ALD (Adrenoleukodystrophy)

What is ALD?

Adrenoleukodystrophy (ALD) is one of a group of genetic disorders called leukodystrophies. ALD affects the nervous system and the adrenal glands.

ALD is a progressive disease. Treatments aim to slow the progression and improve people’s quality of life.

What is a genetic disorder?

A genetic disorder results from a mutation (change) in part of your DNA. DNA contains genetic building blocks — the instructions for how your body works.

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 buildup 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.

How is ALD inherited?

ALD is a genetic condition. People can inherit ALD from one or both parents. It’s sometimes called X-linked ALD because it results from a problem with the X chromosome.

How common is ALD?

ALD is a rare disease, affecting around 1 in 15,000 people worldwide. It affects more males than females.

What causes ALD?

The cause of ALD is a mutation in a particular gene. Your genes are the instruction manual for creating proteins that have critical roles in how the body works. With a genetic mutation, the gene may create faulty protein.

With ALD, there’s a problem with the ABCD1 gene, which creates the ALDP protein. This protein helps break down VLCFAs. Because of the faulty protein, VLCFAs accumulate in the body’s tissues.

What are the forms of ALD?

The most common forms of ALD are:

• Childhood cerebral ALD: Boys with this form of ALD usually start showing neurological symptoms between ages 3 and 10. As infants, these children develop typically. Then they begin to regress, losing skills. Children often display behavioral problems, such as having difficulty paying attention in school. They may also have seizures. Children with this type typically pass away within a few years of developing symptoms.
• ALD plus Addison’s disease: Along with neurological symptoms, ALD may cause adrenal insufficiency, or Addison’s disease. This condition means your adrenal glands don’t make enough of the hormone cortisol. Symptoms include decreased appetite and muscle weakness.
• Adrenomyeloneuropathy (AMN) or adult-onset ALD: This milder form of ALD begins between ages 21 and 35. People with AMN have both adrenal and neurological problems. Adult-onset ALD progresses more slowly than childhood cerebral ALD, but adults can also have deteriorating brain function. Other symptoms include leg stiffness and pain in the hands and feet.

Less-common types of ALD include:

• Adrenal insufficiency-only ALD: Some people have only Addison’s disease, without any neurological problems. About 1 in 10 people with ALD have this type.
• Adult cerebral ALD: About 1 in 5 affected adult males develop cognitive problems similar to childhood cerebral ALD. Over time, they lose most of their mental and neurological function. Many adults with this type eventually pass away from the disease.
• Females with ALD: By age 40, about 1 in 5 women who are ALD carriers have symptoms, but 90% have symptoms by age 60. Symptoms generally less severe, such as mild weakness and stiffness in their legs.

When do symptoms of ALD appear?

ALD symptoms often appear between the ages of 3 and 10, though they can start later in life. The childhood form of ALD is the most severe.

What are the common symptoms of ALD?

Each type has its own symptoms. People often have both neurological and hormonal symptoms.

Childhood cerebral ALD symptoms:

Early symptoms include:

• Behavioral problems, such as attention deficit hyperactivity disorder (ADHD) and learning disabilities.
• Cognitive deficits, or problems with thinking and processing new information. Children may “space out” at school. They may have trouble with reading, handwriting and solving spatial problems.
• Regression, when children lose skills.

As the disease progresses, symptoms include:

• Vision problems.
• Hearing loss
• Trouble walking.
• Weak and stiff limbs.
• Convulsions and seizures.
• Dementia.
• Trouble eating.
• Vomiting.

Eventually, children lose most of their neurological abilities. They lose sight, hearing and voluntary movements. As the disease progresses, children end up in a vegetative state. They often pass away within two to three years of the neurological symptoms’ starting.

Addison’s disease symptoms:

Symptoms of adrenal insufficiency include:

• Fatigue.
• Weight loss.
• Nausea and vomiting.
• Digestive problems.
• Feeling weak.
• Headaches in the morning.
• Hypotension.
• Hypoglycemia.
• Hyperpigmented skin, when the skin darkens unrelated to sun exposure.

Adrenomyeloneuropathy symptoms:

Symptoms include:

• Spasticity (muscle stiffness), weakness or paralysis of the lower limbs.
• Ataxia, neurological conditions affecting movement.
• Numbness and pain.
• Erectile dysfunction.
• Bowel incontinence.
• Bladder control problems.
• Premature baldness.

Why does ALD affect males and females differently?

