment is supportive and includes attention to general care and nutritional requirements; antibiotic treatment for intercurrent infection; antiepileptic drugs (AEDs) for seizure control; and assessment for learning disabilities and cognitive impairment. Surveillance includes examinations at regular intervals by a multidisciplinary team with particular attention to growth, nutritional intake, orthopedic and neurologic status, gastrointestinal function, strength and mobility, communication skills, and psychological complications. 

       Genetic counseling: 

         Alexander disease is inherited in an autosomal dominant manner. The risk to the sibs of the proband depends upon the genetic status of the proband's parents. If a parent is affected or has a mutation in the GFAP gene, the risk to the sibs of inheriting the GFAP mutation is 50%. Sibs of a proband with unaffected parents are at low risk for developing Alexander disease; however, the possibility of germline mosaicism exists. Prenatal molecular genetic testing may be available for families in which the disease-causing mutation has been identified in an affected family member.

      Prevalence:

Although Alexander disease is thought to be rare, actual prevalence figures have not been reported. The disorder is known to occur in diverse ethnic and racial groups. About 500 cases have been reported since the disorder was first described in 1949.

      References:

• Alexander disease - Wikipedia, the free encyclopedia
• Alexander Disease
• Alexander disease - Genetics Home Reference  
• Alexander Disease Information Page: National Institute of ... Alexander Disease information sheet compiled by NINDS.  http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=alexander
• MedlinePlus - Health information