What is Alexander Disease?

Overview

Genes play an underlying role in several diseases that affect the global population and a wide range of these diseases affect our nervous system

Alexander or Alexander’s disease is one of these diseases.  It was named after Stewart Alexander who first described it in the middle of last century. Despite its rarity with an incidence of one in every million births, Alexander's disease  is a serious  genetic disease which extensively damages our nervous systems. This involves the central nervous system (brain and spinal cord) as well as the peripheral nervous system (the nerves that branch out from the brain and spinal cord).

This widely damaging disease needs a cautious approach towards studying its  pathology, causes, interference with  normal  body functions, treatment and fate.

Causes of alexander disease

Alexander’s disease is a  neurodegenerative disorder, where the cells of the central nervous system stop working or die. These include  diseases such as Alzheimer's and Parkinson's diseases. However, it is more comparable to Huntington’s disease since it is also inherited and shows its symptoms at a very young age.

Alexander’s disease is unique in being a  metabolic, genetic and neurologic disorder that affects specific types of cells in the nervous system, known as astrocytes. Astrocytes are specialised nerve cells that are essential for the proper functioning of the nervous system. They have a unique defence mechanism that requires them to be abundant in any disorder that affects the nervous system, including inflammation, infection, tumours, or metabolic disturbances.

The name "astrocytes" comes from the Greek word "astro," which means star-shaped, referring to their star-like appearance with multiple branches. During embryonic development, these cells originate from the outer layers of our body cells and then branch out further within the deeper layers to establish protective communication channels in case of any disturbances.

On exploring the causes of Alexander's disease,  its causes are often related to factors that interfere with the development of the shape and function of the astrocytes.  Based on the genetic predisposition, the main cause is   a variation in the  gene responsible for GFAP (Glial astrocytic fibrillary protein). This protein has a high influence on the development of the communication processes of the astrocytes, that help them to deliver their protective functions in the area where they are needed.¹

Alexander's disease belongs to a group of diseases known as leukodystrophies due to their damaging affection of the white matter in  the brain, including  the surrounding  blood vessels and cerebrospinal fluid brain-filled cavities. Alexander's disease affects a kind of fibre, known as Rosenthal fibres , that forms the myelin sheath, a covering of the axons as well as parts of the cell body of  astrocytes. This leads to a deformed myelin, the main white matter component, in the frontal and temporal lobes and eventually  in the whole cerebral hemisphere and cerebellum.²

Signs and symptoms of alexander disease

The most appropriate management of any disease relies on its proper diagnosis. Nevertheless, it is worth mentioning that the diagnosis of Alexander disease, which is mostly genetic, starts with the clinical picture as  a guide to further genetic testing. The clinical picture of Alexander disease represents variable symptoms and signs according to the age-related staging of the disease.³

Neonatal form 

Affects babies  in their first month after birth. The affected individuals may show generalised  rhythmic muscle contractions and even convulsions, decrease in the muscle tone or even increased excitation of their nerves. 

These newborns may exhibit a decrease in  mental as well as  physical development, and may not  survive due to repeated vomiting. 

Infantile form 

Has the same symptoms as the neonatal form but is less severe. In addition there is a  loss of  high and fine motor skills and linguistic skills that  a child should develop during the first few months. .

Juvenile form 

Affects children and young teenagers and it is milder than the infantile form with a persistent language skill development delay as well as nasal tone or even hypophonia. 

The symptoms may overlap with other diseases and gastrointestinal affection may also occur.

Adult form 

Affects several parts of the brain, including cerebellum, motor cortex and medulla oblongata. 

This may  lead the patients to have disequilibrium, hemiplegia (paralysis of half of the body), recurrent and intermittent quadriplegia (whole body paralysis), dysphonia (change of voice) and dysphagia (difficulty of swallowing).

It is worth noting that the earlier the onset, the more aggressive the clinical picture and the worse the prognosis. This is evident in  the high death rate of the infantile form within the first couple of years of life.

Management and treatment for alexander disease

There is no specific treatment of Alexander's disease apart  from anti-convulsive treatment, feeding, rehabilitation and support. This support includes referral to audiology specialists as well as individualised educational programs to accommodate the affected individuals into leading a normal life. 

FAQs

How is alexander disease diagnosed?

Alexander disease is diagnosed through imaging techniques such as: 

• Computerised tomography (CT) 
• Magnetic resonance imaging (MRI) 
• Ultrasonography on the brain
• Nerve conduction studies 
• Brain wave measurement studies (EEG)
• Genetic testing for the mutations of GFAP gene are confirmatory steps that follow the history and the other investigations.

How can I prevent alexander disease?

As it is mainly a genetic disease, it is non preventable except through  raising  awareness of it. Genetic counselling programs are designed to explore the possibilities of inheritance as well as its role  in a person’s life with a  family history of genetic diseases. Such programs include regular education about the disease and its ways of management.

Who is at risk and how common is alexander disease?

• People who have a mutation in  one of both copies of GFAP gene are at risk of developing Alexander’s disease
• When both parents carry such a mutation on one of their chromosomes, 50% of their offspring have a risk of developing Alexander’s disease 
• The absence of the specific mutation in the gene copy of both patients suggests that the disease may have occurred as a new mutation in the affected individuals, increasing the risk of the condition recurring in the future

This highlights the importance of getting a familial record of genetic testing and screening, despite its high cost if done for the whole population.

What can I expect if I have alexander disease and when should I see a doctor?

The course of Alexander's disease is progressive and can be intermittent with relapse and remission. Yet, the severity of its symptoms cannot be predicted as it can badly affect vital centres of the brain. 

This potentiates the idea of seeking medical help on the appearance of any neurological abnormality in the individuals with positive family history or risk of development Alexander's disease. This would allow the estimation of the depth of the attack and prevent further complications.

Summary

Alexander’s disease is a unique disease in its destruction of the nerve cells in white matter, while being a genetic and a metabolic disease. Thus, the general awareness level of Alexander's disease may positively contribute to limiting its burden in spite of its aggressive course.