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Alexander's Disease

Classification

Alexander’s disease is classified with the other leukodystrophies, diseases that affect the white matter of the brain. Specifically, astrocytes in the brain are affected by a dominant gain-of-function mutation of the GFAP gene. This rare neurodegenerative disease has a variable onset age and a multitude of symptoms ranging from physical to cognitive. It is classified as two types, type 1 and type 2, depending on the symptoms observed.

Signs/Symptoms

Alexander’s disease is recognizable from the very clear presence of Rosenthal fibers located within the astrocytes. The disease is best described as having two forms, type 1 and type 2. Each type accounts for about half of known cases. Symptoms of type 1, which has an onset before the age of 4, typically include failure to gain weight and grow at the expected rate, seizures, and delayed development of specific physical, mental, and behavior skills. Type 1 patients can also suffer from enlargement of the head, difficulty breathing, swallowing, and coughing, and increased muscle stiffness. Almost 90% of infants with type 1 show some signs of developmental problems and seizures, and over 50% show other mentioned symptoms. Patients with type 2, which has an onset any time after the age of 4, don’t usually show delay in development or seizures. Type 2 is associated with difficulty breathing, swallowing, and coughing, lack of coordination, and more rarely increased muscle stiffness. Type 2 is often confused with other disorders because its symptoms are not specific to just Alexander’s. While split into two different types it is possible for a two year old to exhibit the symptoms typical of a 12 year old, and vis-versa.    

Causes -genetics -inheritance Pattern -mutations

Around 95% of Alexander’s disease cases are caused by a dominant gain-of-function mutation in GFAP, a gene that encodes for a structural protein called glial fibrillary acidic protein. The overexpressed GFAP proteins aggregate within the astrocyte, eventually leading to the death of the astrocytes due to high levels to toxicity. The majority of observed Alexander’s disease cases come from a de novo mutation. Mutant GFAP can still be inherited, with males and females have the same percentage risk of contracting Alexander’s from their parents. In a large study of patients with Alexander's Disease, it was determined that more than half of the patients had mutations in one of four residues in the GFAP gene (R79, R88, R239, and R416). Futhermore, it has been shown that the R79 and R239 mutations have a definitive genotype-phenotype correlation (early onset, seizures, motor difficulties, encephalopathy, and cognitive delay), other mutations do not appear to have rigidly defined phenotypes.  

Molecular Mechanism

Alexander’s Disease is caused by mutations in glial fibrillary acidic protein gene (GFAP). Alexander’s Disease primarily interferes with astrocytes as a result of gain-of-function mutations to the GFAP gene. The primary role of astrocytes is to act as a repair mechanism in response to a traumatic brain injury. GFAP protein is predominately expressed by oligodendrocytes in the CNS, which normally function to provide support and insulation to nerve cells. Upon mutation of the GFAP gene, the oligodendrocytes experience a decrease in the production of GFAP filaments. Astrocytes try to compensate for the unexpected reduction of GFAP filament protein by up-regulating expression of the GFAP gene. As increasing amounts of mutant full-length GFAP protein, also known as Rosenthal Fibers, are synthesized by astrocytes in response to the availability of free GFAP monomers, the cells become oversaturated with GFAP protein. As a result, astrocytes self-destruct when they breach the threshold for GFAP protein toxicity. This series of biochemical events creates a positive feedback loop and is a likely explanation for the motor and cognitive dysfunctions associated with the disease. Ultimately, mutations in the GFAP gene still allow for the production of full-length GFAP protein filaments, but the way in which the filaments assemble to make the protein is different. This change in the final conformation of the protein is responsible for the phenotypic symptoms associated with Alexander’s Disease. Additional consequences of mutations in the GFAP gene include increased activation of stress pathways, including p38 kinases and JNK. Constituative activation of p38 kinases leads to an increase in alpha-beta crystallin protein, whose role is to regulate the natural degradation of cells. Unfortunately, this increase in autophagy is ineffective in restoring normal levels of GFAP protein. The glutamate transporter in astrocytes (GLT-1) is also down-regulated. The failure to transport glutamate out of astrocytes results in excitotoxicity and death; this may be an explanation for many of the neurological deficits observed in patients with Alexander's disease, such as seizures due to a loss of myelination.

