Adrenoleukodystrophy – Overview and Diagnosis

Overview

Adrenoleukodystrophy (ALD) is a genetic condition that damages the membrane (myelin sheath) that covers nerve cells in the brain and spinal cord. Myelin acts as insulation around the nerve fibers. When this insolating layer is damaged, nerve signals from the brain cannot communicate across the body properly, causing impaired bodily functions or paralysis.

ALD prevents the body from breaking down very long chain fatty acids (VLCFAs), causing these fatty acid chains to build up in the brain, nervous system and adrenal gland. The accumulation is thought to cause inflammation in the body, damaging the myelin sheath.

What are the Different Types?

ALD can come in several different forms. Symptoms will vary with each one, but often become worse over time.

Cerebral demyelinating ALD: 45% of people with ALD has this type. It’s the most severe form of ALD. Symptoms often start between ages four and eight and include:

• Attention deficit disorder (ADD)
• Problems with vision, hearing, and motor function
• Behavior problems
• Hyperactivity
• Getting tired easily
• Clumsiness
• Low blood sugar
• Eye pain
• Migraines
• Viral infections that keep coming back
• Skin that looks tanned or bronzed

Adrenomyeloneuropathy (AMN): This adult form of ALD tends to have milder symptoms. About half of those who have it don’t show signs until they’re in their 20s or 30s. Still, like ALD, AMN can cause a severe loss of brain function. Some early signs are:

• Trouble walking
• Balance problems
• Changes in gait (how you walk)
• Numbness or tingling in the legs
• Arm weakness
• Feeling an urgent need to pee or poop
• Incontinence
• Not being able to get or keep an erection

Addison’s disease: Over time, ALD causes severe damage to the adrenal glands. This can’t be reversed. The symptoms include:

• Weakness
• Fatigue
• Nausea
• Low blood pressure
• Darkened skin
• Stomach pain

Female ALD: Women who inherit the mutated gene that causes ALD often don’t have the brain disease, but may show mild symptoms. Most of the time, these start after the age of 35. They can include:

• Weakness
• Numbness
• Joint pain
• Urinary problems

Is it inherited?

ALD is an X-linked recessive disorder, which means that only boys are affected and the mother may be a carrier of the disease. Human beings have about 30,000 to 40,000 different genes, each of which has a function in making an individual person. The genes are arranged in pairs (one of the pair from each parent) on 23 chromosomes, so inevitably, some of these genes are faulty.

The chromosome that determines the gender of the child will either contain XX (female) or XY (male). The faulty gene in ALD is on the X chromosome. As females have two X chromosomes, the fault can be completely or partially overcome by the other healthy X in the pair but in males, who only have one X, there is not another X to provide a functioning gene.

Unless there have been other affected boys in the family there may be no way of knowing who is a carrier, as most carriers remain healthy. A proportion of female carriers may develop much milder neurological symptoms in adulthood.

Each pregnancy carries a:

• 25 per cent chance of the child being an unaffected non-carrier girl
• 25 per cent chance of the child being an unaffected carrier girl
• 25 per cent chance of the child being an unaffected boy
• 25 per cent chance of the child being an affected boy

How does ALD affect the body?

People with ALD can’t break down high levels of fat molecules — specifically very-long-chain fatty acids (VLCFAs). As a result, VLCFAs build up in the brain, nervous system and adrenal cortex, the largest part of the adrenal gland.

Scientists aren’t exactly sure how the VLCFA build-up affects the body. But research suggests the accumulation causes inflammation that damages the myelin sheath. Myelin is the protective layer around nerve cells in the brain.

When myelin is damaged, nerve cells cannot send signals from the brain to the body. This causes problems with the body’s functions, including how you move and think.

People with ALD have shortages of some hormones because ALD also damages the adrenal glands. The adrenal glands sit on top of each kidney. They make hormones that affect male and female sex characteristics and your stress response.

Causes and risk factors

The adrenoleukodystrophy protein (ALDP) helps your body break down very long chain fatty acids (VLCFAs). If the protein doesn’t do its job, the fatty acids build up inside your body. This can harm the outer layer of cells in your:

• Spinal cord
• Brain
• Adrenal glands
• Testes

People with ALD have mutations in the gene that makes ALDP. Their bodies don’t make enough ALDP.

