Adrenoleukodystrophy

Adrenoleukodystrophy is a rare genetic condition that causes serious damage to the nervous system and hormone-producing glands. This inherited disorder affects mainly males and can cause rapid loss of abilities in childhood, though some forms develop more slowly in adulthood.

Table of contents

• What is adrenoleukodystrophy?
• Causes and inheritance
• Types of adrenoleukodystrophy
• Symptoms and signs
• Diagnosis
• Treatment options
• Affected body systems

What is adrenoleukodystrophy?

Adrenoleukodystrophy, often shortened to ALD, is a rare genetic condition that damages important parts of the body. It affects the myelin sheath, which is the protective covering around nerve cells in the brain, similar to insulation around electrical wires^[1]. When this protective layer is damaged, nerve cells cannot properly send signals between the brain and body^[4].

The disease also affects the adrenal glands, which are small organs that sit on top of the kidneys and produce important hormones^[1]. ALD is one of a group of disorders called leukodystrophies, which are conditions that affect the white matter of the brain^[4].

ALD affects approximately 1 in 15,000 to 1 in 21,000 people worldwide^[2][4]. The condition occurs more frequently and more severely in males than in females^[1].

X-linked adrenoleukodystrophy, X-ALD, Siemerling-Creutzfeldt disease, bronze Schilder disease

Causes and inheritance

ALD is caused by changes, called mutations, in a gene known as ABCD1^[2]. This gene provides instructions for making a protein that helps break down very long-chain fatty acids, or VLCFAs, which are a type of fat molecule^[2]. When the ABCD1 gene doesn’t work properly, these fatty acids cannot be broken down and instead build up in the brain, nervous system, and adrenal glands^[1][2].

The condition is inherited in an X-linked pattern, which means the faulty gene is located on the X chromosome^[1]. Because males have only one X chromosome, they are more severely affected by the condition. Females have two X chromosomes, and the healthy copy can often compensate for the faulty one, making their symptoms milder or delayed^[7].

A boy with ALD usually inherits the faulty X chromosome from his mother. Mothers who carry the gene mutation may not have symptoms themselves or may develop mild symptoms later in life^[7]. Approximately 80% of women who carry the gene mutation will develop some symptoms as they age^[6].

Types of adrenoleukodystrophy

ALD can present in several different forms, each affecting people at different ages and with different levels of severity. The most common types include^[1][2]:

Childhood cerebral ALD, also called CALD or cerebral adrenoleukodystrophy, is the most severe form of the disease. It usually begins between ages 4 and 10, though it can start as early as age 3^[2][4]. In this form, the white matter of the brain is progressively damaged. Boys with this type develop normally in early childhood but then begin to lose skills they had previously learned^[4]. About 35 to 40 percent of boys with the ABCD1 mutation will develop this form^[2]. Without treatment, childhood cerebral ALD can lead to severe disability and death within four to eight years^[2].

Adrenomyeloneuropathy, or AMN, is a milder form that typically begins in adulthood, usually between ages 21 and 35^[1][4]. This form affects the spinal cord and nerves rather than primarily the brain. People with AMN experience slowly worsening symptoms such as stiff legs, difficulty walking, and problems with bladder and bowel control^[1][5]. Women who carry the gene mutation may develop a mild form of AMN, and approximately half may develop neurological symptoms in adulthood^[2].

Addison’s disease, or adrenal insufficiency, occurs when the adrenal glands fail to produce enough hormones^[1]. Many people with ALD develop this condition, which can occur along with other forms of the disease or sometimes on its own^[2][4].

Asymptomatic ALD refers to people who have the ABCD1 gene mutation but have not yet developed any symptoms^[2].

A person can have more than one type of ALD at the same time^[2]. Adult males with AMN can also develop brain involvement similar to childhood cerebral ALD, and about 1 in 5 affected adult males develop these cognitive problems^[4].

Symptoms and signs

The symptoms of ALD vary depending on the type and when it begins. Boys with childhood cerebral ALD usually start showing symptoms between ages 4 and 10^[2]. The earliest signs often include behavioral changes and problems at school^[5].