ALD is an X-linked genetic disorder. It results from a mutated gene on the X chromosome.

Females, who have two X chromosomes, can be carriers of the disorder. One of the X chromosomes is “shut off.” That means the genes on that chromosome aren’t active.

Females usually don’t have symptoms because the “shut-off” X chromosome carries the mutated gene. Females who have symptoms usually get a milder form that develops during adulthood.

Males have only one X chromosome. The mutated X chromosome can cause more severe ALD because males lack the protective effect of the extra X chromosome.

When is ALD diagnosed?

Some infants are diagnosed at birth during newborn screening. Newborn screening tests babies for certain diseases. About a dozen states screen for ALD during newborn screening in the hospital. More often, parents or providers notice symptoms in a child’s early years.

People with the adult form may receive a diagnosis after seeing their provider about symptoms.

Who should get tested for ALD?

Parents and providers should consider a possible ALD diagnosis when a:

· Boy with ADD or ADHD also has signs of a neurological disorder.

· Young male has walking or movement problems that are getting worse.

· Male of any age has Addison’s disease, even without other symptoms or problems.

· Female adult has worsening muscle weakness.

How is ALD diagnosed?

Healthcare providers evaluate your child’s medical and family history. If the provider suspects ALD, your child may have:

• Blood test to measure levels of VLCFA.
• Genetic test to look for gene changes linked to ALD or other conditions.
• Adrenocorticotropic hormone (ACTH) stimulation test to check adrenal gland function.
• MRI to see how ALD has affected the brain.

If the genetic test confirms ALD, your provider may recommend other family members receive genetic testing.

What are treatment options for ALD?

ALD has no cure at this time. Treatment focuses on slowing the disease’s progression and improving symptoms.

Treatment options depend on the type of ALD and symptoms. Treatments include:

• Adrenal hormone treatment: People with ALD need regular adrenal function testing. Corticosteroid replacement therapy can help treat adrenal insufficiency.
• Stem cell transplant: Transplant is the only treatment that can slow the progression of ALD in children. If doctors diagnose ALD early enough, a transplant may stop the disease. Providers may recommend a stem cell transplant when an MRI shows evidence that ALD affects the brain, but the child does not show obvious symptoms during a neurological exam.
• Medications: Providers can prescribe medications to help with symptoms such as seizures or muscle stiffness.

Other supportive treatments include:

• Physical therapy.
• Psychological support.
• Special education.

Investigational therapies include:

• Gene therapy can replace the defective gene with a typically functioning gene.
• Lorenzo’s oil, a mixture of oleic acid and erucic acid, may lower blood levels of VLCFA. The therapy may delay or slow symptoms when given to children before they have symptoms.

Can ALD be prevented?

There is no known way to prevent ALD. If a family member has ALD, follow your provider’s recommendation for genetic testing and counseling.

What’s the outlook for children with ALD?

The prognosis for people with ALD depends on the type. Children with childhood cerebral X-ALD generally have a poor prognosis. Unless they receive a stem cell transplant early in the disease, their neurological function deteriorates. In many cases, children pass away within a few years after symptoms begin.

For people with adult-onset AMN, the disease can progress over many decades.

How can I care for my child with ALD?

Early intervention may offer the best chance for successful treatment. If you notice signs in your child, including behavioral or cognitive changes, talk to your healthcare provider. Also talk to your provider if your child seems to lose abilities they once had.

Your child’s care team should include:

• Pediatrician.
• Pediatric and adult neurologist (specialist in the brain and nervous system).
• Urologist (specialist in the urinary system).
• Endocrinologist (specialist in the endocrine system).
• Psychiatrist.
• Physical therapist.
• Genetic counselor.
• Other specialists as needed.

What should I ask my healthcare provider about ALD?

If your child receives a diagnosis of ALD, ask your provider:

• Can my child receive a stem cell transplant?
• Does my child need steroid treatment?
• What’s the outlook for my child?
• How else can we improve my child’s symptoms?
• Should family members get genetic testing?
• Are there clinical trials my child can join?

A note from Cleveland Clinic

ALD is a genetic disorder that affects the nervous system and adrenal glands. Symptoms often start in early childhood, when children lose skills they previously had. If your child shows behavioral changes or regresses in other areas, talk to your healthcare provider. The earlier treatment for ALD starts, the better the chances of slowing the disease. Several ALD treatments are available, including stem cell transplant, medications and supportive therapies. Your care team will talk to you about your child’s specific condition and outlook.