What is Alexander disease?
Alexander disease (ALX) is a rare and often fatal nervous system disorder that
primarily occurs in infants and children.
The main features of Alexander disease are progressive mental impairment and loss of motor control. Based on the age of onset and type of symptoms present, ALX has been classified into three forms: infantile, juvenile, and adult. Alexander disease is named for Dr. W. Stewart Alexander, an Australian pathologist who first described an infantile case in 1949. Since that time, 80% of cases described have also been the infantile form. About 14% of patients have the juvenile form, and adult cases are rare. All three forms of ALX are unified by the presence of Rosenthal fibers (RF), microscopic protein aggregates that are found in astrocytes in the brain and spinal cord. Though Rosenthal fibers are associated with other conditions, the numbers and distribution of RF-containing astrocytes are unique to Alexander disease. ALX is one of the leukodystrophies, a group of disorders characterized by imperfect formation or maintenance of white matter, the myelin sheath (insulation) that covers the nerves in the brain and spinal cord. Patients with ALX usually display loss of white matter, most prominently in the frontal lobes of the brain.
Demographics
Alexander disease is thought to be quite rare with approximately 200 cases described. Although there are no known prevalence estimates, the disease has been reported in both males and females and in various ethnic and racial groups.
Causes and symptoms
Most cases of Alexander disease are genetic, caused by a dominant mutation (change) in the glial fibrillary acidic protein (GFAP) gene on chromosome 17. Usually this mutation occurs randomly in an individual without a family history of the disease. There are reports of rare familial cases with affected siblings. Therefore, unaffected parents of a child with ALX are at a low risk to have another affected child. Individuals with ALX who live long enough to reproduce have a 50% chance for an affected child. Since GFAP mutations have not been found in all cases of ALX, there may rarely be other genetic or non-genetic explanations for this disease.
The glial fibrillary acidic protein gene encodes a protein by the same name. GFAP helps to provide structural stability to the astrocytes, which are supporting cells in the brain similar to blood vessels. GFAP is found in Rosenthal fibers. Reports have suggested that GFAP gene mutations result in a toxic gain of function of the protein (GFAP) that leads to a minimal or absent production of myelin. As of 2003, the precise mechanisms by which GFAP mutations cause ALX were unresolved.
In the infantile form of the disease, average age of onset is six months, with a range of birth to two years. Affected children tend to have progressive physical and mental retardation with loss of previously attained milestones. Head size becomes increasingly large and the forehead appears prominent as a result of megalencephaly (enlarged head and brain). Other disease manifestations include seizures, spasticity (stiffness of the arms and legs), quadriparesis, feeding problems, and ataxia (poor coordination). Hydrocephalus may also occur, especially in children with early onset of symptoms.
The juvenile form of ALX usually presents between age four and the early teens. Patients may develop some or all of the following symptoms: speech problems, difficulty swallowing, frequent vomiting, spasticity of the legs, ataxia, gradual intellectual decline, seizures, megalencephaly, or breathing problems. White matter abnormalities in the juvenile form are less prominent than in the infantile form.
The adult form of ALX represents the most variable and least common form of the disorder. Patients with the adult variant may have symptoms that mimic multiple sclerosis, or may display symptoms similar to the juvenile form of the disease, except with later onset and slower progression. White matter changes may or may not be present. Some adult cases have been discovered by chance when an autopsy reveals Rosenthal fibers, a characteristic finding of this disease.
Diagnosis
A diagnosis of Alexander disease is usually based on radiologic findings and/or genetic test results in an individual who has symptoms suggestive of this condition. Radiologic studies that may aid in diagnosis include magnetic resonance imaging (MRI), a computerized tomography (CT) scan, or a head ultrasound. For example, an MRI of an individual with the infantile form typically reveals white matter loss that involves the frontal lobes of the brain, abnormalities of the basal ganglia and thalamus, and possibly, enlargement of the ventricles. Genetic testing is accomplished by looking for known or detectable mutations in the GFAP gene. In up to 94% of cases of ALX, a GFAP mutation is found. Prenatal diagnosis for couples with an affected child can be performed when the mutation responsible for ALX is known. The DNA of a fetus can be tested using cells obtained from chorionic villus sampling (CVS) or amniocentesis.
Prior to the discovery of the gene responsible for the disease, diagnosis of ALX was made by demonstration of Rosenthal fibers in a biopsy or autopsy sample from the brain. Though genetic testing has largely replaced these histologic studies, a brain biopsy or autopsy may be indicated in select cases if the diagnosis cannot be made through other means.
Treatment
There is no cure for Alexander disease. Treatment, which is symptomatic and supportive, primarily consists of attention to general care and nutritional needs, antibiotic therapy for infections, and management of associated complications such as anti-epileptic drug therapy for seizures. Surgical interventions, including placement of a feeding tube and/or shunting for hydrocephalus, may also be required. Orthopedic surgery for scoliosis has been reported in a case of Alexander disease.
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