Men are typically affected by ALD at an earlier age than women and usually have more severe symptoms. ALD affects males more than females because it is inherited in an X-linked pattern. This means that the responsible gene mutation is on the X chromosome. Men only have one X chromosome, while women have two. Because women have two X chromosomes, they can have one normal gene and one copy with the gene mutation.

Women who have only one copy of the mutation have much milder symptoms than men. In some cases, women who carry the gene don’t have symptoms at all. Their normal copy of the gene makes enough ALDP to help mask their symptoms. Most women with ALD have adrenomyelopathy. Addison’s disease and childhood cerebral ALD are less common.

Symptoms of Adrenoleukodystrophy

Symptoms of childhood cerebral ALD include:

• Muscle spasms
• Seizures
• Trouble swallowing
• Loss of hearing
• Trouble with language comprehension
• Impaired vision
• Hyperactivity
• Paralysis
• Coma
• Deterioration of fine motor control
• Crossed eyes

Signs of adrenomyelopathy include:

• Poor control of urination
• Weak muscles
• Stiffness in the legs
• Difficulty thinking and remembering visual perceptions

Signs of adrenal insufficiency or Addison’s disease include:

• Poor appetite
• Weight loss
• Decreased muscle mass
• Vomiting
• Weak muscles
• Coma
• Darker areas of skin colour or pigmentation

Possible Complications of Adrenoleukodystrophy

These complications can occur:

• Adrenal crisis
• Vegetative state

Diagnosis of Adrenoleukodystrophy

To diagnose ALD, your doctor will review your symptoms and your medical and family history. Your doctor will conduct a physical examination and order several tests, including:

• Blood testing. These tests check for high levels of very long-chain fatty acids (VLCFAs) in your blood, which are a key indicator of adrenoleukodystrophy.

• Doctors use blood samples for genetic testing to identify defects or mutations that cause ALD. Doctors also use blood tests to evaluate how well your adrenal glands work.
• Powerful magnets and radio waves create detailed images of your brain in an MRI scan. This allows doctors to detect abnormalities in your brain that could indicate adrenoleukodystrophy, including damage to the nerve tissue (white matter) of your brain. Doctors may use several types of MRI to view the most-detailed images of your brain and detect early signs of leukodystrophy.
• Vision screening. Measuring visual responses can monitor disease progression in males who have no other symptoms.
• Skin biopsy and fibroblast cell culture. A small sample of skin may be taken to check for increased levels of VLCFA in some cases.

How is Adrenoleukodystrophy (ALD) Treated?

The list of treatments for ALD is short:

Bone marrow transplant: Boys with early signs of ALD can benefit from this procedure. Healthy red blood cells from a donor can help prevent further myelin damage. The process can take months and recovery is long, but children who get a transplant early enough can have normal or near-normal lives.

Gene therapy: This new treatment takes out damaged stem cells, repairs the “faulty” gene that causes ALD, then puts a healthy version back in. It carries fewer risks than a bone marrow transplant, but more research needs to be done before it’s widely used.

Steroids: A daily pill can help manage Addison’s disease.

Physical therapy: If walking is a problem, a physical therapist can provide exercises to help strengthen your muscles and make it less painful.

Lorenzo’s oil: This mix of rapeseed and olive oils stops the body from making certain fatty acids that cause myelin to break down. Although it may slow the onset of ALD in boys, Lorenzo’s oil isn’t yet approved by the Food and Drug Administration. It’s also unclear whether it helps men with AMN.

Prevention of Adrenoleukodystrophy

Genetic counseling is recommended for couples with a family history of X-linked adrenoleukodystrophy. Mothers of affected sons have an 85% chance of being a carrier for this condition.

Prenatal diagnosis of X-linked adrenoleukodystrophy is also available. It is done by testing cells from chorionic villus sampling or amniocentesis. These tests look for either a known genetic change in the family or for very long chain fatty acid levels.