Alexander Disease

Etiology

Alexander disease usually occurs through a mutation of the GFAP gene. The disease is inherited in an autosomal dominant manner.[4][5] The GFAP gene was identified in the region of chromosome 17q21.[6] This gene (nine exons with a length of 9.8 kb) encodes for a 432 amino acid protein that belongs to the intermediate filament proteins and appears to play a role in regulating the morphology and motility of astrocytes as well in the interaction between astrocytes and oligodendrocytes. These filaments are rapidly synthesized during reactive astrogliosis and CNS injury. The precise mechanism is not fully understood. It is thought that the GFAP mutations act as a gain of function mutation that disrupts the dimerization of intermediate filaments.[7] This results in abnormal protein aggregation and cytoskeleton collapse.[8]

There is also a suggestion of the GFAP accumulation disrupts filament assembly. The most frequent mutations affect exon 1 (54%), exon 4 (31%), exon 8 (7%), exon 6 (4%), exon 5 (3%), and consist of point mutations that bind to an alternative transcript and different mRNAs by transcription start site or by alternative RNA splicing. Of note, despite the genetic homogeneity, there are different clinical phenotypes.[9]

Epidemiology

Alexander disease is a very rare disorder with the true prevalence not known. Since the initial description of Alexander disease, only around 550 cases have been described. A Japanese study estimated an incidence of 1/2.7 million.[10] Additionally, Alexander disease has only been found to account for approximately 1.6 percent of leukodystrophies.

Pathophysiology

The alteration and increased expression of GFAP induce the development of protein aggregates (Rosenthal fibers) in the astrocyte cytoplasm. In turn, reactive gliosis and astrocyte dysfunction induce a set of secondary changes in neurons and other types of glia.[11] Apart from the accumulation of protein aggregates (GFAP toxicity), other mechanisms such as impaired degradation and GFAPs interfering with the function of the proteasome could be responsible for the pathogenesis of the disease. Whatever the cause, the damage begins at the astrocytic level and extends beyond involving other cellular elements through probably microglial activation.

In the pathogenesis of the disease, therefore, an important role is played by the overexpression of the mutant protein and, thus, filament accumulation. Indeed, experiments conducted on GFAP-null mice have shown that the reduction of GFAP expression is associated with a low morbidity phenotype.[12] Moreover, no null variants were demonstrated in human patients. Thus, Alexander's disease is an example of a gain-of-function disease. This feature could have important therapeutic implications. For instance, Hagemann et al. conducted interesting investigations by using the antisense oligonucleotides for suppressing GFAP expression through single intracerebroventricular injections in a GFAP mutant mouse models of Alexander disease. They proved that this approach reduced the level of Rosenthal fibers and the activation of astrocytes and microglia.[11]

Histopathology

The white matter of the frontal lobes and, less often, of the temporal lobes, is affected by extensive demyelination, which sometimes evolves into real cavity lesions. In the subsequent stages, the pathological process can involve all the white matter of the cerebral hemispheres, cerebellum, and brainstem with dilation of the ventricular cavities.

From the histological point of view, in the areas affected by the disease process, it is shown widespread vacuolation due to the degeneration of the myelin sheaths. This degeneration is characterized by the finding, in subpial, subependymal, and perivascular sites, of eosinophilic fibers with radial arrangement with respect to adjacent surfaces, called Rosenthal fibers that increase in number and volume over the course of the disease. These fibers, composed of fibrillary acidic protein, vimentin, αβ-crystallin, and heat shock protein 27 (HSP27), are contained exclusively in the soma and the astrocytic axons, and they were initially thought to be pathognomonic of Alexander disease. Subsequently, however, they have been found in numerous other pathological processes such as central pontine myelinolysis and multiple sclerosis as well as no-neurodegenerative diseases such as cancer disease, respiratory and heart failure, and diabetes mellitus.[13]

The relief of Rosenthal fibers remains, however, a differential diagnostic criterion between Alexander disease and the other leukodystrophies.[14]

History and Physical

Alexander disease most often affects infants and children. Patients usually present with macrocephaly, developmental delay, progressive quadriparesis, and seizures.

Traditionally, Alexander disease has been divided into four subtypes, which include neonatal, infantile, juvenile, and adult.[15]

• Neonatal form: It is characterized by seizures, increased intracranial pressure, and severe motor dysfunction. Of note, unlike infantile, ataxia and hyperreflexia are not present. Death usually occurs within the first couple of weeks to years.
• Infantile form: The onset is before age 2, accounting for approximately 42 percent of all cases. This form is associated with seizures, ataxia, hyperreflexia, hydrocephalus, megalencephaly, feeding difficulties, and spasticity. It is possible to detect progressive psychomotor retardation with changes in developmental stages. Death typically occurs within weeks or several years of life.[16]
• Juvenile form: Onset is usually slower than infantile form and is normocephalic. It is characterized by bulbar and pseudobulbar signs, such as speech difficulties and swallowing. Patients may also have spasticity and ataxia. A progressive worsening of intellectual faculties and epilepsy can be found. The survival is variable with death, which may occur in early adolescence or up to 20-30 years. 
• Adult form: It is the least common form of the disease and has variable features. Some of these features, including pseudobulbar and bulbar signs (dysphasia, dysarthria, dysphonia), progressive ataxia, quadriparesis, dysmorphic features, and dysautonomia.[17] Other clinical features may include sleep disturbances (sleep apnea), postural alterations (scoliosis, kyphosis), palatal abnormalities, short neck, epilepsy, and diplopia. Survival is variable with death after a few years or even after a few decades of illness. Many cases are occasionally detected at autopsy, and death is often, in these circumstances, attributable to other intercurrent illnesses.

Alexander disease classification was revised in 2011 based on statistical analysis.[18] Although this model system predicts trends, it does not allow the classification of an individual with complete certainty.  