Diagnosis

Clinical symptoms

The severity of the symptoms shown in those with Alexander's Disease typically depend on the age of onset of the disease. For instance, for those with infantile Alexander's, patients typically present with frequent seizures, macrocephaly, major cognitive disorders, and failure to thrive. These symptoms typically begin in the first months of life, and they tend to increase in severity as time passes. Eventually, those with infantile Alexander's die before the age of 6. On the contrary, for those with juvenile and adult onset Alexander's, the magnitude of the symptoms are typically less severe. For instance, Li et al., (2005) gathered 44 individuals with Alexander's (including 15 with juvenile Alexander's, and 3 with adult onset Alexander's), and found that those with the juvenile onset of the disease were 3 times less likely to present with macrocephaly, while none of those with adult onset Alexander's presented with it. In addition, those with adult-onset Alexander's did not suffer from seizures or major cognitive defects.

Genetic Testing

Genetic testing is currently available to check the GFAP gene to scan for mutations. However, since most of those suffering from Alexander's have a de novo mutation, scanning the gene is quite difficult. MRI scanning is often typically done to scan for characteristic patterns in brain development in those who are suspected to have Alexander's. MRIs will nearly always reveal lesions to the white matter of the brain and deformities of the basal ganglia and the thalamus.

Treatment/Management

There are currently no treatments available to cure Alexander’s disease. The only treatments that are available are those that can aid in managing symptoms caused by the disease. Drugs can be prescribed to help with vomiting and seizures, antibiotics for infection and feeding tubes for nourishment.

Ishigaki et al. (2006) reported his success in treating a 9 year old child affected by Alexander’s Disease using thyrotropin releasing hormone (TRH). Patient receiving therapy showed improvements such as increased mental state and speech, decreased frequency of vomiting, ataxia and sleep apnea. However, prolonged usage of TRH causes some of the improvements in symptoms to fade over time. Using TRH as a therapy was used based on previous studies that TRH could aid with spinocerebellar deficits and ataxia. TRH could potentially be a therapeutic cure for those with Alexander’s disease but more research is needed.

Symptoms vary greatly for those with Alexander’s disease therefore, every patient will have a different management plan. After initial diagnosis of the disease patients need to get a complete neurologic and feeding assessment, EEG monitoring of seizures, psychological assessment for older patients that are better able to understand what the disease entails, genetic counseling, and make sure patient has a good support system. Patients depending on age, should be examined frequently by a multidisciplinary team to assess the progression of symptoms.

Outcomes/Prognosis

Alexander disease commonly comes in three forms: infantile, juvenile and adult. Each form of Alexander disease presents itself with varied symptoms, age of onset, as well as life expectancy. However, there are infants that are diagnosed within 30 days after birth, thereby creating a neonatal form. The majority of those affected by Alexander disease are infants and children making up 42% of all reported cases. Juvenile form makes up only 22% and adults make up 33%.

Neonatal form is typically diagnosed within one month after birth. Infants that develop Alexander’s at this time typically exhibit rapid progression of symptoms often leading to death before 2 years of age or become severely disabled. Symptoms include frequent and generalized seizures, hydrocephalus, impaired intellectual and motor skills, megalencephaly, vomiting, difficulty sucking and swallowing..

Infantile Form typically found in children between the ages of 2 - 4. Those affected also exhibit rapid progressing symptoms causing the survival period of the children to range between a few weeks to several years. Children with infantile form of this disease usually do not make it into their teenage years. Symptoms of this form include seizures, megalencephaly, enlargement of cerebellum and brain stem, ataxia (loss of coordination), progressive retardation, and hydrocephalus..

Juvenile Form typically found in patients between the ages of 4 - 10 and occasionally found in teenagers. The survival period of these children will range from their early teens to their 30s. This form of Alexander’s Disease will progress more slowly than infantile. Symptoms include bulbar/pseudobulbar signs which causes speech abnormalities, difficulties in swallowing and vomiting. Other symptoms include  seizures, breathing problems, megalencephaly, loss of intellect, ataxia and spasms of the lower limbs.

Adult Form typically occurs between 13 years or older with varied in presentation and symptoms. Just like the juvenile form, progression is much slower, therefore survival ranges from a few years to decades. Symptoms include bulbar and pseudobulbar signs cause difficulties in swallowing, problems with speech, sleep apnea, seizures, hemi/ quadrapleigia, constipation, incontinence, polyuria, coordination issues, etc.

