Alexander Disease - Symptoms, Causes and Treatment

Alexander disease is a rare genetic disorder involving astrocyte malfunction and improper development of the myelin sheath. Given below are a few details pertaining to the genetic causes, types as well as the symptoms and treatment options for this disorder.

Alexander disease (AD) is named after W. S. Alexander (an Australian pathologist) who reported the first incidence in a 16-month old boy in 1949. It is an extremely rare type of leukodystrophy, and inherited in an autosomal dominant fashion.

Leukodystrophies refer to diseases/disorders involving deterioration of the myelin sheath -- the insulating layer present around the nerves.

This disease predominantly affects infants, and follows a progressively fatal course. It is characterized by the presence of Rosenthal fibers.

Named after their discoverer -- Werner Rosenthal -- these are thick, elongated, eosinophilic structures that accumulate abnormally in certain cells of the central nervous system. In case of AD, they are abundantly present in the cytoplasm of astrocytes.

The integrity of eukaryotic cellular structure is maintained by actin microfilaments (5-7 nm diameter), microtubules (20-25 nm diameter) and intermediate filaments (8-12 nm diameter).

The intermediate filaments consist of protein units that vary with the cell type, whereas, the actin microfilaments and microtubules are conserved to a great extent. GFAP (glial fibrillary acidic protein) is a type of such intermediate filaments and is present abundantly in fibrous astrocytes.

AD arises due to a gain-of-function mutation in the gene that codes for GFAP. In simple words, it is the result of a mutation that causes the over-expression of GFAP.

It is the partially degraded fragments of the excess GFAP as well as ubiquitin (protein responsible for non-specific degradation of other proteins), and other proteins that are present as a structural component of the Rosenthal fibers.

The excess Rosenthal fibers, thus generated, accumulate in the astrocytic cytoplasm. Such GFAP toxicity beyond a particular threshold causes a deleterious effect on the function of astrocytes.

As a result, the myelin sheath deteriorates, affecting the transmission of nerve impulses, thus impairing various functions of the nervous system.

In addition to this, a small set of cases have been reported wherein the AD patients do not show any genetic abnormalities in the GFAP protein.

Being so, the presence of other genetic and non-genetic causes have been postulated, but remain to be precisely identified, as yet.

Inheritance

AD is inherited in an autosomal dominant pattern, that is, even a single mutated allele can lead to the development of this disease.

However, the number of AD cases arising due to sporadic mutations in the GFAP gene are more than the number of cases due to direct inheritance of the mutated allele. This can be attributed to the fact that this disease more commonly affects infants, and has a poor prognosis. In most cases, the affected infants do not survive beyond their early teens.

Types and Symptoms

AD is classified into the following types depending on the age of onset of the disease.

Infantile Alexander Disease

Age of onset: 0-2 years
Proportion: 51%

It is the most aggressive form and is characterized by megalencephaly (abnormally large brain) and/or hydrocephaly (abnormal buildup of cerebrospinal fluid in the brain ventricles). The affected infants do not survive beyond childhood. The symptoms associated with this form are:

• Progressive psychomotor retardation
• Seizures
• Spastic quadriparesis
• Ataxia
• Vomiting
• Juvenile Alexander Disease

Age of onset: 2-12 years
Proportion: 23%

The onset of this form is generally observed in school-going ages and the children survive up to 30-35 years of age. In certain children, lesions or tumors may develop. The commonly observed symptoms include:

• Spastic paraplegia (progressive weakness in lower extremities)
• Gradual loss of intellect
• Breathing problems
• Problems in coordination of movements
• Difficulty while walking

Adult-onset Alexander Disease

Age of onset: Above 12 years
Proportion: 24%

The onset of this form of disease is highly variable, the survival depends on the age of onset. This form progresses slowly, and is often misdiagnosed and presents the following symptoms:

• Difficulty in swallowing
• Spasms in the palatal muscles
• Slurred speech
• Difficulty in walking
• Sleep apnea
• Double vision
• Hemiparesis (weakness in one side of the body)

Certain cases of neonatal form of the disease have also been reported wherein the onset is within the first month of life followed by a rapid progression, and death within the first two years.

Diagnosis

Apart from the physical abnormalities coupled with the symptoms, neuroimaging studies like electroencephalogram (EEG) and Magnetic Resonance Imaging (MRI) are performed.

Various genetic tests are generally used to confirm the diagnosis, since the symptoms and clinical manifestations for AD generally overlap with other nervous system diseases. Prenatal genetic tests are also advised for pregnant women who have a family history of AD.

Treatment

The current treatments available for AD are symptomatic. There is no specific treatment that can help to control or prevent the progression of this disease.

Genetic counseling is advised for the family members of AD patients in order to educate them about the disease, its consequences, the prenatal diagnostic measure available in order to prevent the further generations from acquiring the mutation.

Alexander disease is the result of a mutated GFAP gene that is characterized by impaired astrocyte function. It poses a challenge as far as the causes, molecular mechanisms, precise diagnostic tools and treatment are concerned.

Disclaimer: This story is for informative purposes only, and should not be used as a substitute for professional medical advice.