Adrenoleukodystrophy (ALD)

Overview

Adrenoleukodystrophy (ALD) is a rare hereditary metabolic disease that affects the nervous system and adrenal glands. In this disease, the body cannot break down very long-chain fatty acids (VLCFA), and these fats accumulate in various tissues, especially the brain, spinal cord, and adrenal glands, causing damage.

"Adreno" refers to the adrenal glands, "leuko" to the brain's white matter (the sheath surrounding nerve fibers), and "dystrophy" to abnormal development.

The disease is inherited as X-linked recessive, meaning it primarily affects boys. Girls are usually carriers and may show milder symptoms. The course of ALD varies greatly from person to person. The most severe form, childhood cerebral ALD, progresses rapidly in boys aged 4-10, leading to serious neurological losses. The milder and more slowly progressive form, adrenomyeloneuropathy (AMN), appears in young adulthood.

The disease was the subject of the film "Lorenzo's Oil" (1992) and became known to wider audiences through this film. Today, early diagnosis, especially through newborn screening, is vital in preventing the devastating effects of the disease.

Symptoms

The symptoms of ALD vary according to the form of the disease, age of onset, and which organs are affected. The most common forms and symptoms of the disease are:

Childhood Cerebral ALD (Most severe form). Usually seen in previously completely healthy boys aged 4-10.

Symptoms start insidiously and progress rapidly:

Early symptoms: Sudden drop in school performance, attention deficit, hyperactivity (can often be confused with attention deficit hyperactivity disorder), withdrawal, vision and hearing problems.

In the progressive period: Walking disorder, muscle stiffness (spasticity), speech disorder (dysarthria), swallowing difficulty (dysphagia), seizures (epilepsy), vision and hearing loss. The disease progresses rapidly, leading to a vegetative state and usually death within 2-5 years.

Adrenomyeloneuropathy (AMN) (Adult form). This is the most common form and usually appears in men in their 20s-40s. In female carriers, it can be seen milder and later (age 40-50).

Symptoms progress slowly:

• Progressively increasing weakness and stiffness in the legs
• Walking difficulty (spastic paraparesis)
• Urinary incontinence and sexual dysfunction
• Sensory loss

Adrenal Gland Insufficiency (Addison's Disease). Seen in approximately 80% of males with ALD and can sometimes appear before neurological symptoms.

Symptoms include:

• Extreme fatigue and weakness
• Loss of appetite, nausea, weight loss
• Low blood pressure
• Darkening of skin (hyperpigmentation), especially noticeable on elbows, knees, gums, and skin folds

Any of these forms can be seen even in different individuals in the same family.

When to See a Doctor

You should consult a pediatric neurology or metabolism specialist in the following situations:

• If you notice unexplained decline in school performance, behavioral changes, or walking problems in your child
• If your child, especially a boy, has any of the neurological symptoms described above
• If there is unexplained fatigue, weight loss, low blood pressure, or skin darkening
• If there is an individual diagnosed with ALD in the family, for screening of other children
• If female carriers develop weakness in their legs or walking problems, especially after age 30

Causes and Risk Factors

ALD is a genetic disease and the exact cause is a mutation in the ABCD1 gene located on the X chromosome.

Genetic cause (ABCD1 gene mutation). This gene provides instructions to the body to break down very long-chain fatty acids (VLCFA). When the gene is mutated, cellular structures called peroxisomes cannot break down these fatty acids. As a result, VLCFA accumulates especially in the brain (myelin sheath), spinal cord, and adrenal glands, leading to cell damage. Myelin is a protective sheath surrounding nerve fibers; when damaged, nerve signals cannot be transmitted properly.

Inheritance pattern (X-linked recessive). The disease is carried on the X chromosome:

Boys (XY): Receive their single X chromosome from their mothers. If there is a mutation on this X chromosome, the disease appears because there is no backup healthy gene.

Girls (XX): Have two X chromosomes. Even if one is mutated, the other healthy X chromosome usually prevents the severe form of the disease. These girls become "carriers" and may show mild AMN symptoms in later years (especially after 40).

Inheritance probabilities. For a carrier mother:

• Each male child has a 50% risk of being affected.
• Each female child has a 50% risk of being a carrier.

In a small portion of patients, there is no family history of the disease; this is due to a new (de novo) mutation that occurred during pregnancy.

Incidence. ALD is seen in approximately one in every 17,000-20,000 male births and affects all ethnic groups equally.

Complications

If left untreated, ALD leads to serious and life-threatening complications.

• Rapid neurological destruction (Cerebral ALD). This is the most feared complication. Inflammation in the brain and demyelination (myelin loss) progress rapidly, causing a once-healthy child to lose vision, hearing, and walking ability within a few years, become bedridden, and ultimately die.
• Adrenal crisis (Adrenal insufficiency crisis). The adrenal glands produce the hormone cortisol, which enables the body to respond to stress (infection, accident, surgery). Due to damage to these glands in ALD, sufficient cortisol cannot be produced. During stress (for example, a febrile illness), the body cannot respond and an "adrenal crisis" can develop, which can result in sudden drop in blood pressure, shock, coma, and death.
• Loss of mobility (In AMN). In the AMN form, progressive weakness and stiffness develop in the legs due to damage to nerves in the spinal cord. Over time, patients may lose the ability to walk and become wheelchair-dependent. Loss of urinary and bowel control (incontinence) may also develop.
• Serious decline in quality of life. Every form of the disease profoundly affects the quality of life of the patient and family. Physical dependency, psychological burden, need for continuous medical follow-up, and financial difficulties arise.

Diagnosis

Early diagnosis of ALD is vital, especially for treatment options to be successful.