• Type 1: This type is typically more severe, with a median survival of 14 years. It is characterized by seizures, early-onset, macrocephaly, encephalopathy, motor delay, failure to thrive, and the typical imaging features (described below).[18]  
• Type 2: This type is usually less severe, with the median survival of 25 years. It is characterized by autonomic dysfunction, bulbar symptoms, eye movement abnormalities, lacking neurocognitive deficits, and the atypical neuroimaging features (described below).

Evaluation

Signs of Alexander disease can be demonstrated on CT and MRI, with MRI being the preferred imaging modality because of its sensitivity. Findings usually demonstrate cerebral white matter changes and swelling. The disease begins anteriorly and extends posteriorly. The subcortical U-fibers are generally spared early on in the course.  

MRI - typical features: Demonstrates abnormal signal in the following locations (enhancement may be seen in the same areas):

• Symmetric bifrontal white matter
• Periventricular rim
• Caudate head and less commonly globus pallidus, thalamus, and brain stem

Of note, there is relative sparing of the temporal and occipital lobe white matter.

MRI criteria for diagnosis: Four out of five required to make a diagnosis.[19]

1. White matter changes more pronounced in the front.
2. Periventricular rim abnormalities 
3. Basal ganglia and thalami abnormalities
4. Brainstem abnormalities
5. Contest enhancement of one of the following structures (ventricular lining, frontal white matter, optic chiasm, basal ganglia, thalamus, fornix, dentate nucleus, brainstem) 

MRI- atypical features: Demonstrates abnormal signal in the following locations:[20]

• Upper cervical cord and medulla
• Pons, superior/middle cerebellar peduncle
• Ventricular garlands   

Magnetic resonance spectroscopy:[21]

• Increased choline in the basal ganglia
• Reduce N-acetylaspartylglutamate (NAAG) in the frontal white matter
• Elevated lactate in the frontal white matter

The diagnosis of Alexander disease is primarily based on imaging features and clinical presentation. The diagnosis is typically confirmed genetically because of the variability of this disease. When children with Alexander disease present with typical clinical symptoms, the diagnosis can be made if four out of the five MRI criteria are met. The MRI findings are also invaluable when genetic testing is equivocal. But in children with atypical imaging features, the imaging findings cannot exclude the diagnosis. Thus, genetic testing is necessary to confirm the diagnosis in children with atypical imaging findings. In this regard, tests for the most frequent mutations (exons 1,4,8) are available in the clinical setting, and it is possible to resort to the sequencing of the entire gene in the case of recurrent mutations. The genetic study is also practicable in the field of prenatal diagnosis.

Treatment / Management

Treatment of Alexander disease is centered upon supportive care and utilizing a multidisciplinary team.[22] Using these methods can improve the quality of life of the affected individuals. These methods are based on the treatment of manifestations and maintaining close surveillance. Some examples include:(B3)

• Controlling seizures with anti-seizure drugs
• Improving spasticity and hypertonia with physical therapy and baclofen
• Increasing mobility by utilizing properly fitted equipment such as ankle braces
• Treating obstructive hydrocephalus with a ventriculoperitoneal shunt
• Improving malnutrition with a feeding specialist
• Controlling reflux or vomiting with a proton pump inhibitor
• Treating urinary retention and incontinence with bladder training, catheterization, and various medications

Overall the treatment of Alexander disease remains supportive in nature. Nevertheless, decreasing the expression of the GFAP gene can represent an interesting future therapeutic perspective.

Differential Diagnosis

The differential diagnosis of Alexander disease is centered on disorders with cerebral white matter changes or macrocephaly. In younger children, all conditions characterized by megalencephaly, developmental delay, and spasticity must be addressed. In older children, the differential diagnosis must be made with disorders presenting with spasticity, signs ofinvolvement of the brain stem with or without megalencephaly, and convulsions.

However, Alexander disease can be distinguished from similar diseases by utilizing the MRI criteria and the clinical presentation. The differential that should be considered includes:

• Adrenoleukodystrophy: Lesions are predominantly in the occipitoparietal region and are bilateral.
• Canavan disease: Lesions have a frontal predominance. There is increased N-acetylaspartic acid on magnetic resonance spectroscopy. However, there is no contrast enhancement.[23]
• Metachromatic leukodystrophy: Lysosomal storage disease. Lesions have a frontal predominance. However, it is not associated with contrast enhancement.
• Megalencephalic leukodystrophy: Lesions have a frontoparietal and anterior-temporal predominance.
• Classic congenital muscular dystrophy: Extensive cerebral white matter changes with relative sparing of the occipital lobe.

Very often, the type of distribution of white matter lesions helps the diagnosis. The distribution of the cerebral white matter involvement is, in Alexander disease, pathognomonic. The alterations, in fact, are predominantly of frontal distribution with rostral-caudal progression.

Prognosis

The prognosis of Alexander disease is generally poor.

Traditional classification scheme:

• Neonatal form: Death occurs within weeks to years.
• Infantile form: Death occurs within weeks or several years of life.
• Juvenile form: Death occurs between early adolescence to 20-30 years of life.
• Adult form: Has the best prognosis overall with death occurring later on in life.

Revised classification scheme:

• Type 1: The onset is earlier, and the prognosis is worse with a median survival of 14 years.
• Type 2: Has a later onset, and the prognosis is better with the median survival of 25 years.

Complications

The treatment of Alexander is centered upon supportive care of the long-term complications. Some of these long-term complications include seizures, spasticity, mobility problems, hypotonia, scoliosis, obstructive hydrocephalus, dysphagia, gastrointestinal symptoms (vomiting and reflux), failure to thrive, and urinary retention. Interestingly, these findings may wax and wane throughout the treatment course.