Adrenoleukodystrophy (ALD)

Adrenoleukodystrophy (ALD)

Adrenoleukodystrophy (also known as X-linked adrenoleukodystrophy, ALD) is a rare, genetic disorder characterized by the breakdown or loss of myelin – the fatty covering surrounding nerve cells in the brain – and progressive dysfunction of the adrenal gland.  As an X-linked disorder, ALD presents most commonly in males and occurs in about one out of every 17,000 births. Approximately two-thirds of ALD patients will present with the childhood cerebral form of the disease, which is the most severe form. It is characterized by normal development in early childhood, followed by rapid degeneration to a vegetative state. The other forms of ALD vary in terms of onset and clinical severity, ranging from adrenal insufficiency to progressive paraparesis in early adulthood (this form of the disease is typically known as adrenomyeloneuropathy or AMN).

If you or someone you know has been diagnosed with ALD or AMN and would like information regarding treatment options, we recommend contacting the Moser Center for Leukodystrophies at the Kennedy Krieger Institute. If you live in the United States, click here (for United States residents only) or call toll-free (844) 334-3211. To contact International Care Management Coordinators, please call (888) 554-2080 or email international@kennedykrieger.org.

Diagnosis

The clinical presentation of ALD can vary greatly, making diagnosis difficult. With the variety of phenotypes, clinical suspicion of ALD can result from a variety of different presentations. Symptoms vary based on the disease phenotype, and even within families or between twins. When ALD is suspected based on clinical symptoms, the initial testing usually includes plasma very long chain fatty acid (VLCFA) determination using gas chromatography-mass spectrometry. The concentration of unsaturated VLCFA, particularly 26 carbon chains are significantly elevated in males with ALD, even prior to the development of other symptoms.Confirmation of ALD after positive plasma VLCFA determination usually involves molecular genetic analysis of ABCD1. In females, where plasma VLCFA measurement is not always conclusive (some female carriers will have normal VLCFA in plasma), molecular analysis is preferred, particularly in cases where the mutation in the family is known. Although the clinical phenotype is highly variable among affected males, the elevations of VLCFA are present in all males with an ABCD1 mutation.

Because the characteristic elevations associated with ALD are present at birth, well before any symptoms are apparent, there have been methods developed in the interests of including it in newborn screening programs.One of the difficulties with ALD as a disease included in universal newborn screening is the difficulty in predicting the eventual phenotype that an individual will express. The accepted treatment for affected boys presenting with the cerebral childhood form of the disease is a bone marrow transplant, a procedure which carries significant risks.However, because most affected males will demonstrate adrenal insufficiency, early discovery and treatment of this symptom could potentially prevent complications and allow these patients to be monitored for other treatment in the future, depending on the progression of their disease.

The Loes score is a rating of the severity of abnormalities in the brain found on MRI. It ranges from 0 to 34, based on a point system derived from the location and extent of disease and the presence of atrophy in the brain, either localized to specific points or generally throughout the brain. A Loes score of 0.5 or less is classified as normal, while a Loes score of 14 or greater is considered severe. It was developed by neuroradiologist Daniel J. Loes MD and is an important tool in assessing disease progression and the effectiveness of therapy.

If you or someone you know has been diagnosed with ALD or AMN and would like information regarding treatment options, we recommend contacting the Moser Center for Leukodystrophies at the Kennedy Krieger Institute. If you live in the United States, click here (for United States residents only) or call toll-free (844) 334-3211. To contact International Care Management Coordinators, please call (888) 554-2080 or email international@kennedykrieger.org.

Treatment

Unfortunately, treatments for ALD are pretty limited, but there are options which include Lorenzo’s Oil, bone marrow transplant, physical therapy, and steroids.

Lorenzo’s Oil
Lorenzo’s Oil has been successfully used as a therapy for boys with aLD. If started early, it can help lessen the risk of developing the childhood cerebral form of ALD. This oil, along with a low-fat diet, can help to reduce the very long chain fatty acids that accumulate. Lorenzo’s Oil is not approved by the FDA, but can be obtained under the direction of Dr. Gerald Raymond. For more information regarding how to get the oil, click here.