• Very long-chain fatty acids (VLCFA) test in blood. This is the first and most important step in diagnosis. High levels of VLCFA in the blood (especially C26:0) are a strong indicator for ALD. This test is positive in almost all patients.
• Genetic test. Done to detect the mutation in the ABCD1 gene. Confirms the diagnosis definitively and is necessary for family screening.
• Magnetic Resonance Imaging (MRI). Used to show white matter damage (demyelination) in the brain. Especially in childhood cerebral ALD, symmetric involvement is seen in characteristic regions (usually posterior regions). MRI findings are evaluated with the "Loes score" used to grade disease severity.
• Adrenal gland function tests. Blood levels of cortisol and ACTH are checked to investigate whether there is adrenal gland insufficiency.
• Newborn screening. In some countries (for example, in many states in the USA), ALD is included in the newborn screening program. With a test done from heel blood, the disease can be detected before symptoms appear, giving a chance for early treatment.

Treatment

While there is no definitive cure for ALD, treatments exist that can stop or slow disease progression and manage symptoms. Treatment is planned according to the form and stage of the disease.

Hematopoietic Stem Cell Transplantation (HSCT) / Bone Marrow Transplantation. Currently the only effective treatment method that can stop disease progression in childhood cerebral ALD. However, it must be done very early, before symptoms worsen and while damage on MRI is limited (when Loes score is low). The transplant allows stem cells taken from a healthy donor to produce the missing enzyme in the patient's body and stop damage in the brain. If done in an advanced stage, it does not help and may even be harmful.

Gene Therapy. A promising treatment method still in the experimental phase. The patient's own stem cells are taken, a healthy ABCD1 gene is added in the laboratory environment, and returned to the patient. Successful results have been obtained in clinical trials in some countries.

Lorenzo's Oil. An oil composed of a mixture of oleic acid and erucic acid. It lowers blood levels by suppressing VLCFA production in the body. However, it is not effective after brain damage has started. It can only be used in boys who have not yet shown symptoms and have normal MRI to delay or prevent disease onset.

Adrenal Gland Insufficiency Treatment. Quite simple and effective. The missing cortisol hormone is replaced with orally taken steroid medications (for example, hydrocortisone). Increasing the dose in stressful situations (febrile illness, tooth extraction, accident) is vital.

Diet Therapy. Although not sufficient on its own, it is an adjunct treatment. The aim is to reduce very long-chain fatty acids (VLCFA) taken through diet.

Therefore:

• Foods such as fatty meats (offal, salami, sausage), fatty fish (salmon, sardines), full-fat dairy products, avocado, olives, oily seeds (walnuts, hazelnuts), and chocolate are restricted.
• Specially formulated glycerol trioleate (GTO) oil is used for cooking.
• The diet must be applied under the control of a dietitian.

Supportive Treatments. To improve quality of life in advanced stages of the disease:

• Physiotherapy: To reduce muscle stiffness and preserve mobility

Living with ALD

ALD is a challenging disease that affects not only the patient but the entire family. However, it can be managed with correct information, a multidisciplinary medical team, and a strong support system.

• Regular follow-up is essential. Every individual diagnosed with ALD should be regularly monitored by a pediatric neurology or metabolism specialist. Follow-up should include neurological examination and MRI every 6 months, and adrenal gland function tests at least once a year.
• Do not neglect medications. Steroid medications used for adrenal gland insufficiency are vital. They should never be stopped or the dose changed without consulting a doctor. In situations such as fever, vomiting, or diarrhea, definitely apply the "stress dose" recommended by your doctor. Patient relatives should be trained on steroid injection to be given in emergencies.
• Have family screening done. Carrier testing is recommended for all first-degree female relatives (mother, sisters) of a diagnosed individual, and VLCFA testing for male siblings. This way, other individuals who have not yet shown symptoms can be detected and preventive measures can be taken.
• Pay attention to nutrition. Stick to the low VLCFA nutrition program prepared by a dietitian. If Lorenzo's oil is being used, it should be taken in the recommended dose and regularly.
• Get support. Remember you are not alone in fighting ALD. Patient associations (for example, ALD Alliance), social media groups, and psychological counseling services are very valuable for information sharing and moral support.
• Carry an emergency ID card. Having the patient carry a card or medical alert bracelet that says "Adrenal Insufficiency (Requires Steroid Treatment in Emergency)" can be life-saving.

Preparing for Your Appointment

Preparing before a doctor's appointment ensures the process goes efficiently.

What you can do:

• Note your symptoms: Write down the slightest changes you notice in your child (behavior, walking, school performance), when they started, and how they progressed.
• Create your family tree: Note individuals in the family who had similar problems, died unexplained at an early age, or had neurological disease.
• List medications used: Including vitamins and supplements.
• Write your questions: Prepare a list in advance so you don't forget.
• Bring previous tests and imaging if available.

Questions you can ask your doctor:

• What is the likelihood my child has ALD? Which tests should be done?
• If ALD diagnosis is confirmed, which type? What is the prognosis?
• What treatment options are available? Is my child a suitable candidate for stem cell transplantation?
• Is there adrenal gland insufficiency? Do we need to use medication?
• How often should we come for checkups? Which tests will be done?
• Do my other children need to be tested?
• What should we pay attention to in daily life? How should nutrition be?
• What should we do when they have fever or get sick?
• Can you recommend patient associations or support groups?

Your doctor may ask you:

• Was your child's development normal? How is school performance?
• Have you noticed behavioral changes or attention deficit recently?
• Is there deterioration in walking or balance?
• Are there seizure-like movements?
• Does your child tire easily, is there loss of appetite?
• Have you noticed darkening of skin (especially at joint areas)?
• Is there a family history of similar disease or unexplained early death?