Alexander Disease Causes, Types, Symptoms, Diagnosis, Treatment, Prevention

Alexander Disease Causes, Symptoms, Diagnosis, Treatment, Prevention


What is Alexander disease?


Alexander disease is a rare disorder of the nervous system. It is one of a group of disorders, called leukodystrophies, that involve the destruction of myelin. Myelin is the fatty covering that insulates nerve fibers and promotes the rapid transmission of nerve impulses. If myelin is not properly maintained, the transmission of nerve impulses could be disrupted. As myelin deteriorates in leukodystrophies such as Alexander disease, nervous system functions are impaired.

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.

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.

Alexander disease is also characterized by abnormal protein deposits known as Rosenthal fibers. These deposits are found in specialized cells called astroglial cells, which support and nourish other cells in the brain and spinal cord (central nervous system).

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What genes are related to Alexander disease?


Mutations in the GFAP gene cause 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.

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.

Causes of Alexander Disease


Alexander disease is caused by a genetic mutation. The gene is known as GFAP (glial fibrillary acidic protein) and is located on the long arm of chromosome 17 (17q21.31). A mutation in the GFAP gene causes abnormal production and accumulation of structurally altered glial fibrillary acidic protein, GFAP, in glial cells. As a consequence, the glial cells are unable to support nerve cells in the brain and myelin. Myelin is the covering tissue that insulates all nerve fibres.

Heredity


The inheritance pattern of Alexander disease is autosomal dominant. 
In most cases, the disease occurs as a result of new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. The new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children. However, individuals with the infantile or juvenile forms will not have children of their own.

Very rarely, healthy parents have more than one child with the disease. In these cases the pattern of inheritance is likely to be autosomal recessive (meaning that both parents are healthy carriers of a mutated gene, and each time they become pregnant there is a 25 per cent risk that the child will have the disease). Another cause may be that the gonads (the reproductive glands) of one parent has a mixture of cells with normal GFAP genes and cells with mutated GFAP genes.

Types and Symptom of Alexander Disease


Infantile Alexander Disease


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


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


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 of Alexander Disease


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/interventions for Treatment/interventions


There is currently no cure for Alexander disease, nor is there any way of preventing its progression. Treatment aims to alleviate symptoms and to provide as good care as possible. In infantile forms of the disease, haematological stem cell transplantation (often referred to as bone marrow transplantation) has been tried, but has not proven effective.

When the diagnosis is established, support to the family should be offered from a team that includes the treating physician, a nurse, psychologist and social worker. Treatment in the infantile form aims to provide good, supportive care and to ensure the best life quality possible. This is usually best accomplished at the local paediatric clinic, where one and the same team of healthcare professionals take care of the child, or with the help of the habilitation services. The child can also be cared for in the home in cooperation with the local hospital. As these children often have feeding difficulties, parents may need to be in contact with a dietician and a speech pathologist. At large hospitals there are specialist teams (dysphagia and nutrition teams). Nutrition or nutritional supplements can be administered through a nasogastric tube or via a feeding tube surgically inserted into the abdominal wall (percutaneous endoscopic gastrostomy). Some of the symptoms, such as involuntary spasms, may be treated medically. Epilepsy can also be treated medically. It is important to remember that families of children with a rapidly progressing disease require assistance in coordinating interventions.

As many of the children with the infantile form are severely ill and the condition is life-threatening, palliative care may be needed. Palliative care aims to ensure that the dying child is as comfortable and pain free as possible. This requires close, intensive cooperation between parents, other relatives of the child, and healthcare personnel.

Many parents wish to care for the child in the home as far as possible, with help from healthcare staff. Often the child is cared for alternately in the home and in the hospital. Parents and siblings should be offered social and psychological support.

In the juvenile form of the disease the family should be in contact with a habilitation team made up of professionals with special expertise in how disability affects everyday life, health and development.

Support and treatment take place within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information about support offered by the local authority as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings can also receive support.

Habilitation is planned to meet current needs. Interventions vary over time, but are always planned in collaboration with people close to the child.

Psychological support adapted to the age and maturity of the child should be continuously available.

The local authority can offer different forms of support to facilitate the family’s everyday life. Respite care, including personal assistance, a contact family, or short-term residential care are examples of support measures.

Prevention for Alexander Disease


The cause of de novo genetic mutations is unknown, thus, no form of prevention is available. Although prenatal testing can be performed in families where the spontaneous mutation in the GFAP gene is identified, the utility of this testing is likely to be extremely limited because familial cases of Alexander disease are so rare.

What is the prognosis?


The prognosis for individuals with Alexander disease is generally poor. Most children with the infantile form do not survive past the age of 6. Juvenile and adult onset forms of the disorder have a slower, more lengthy course.

What research is being done?


Recent discoveries show that most individuals (approximately 90 percent) with Alexander disease have a mutation in the gene that makes glial fibrillary acidic protein (GFAP). GFAP is a normal component of the brain, but it is unclear how the mutations in this gene causes the disease. In most cases mutations occur spontaneously are not inherited from parents. A small number of people thought to have Alexander disease do not have identifiable mutations in GFAP, which leads researchers to believe that there may be other genetic or perhaps even non-genetic causes of Alexander disease. Current research is aimed at understanding the mechanisms by which the mutations cause disease, developing better animal models for the disorder, and exploring potential strategies for treatment. At present, there is no exact animal model for the disease; however, mice have been engineered to produce the same mutant forms of GFAP found in individuals with Alexander disease. These mice form Rosenthal fibers and have a predisposition for seizures, but do not yet mimic all features of human disease (such as the leukodystrophies). One clinical study is underway to identify biomarkers of disease severity or progression in samples of blood or cerebrospinal fluid. Such biomarkers, if found, would be a major advantage for evaluating the response to any treatments that are developed in the future.