Bone Marrow Transplant
Bone marrow transplant is used to treat boys with early signs of ALD. Once early brain MRI changes are identified, evaluation for transplant is an option. Although this procedure is considered risky, successful transplants are possible with early intervention.  Outcomes depend on the child’s clinical status at the time of the evaluation, along with interpretation of the brain MRI. Only about roughly 30% of boys who undergo transplant will go on to develop childhood cerebral disease.  Currently, doctors typically will not perform stem cell transplantation on adults with the disease, generally because the risks of the treatment are considered to outweigh the potential benefits. But as transplantation technology improves and becomes safer, it is possible that stem cell transplantation will be available for men with AMN.

Exercise & Physical Therapy
Patients who experience walking difficulties may benefit from seeing a physical therapist, who can provide exercises to strengthen muscles and improve walking ability.

Other Treatments:

  • Adrenal dysfunction is treated with steroids (such as cortisol)
  • Eating a diet low in very-long-chain fatty acids and taking special oils can lower the blood levels of very-long-chain fatty acids, such as Lorenzo’s Oil, which may be help slow the progression of the disease.
  • To learn about home remedies for ALD, click here.

If you or someone you know has been diagnosed with ALD or AMN and would like information regarding treatment options, we recommend contacting the Moser Center for Leukodystrophies at the Kennedy Krieger Institute. If you live in the United States, click here (for United States residents only) or call toll-free (844) 334-3211. To contact International Care Management Coordinators, please call (888) 554-2080 or email international@kennedykrieger.org.

Symptoms

ALD symptoms can vary depending on age, gender, and the body tissues affected. The tissues that are most severely affected in ALD are myelin, blood, and the adrenal glands. Not all tissues are affected at the same time in all patients. In the world of genetic disorders, doctors group collections of symptoms into “phenotypes” based on the cells and tissues that are most severely affected by a gene abnormality. Individuals with the ALD gene may have different phenotypes. In ALD, the phenotypes are not mutually exclusive. In fact, it is common for individuals to have more than one phenotype at any given time.

There are 4 primary phenotypes that can occur in MALES with the ALD gene:

1. Asymptomatic phenotype:

All individuals with the ALD gene are free of clinical symptoms for at least the first three years of life. And some may continue to have no symptoms. But the percentage of asymptomatic men and women decreases with age.

2. Adrenomyeloneuropathy (AMN) phenotype symptoms:

Walking and balance problems

General leg weakness and stiffness progresses into walking difficulty and reduced balance. With the weakening of leg muscles, changes in gait, or how a person walks, becomes noticeable. The use of mobility devices, such as canes, walkers, and wheelchairs may become necessary.

  • Pain, numbness, or tingling in the legs
Mild to moderate weakness of the arms/hands
Urinary problems or incontinence and bowel urgency or incontinence
Sexual dysfunction, or the inability to obtain or maintain an erection.

3. Adrenal insufficiency (Addison’s disease) phenotype symptoms:

Adrenal insufficiency occurs as a result of permanent injury to the adrenal glands. Most men with ALD will eventually develop adrenal insufficiency over their lifespan. Women develop adrenal insufficiency much less commonly. Although it is easily treatable, adrenal insufficiency can be life-threatening if it is not recognized promptly. Symptoms are often non-specific and can include weakness/fatigue, nausea, abdominal pain, and low blood pressure. Darkening of the skin is also common.

Adrenal insufficiency is sometimes referred to as Addison’s disease (based on the doctor, Thomas Addison MD, who first described it). There are many causes of adrenal insufficiency in the general population. ALD is the cause of approximately 33% of all cases of adrenal insufficiency. This means that not all patients diagnosed with adrenal insufficiency have ALD. Nonetheless, all patients with adrenal insufficiency should be tested for ALD (and vice versa).