There are a few cases (3%) where patients are diagnosed with the GFAP pathogenic variant, but these cases are asymptomatic. Due to a lack of information and studies, little information is known about them and whether or not they stay asymptomatic or  will develop symptoms later on in life.

Epidemiology

Alexander’s disease has been seen in many ethnic and racial groups. This disease is thought to be rare, therefore, prevalence remains unknown. Those with GFAP pathogenic variants have been confirmed in 293 of the 550 reported cases. Age distribution of Alexander’s disease is as follows: infantile form (ages 2-4)  42%, juvenile form (ages 4-10)  22%, adult form (ages 13+) 33%, asymptomatic 3%.

Although most would expect for the ratio of affected males to females to be equal. There have been some discoveries to suggest that there are differences among the sex ratio with those that have juvenile and adult forms. It has been reported that there is a lower proportion of females with juvenile forms but a higher number of them with adult forms. There is no significant difference between the number of affected males and females with infantile form, but females with the juvenile form of this disease are less often show symptoms often seen in Alexander disease such as macrocephaly, seizures, spasms and developmental delay.

Discovery

Discovery of Disease

Early investigation of Alexander’s Disease occurred in 1949 by scientist W. Stewart Alexander who observed unusual symptoms in a 15-month-old boy. The patient presented with persistent vomiting, sluggish movements, progressive megalencephaly, Klazomania, and elevated temperatures. One month later, 15-month-old patient died from what is known as pulmonary emboli. Further investigation discovered the accumulation of protein aggregates, now known as Rosenthal fibers, in the astrocytes of the white matter of the brain. Years later physicians noticed recurrent episodes of these symptoms and later classified this phenotype as a form of Leukodystrophy, a type of rare genetic disease that has an affect on the brain and central nervous system, by the degradation of what was later classified as Alexander’s Disease, based on the founder of the initial symptoms.

Discovery of Gene

Underlying factors that pertained to Alexander’s disease remained unclear. For a period of time researchers and physicians posed questions regarding whether environmental factors, genetic inheritance, or both, influenced the phenotype of the disease.  The disease was rarely seen in generations of families and therefore it was assumed that Alexander’s Disease was the result of a recessive mutation. Additionally, researchers Becker and Teixeira noticed that when patients were exposed to nickel intoxication, there was an accumulation of protein aggregates that resembled what is today known as Rosenthal fibers. In 1988, Becker and Teixeira correlated this phenotype to a mutation in the GFAP gene that was further investigated by conducting a transgenic mouse study and proved to be the correct gene of interest. Overexpressing GFAP levels in the astrocytes of the mice was shown to be fatal and autopsies concluded that due to the abundant production of Rosenthal fiber protein aggregates formed in the astrocytes of the central nervous system of the mice, the function of the normal glial cells were perturbed.

Future Directions

With no current treatments available for Alexander’s Disease, researchers are pursuing possible drug treatments that aim to target the affects of the GFAP mutation on astrocytes and the overall neuronal function of affected patients. Recent studies have shown that glutamate uptake is deficient in patients with Alexander’s disease and that the excessive glutamate is the main cause of seizures in infantile patients as well as the degradation of oligodendrocytes and neurons. The plausible error for the excessive glutamate in the astrocytes is the toxicity of tumor necrosis factor-α (TNFα), a cytokine that is increased by the production of Iron, which is a symptom commonly seen in patients affected by Alexander’s disease. Researchers are further investigating the underlying mechanism of the glutamate transporter in order to develop new drug therapies that target this specific deficiency.

A recent study performed by Wang et al. (2015) has gained an insight into the characteristic astrocyte dysfunction in an animal model using Drosophila. Through genetic screening, the Nos gene that codes for the Nos protein was up-regulated in Drosophila carrying a GFAP-mutation. This up-regulation of Nos suggests the Nitric oxide (NO), is the primary messenger in neuronal cell death. The study further demonstrated that Nitric oxide is critically important in the neuronal destruction pathway through DNA damage, p53 activation, and through oxidative stress. Researchers are currently developing ways to regulate Nitric oxide production and signaling as a potential therapeutic agent in treating Alexander's Disease.