X-Linked Adrenoleukodystrophy: Types, Causes, Symptoms, Diagnosis, and Management

Introduction

X-linked adrenoleukodystrophy (ALD) is a genetic condition that destroys the myelin sheath, which acts as a protective membrane that insulates the nerves of the brain and spinal cord, called demyelination. This condition disturbs the peripheral and central nervous system and the adrenal gland. The symptoms of adrenoleukodystrophy involve behavioral and cognitive changes, which affect males much higher than females. This condition cannot be cured completely, but the treatment helps prevent the rapid progression of this disease.

What Is Meant by X-Linked Adrenoleukodystrophy?

X-linked adrenoleukodystrophy is a hereditary condition that affects the myelin sheath. When this sheath that covers the nerves is damaged, it decreases the ability of the nerves to transfer information to the brain. This condition also affects the adrenal cortex, the outer part of the adrenal gland, which results in a shortage of certain hormones produced by this gland, causing adrenocortical insufficiency. Adrenocortical insufficiency results in weakness, weight loss, coma, and skin changes.

In the case of adrenoleukodystrophy condition, the body cannot break down the long-chain fatty acids, resulting in saturated fatty acids deposited in the nervous system, brain, and adrenal cortex. X-linked adrenoleukodystrophy is the most common type of this condition, resulting from a genetic defect of the X-chromosome. Males are much more affected than females.

What Are the Types of X-Linked Adrenoleukodystrophy?

There are three main types of X-linked ALD these are:

• Childhood-Onset Adrenoleukodystrophy: This type of adrenoleukodystrophy usually occurs at four to ten years old. In this type, the white matter present in the brain gets damaged, called leukodystrophy. If this condition is not diagnosed early, it worsens and may cause death within five to ten years. This condition usually affects boys with difficulty reading, writing, understanding, etc.

• Addison's Disease: When ALD affects the adrenal gland, it tends to reduce the hormones produced by the gland, resulting in adrenal insufficiency, causing Addison's disease and neurological conditions. This condition can occur during the first year of life and adulthood. The life expectancy of the affected people depends on the signs and symptoms that the person experiences, but this form is the mildest of all the three.

• Adrenomyeloneuropathy: This type of ALD is usually less severe and progresses slowly, and the symptoms caused are stiff gait and bladder and bowel dysfunction. Females carriers of ALD have a higher chance of a mild form of adrenomyeloneuropathy. The symptoms of this condition usually occur in early childhood and middle age. The affected individual experiences infections of the urinary and genital tract.

Some rare types are

• Adrenal Insufficiency Only: In this type, the affected person will have only Addison's disease without any neurological condition.

• Adult Cerebral Adrenoleukodystrophy: People affected by this form lose their mental and neurological function, usually seen in one in every five affected males.

• Females Affected by ALD: Females are less affected, but those who are carriers of ALD experience mild symptoms of weakness and stiffness of the legs during their 60s.

Some affected children do not display signs and symptoms, and brain and biochemical abnormalities can be seen only during medical testing. These individuals with asymptomatic conditions can also result in other types of X-linked ALD in later life. Some affected people display multiple features of the condition in early childhood or adolescence. Along with adrenocortical insufficiency, the person can have a psychiatric condition and lose intellectual functioning.

What Is the Cause of X-Linked Adrenoleukodystrophy?

This is a genetic condition that is caused due to mutation of the gene ABCD1, which instructs the production of adrenoleukodystrophy protein (ALDP). This protein is responsible for transporting very long-chain fatty acids (VLCFAs) into peroxisomes, and these are small sacs present in the cells that process various forms of molecules, including VLCFAs.

Due to the mutation of the ABCD1 gene, there will be reduced production of ALDP protein which is responsible for the breakdown of very long-chain fatty acids. When there is a shortage of these proteins, the breakdown of VLCFAs gets disturbed, and these fats accumulate in the body. When VLCFAs accumulate in the nervous system and adrenal glands, they initiate an inflammatory response in the brain, which may destroy the myelin sheath, resulting in X-linked adrenoleukodystrophy.

How Is X-Linked Adrenoleukodystrophy Inherited?

A condition is called X-linked when the altered gene is present in the X-chromosome. In the case of males, one altered copy of the ABCD1 gene can cause X-linked ALD. The affected male will pass the mutated gene to the daughters, not their sons.

What Are the Signs and Symptoms of X-Linked ALD?

The common symptoms include

• Learning disability and ADHD (attention deficit hyperactivity disorder).

• Cognitive deficit.

• Issues with thinking, understanding, and processing new information.

• When an affected child loses skill, it results in regression.

• Vision issues, hearing loss, trouble walking, weakness, and limb stiffness.

• Seizure the sudden outburst of the brain's electrical activity.

• Dementia is a group of thinking symptoms that interfere with daily activity.

• Trouble eating and vomiting.

• Loss of neurological activity.

How Is X-Linked ALD Diagnosed?

The initial diagnosis is based on the physical examination, family history, and personal medical history. During newborn screening, some infants are diagnosed with this condition. The diagnosis is usually made based on the symptoms. If the doctor suspect of ALD, the child may have

• Blood test to monitor the level of very long-chain fatty acids, which are not broken into simpler forms.

• Genetic test is performed to rule out the mutation of the ABCD1 gene.

• An adrenocorticotropic hormone stimulation test tests the adrenal gland's functioning.

• MRI (magnetic resonance imaging) is done to see the affected region of the brain.

How Is X-Linked ALD Managed?

There is no complete and permanent cure for this condition. Treatment options help to prevent the rapid progression of this condition. Some common treatment options are:

• Adrenal Hormone Management: X-linked ALD, which affects the adrenal gland, results in adrenal insufficiency, so this testing is done to check the functioning of the adrenal gland regularly. Corticosteroid replacement therapy can help with adrenal insufficiency.

• Stem Cell Transplant Method: A stem cell transplant is the only way to slow the progression of this condition. If an early diagnosis of X-linked ALD is made, a stem cell transplant may help to stop the disease. Doctors recommend this method if MRI shows the affected region of the brain caused due to ALD.

• Medications: Some symptoms, such as seizures, muscle stiffness, and weakness, can be managed through medications.

• Therapy: In addition to medication, physical and psychological therapy can help to manage the symptoms.

• Gene therapy can be recommended where the affected gene can be replaced.

• Lorenzo's Oil:

It is a combination of oleic acid and erucic acid which help to decrease the VLCFAs blood level. When given to the child before the start of symptoms, it can reduce the progression of this condition.

Conclusion

X-linked adrenoleukodystrophy is a hereditary condition that is caused due to mutation of the ABCD1 gene. This condition affects the nervous system and the adrenal gland, caused by very long-chain fatty acids accumulating in these areas. Early diagnosis of this condition can help to reduce the progression of the condition and help to manage the symptoms, but there is no permanent cure for X-linked ALD.