4. Cerebral demyelinating ALD (cerALD) symptoms:

Affected boys’ symptoms may include “spacing out” in school: inattention, deterioration in handwriting skills, and decreased school performance; difficulty in understanding speech (though sound perception is normal); difficulty in reading and understanding written material; clumsiness; visual disturbances and occasionally double-vision; and aggressive or unexplained inappropriate behavior. In some boys, seizures may be the first symptom. Symptom severity varies from patient to patient and is not determined by phenotype. Even identical twins may have different experiences with symptom onset and severity. Other symptoms may include:

  •  Behavioral problems
  • Hyperactivity
  • Eye pain/Childhood onset migraines
  • Recurring viral infections
  • Lethargy, tires easily, clumsiness
  • Hypoglycemia
  • Tanning or bronzing of the skin
  • Adrenal insufficiency
  • Attention deficit disorder (ADD)
Clinical Trials

An international clinical research study by bluebird bio, called the Starbeam Study, is now enrolling boys, aged 17 and younger, who have been diagnosed with Childhood Cerebral Adrenoleukodystrophy (CCALD). CCALD symptoms usually occur in early childhood and progress rapidly, if untreated, ultimately leading to death. The Starbeam Study will assess the effectiveness and safety of an investigational gene therapy approach, known as gene transfer. The study involves transferring a new copy of the ABCD-1 gene into the patient’s own blood stem cells. The goal of the Starbeam Study is to determine if the one-time investigational gene therapy treatment can stop the progression of CCALD and if it is safe and well-tolerated. Click here to learn more.

The following is a guide from the Kennedy Krieger Institute for diagnosing and treating ALD, answers to commonly asked questions, and resources available to families and medical professionals:

Inheritance
ALD is caused by mutations in ABCD1, a gene located on the X chromosome that codes for ALD, a peroxisomal membrane transporter protein. The ALD gene can be passed on to a child from either the mother or the father. If a father passes the gene, then all of his daughters will be carriers, but sons will not have the ALD gene. If a mother passes the gene, there is a 50% chance with each pregnancy that the child, whether a boy or girl, will have the ALD gene. Genetic counseling is strongly encouraged. The exact mechanism of the pathogenesis of the various forms of ALD is not known.

Testing Options
For males, testing is easy and can be completed in seven to ten business days. the test used to diagnose ALD, called the “very long chain fatty acid test,” is definitive for males. For females, that same test is only 80% accurate, so further DNA testing is needed for confirmation.

Prenatal testing is available, with options including chorionic villi sampling (CVS) and amniocentesis. In addition, there are in-vitro fertilization options to ensure that babies do not have the ALD gene.  A genetic counselor can discuss these options with you. for test requisitions, see www.genetics.kennedykrieger.org.

Newborns with ALD
If a child is born with the ALD gene, no immediate intervention is suggested. Babies can be breastfed or given regular formula. Monitoring for adrenal insufficiency should begin at the age of 18 months and should include yearly MRIs of the brain.

Childhood Presentation: childhood cerebral x-ALD
Onset of the childhood form of ALD, which is the most severe, affects only boys and generally develops between the ages of 4 and 8 years. Early symptoms can be similar to those of attention deficit disorder (ADD), such as difficulty paying attention, mild confusion or forgetfulness, or difficulty in school, are all potential signs that that the brain has been affected by ALD. If untreated, the symptoms may progress to inability to walk, talk, or eat, and could eventually lead to death. Children need to be monitored by brain MRIs every six to twelve months in order to identify early signs of disease progression.

Adult Presentation: Adrenomyeloneuropathy (AMN)
In the adult onset of the disease, symptoms typically are seen as early as 20 years old and then throughout adulthood. It includes spinal cord symptoms, as well as difficulty walking, muscle spasms, peripheral neuropathy (numbness or tingling in the feet and legs) and bladder or bowel symptoms. Although adult-onset ALD progresses more slowly than the classic childhood form, it can also result in deterioration of the brain function, which can be monitored by MRIs.

Women Carriers of ALD
Women carriers of ALD can experience symptoms similar to men with AMN later in life.  Symptoms vary in women, but may include walking difficulties, numbness and tingling of feet and toes, and bladder or bowel symptoms. It is rare to see cerebral disease or adrenal insufficiency in women with ALD. Symptoms management is the focus.

Addison’s Disease
At some point, most boys and men with ALD will develop Addison’s Disease (adrenal insufficiency). Although this condition can be life threatening if left untreated, it can be managed with a daily intake of steroids. If Addison’s is identified,  patients must be closely monitored by an endocrinologist.