Common early symptoms in childhood cerebral ALD include^[2][5]:

• Behavioral problems, such as withdrawal or aggression
• Difficulty paying attention in school
• Poor memory
• Poor school performance
• Difficulty reading, writing, and understanding speech
• Emotional instability and hyperactivity

As the condition progresses, more severe symptoms develop, including^[2][5]:

• Vision loss or blindness
• Hearing loss or deafness
• Seizures
• Difficulty swallowing
• Problems with walking and coordination
• Progressive loss of ability to speak clearly
• Worsening thinking abilities and memory

People with adult-onset ALD or adrenomyeloneuropathy typically experience different symptoms that develop more slowly^[4][5]:

• Stiffness in the legs
• Weakness or difficulty moving the lower limbs
• Problems with balance and walking
• Bladder and bowel problems
• Pain in the hands and feet
• Difficulty with coordination

Symptoms of adrenal insufficiency, or Addison’s disease, can occur with any form of ALD and include^[4]:

• Decreased appetite
• Muscle weakness
• Fatigue
• Weight loss
• Increased skin pigmentation
• Vomiting

Diagnosis

To diagnose ALD, doctors review symptoms, medical history, and family history, and conduct a physical examination^[8]. Several tests are used to confirm the diagnosis.

Blood tests are the primary method for diagnosing ALD. These tests check for high levels of very long-chain fatty acids in the blood, which are a key indicator of the condition^[8]. Doctors also use blood samples for genetic testing to identify changes or mutations in the ABCD1 gene that cause ALD^[8]. Blood tests can also evaluate how well the adrenal glands are working^[8].

Magnetic resonance imaging, or MRI, uses powerful magnets and radio waves to create detailed pictures of the brain^[8]. This allows doctors to detect abnormalities in the brain that indicate ALD, including damage to the nerve tissue, also called white matter^[8]. Doctors may use several types of MRI to view the most detailed images and detect early signs of the disease^[8].

Additional tests may include vision screening to measure visual responses and monitor disease progression, particularly in males who have no other symptoms^[8]. In some cases, a small skin sample may be taken to check for increased levels of VLCFAs^[8].

Many states in the United States now include ALD in routine newborn screening programs, which allows the disease to be identified and monitored early, before symptoms develop^[2][9]. Early detection through newborn screening has been revolutionary for managing ALD because it enables close monitoring and timely treatment if cerebral disease develops^[3].

Treatment options

ALD has no cure, but several treatment options can help manage symptoms and slow disease progression^[8]. The choice of treatment depends on the type and stage of ALD.

Stem cell transplantation, also called hematopoietic stem cell transplant or bone marrow transplant, is currently the only treatment that can stop the progression of childhood cerebral ALD^[8][12]. This treatment works best when performed early in the disease, after brain changes are visible on MRI but before severe symptoms develop^[11][12]. The procedure involves replacing the patient’s defective stem cells with healthy ones from a donor^[11].

Stem cell transplantation has significant risks, including transplant-related death in 8% to 12% of patients, graft failure in 5% to 18% of cases, and graft-versus-host disease in 18% to 39% of patients^[12]. The procedure requires intensive chemotherapy or radiation to prepare the body, leaving patients vulnerable to infections^[11]. Despite these risks, early transplantation has shown better survival outcomes, with 91% of patients with early disease remaining free of major disabilities at two years, compared to only 20% of those with advanced disease^[12].

Gene therapy is a newer treatment option for cerebral ALD that involves modifying the patient’s own stem cells to produce the missing protein^[2]. This approach can halt the decline in brain function if given early enough^[2]. Gene therapy may offer advantages over traditional stem cell transplant because it uses the patient’s own cells, potentially reducing some risks^[2].

Lorenzo’s Oil is a mixture of two fats extracted from olive oil and rapeseed oil that works to reduce the levels of very long-chain fatty acids in the body^[11]. Studies indicate that Lorenzo’s Oil may be effective in preventing symptoms in boys who have the disease but have not yet developed symptoms^[5][11]. However, it does not help boys who already have symptoms of cerebral ALD^[5].

Treatment of adrenal insufficiency is essential for all ALD patients with Addison’s disease. Treatment with adrenal hormones can be lifesaving and must be tested and monitored periodically in all patients^[5][8].

Supportive treatments play an important role in managing ALD. These include physical therapy for mobility issues, psychological support for behavioral and emotional challenges, special education services, and speech therapy to address communication difficulties^[5]. Some patients may benefit from palliative care, which provides supportive care to improve quality of life^[16].

Currently, stem cell transplantation is generally not performed on adults with adrenomyeloneuropathy because the risks are considered to outweigh the potential benefits, though this may change as transplantation technology improves^[11].

Affected body systems

• Brain (white matter)
• Spinal cord
• Nervous system
• Adrenal glands