ALD and Other Leukodystrophies
What is ALD?
Adrenoleukodystrophy (ALD) is an X-linked inborn error of metabolism involving a mutation of the ABCD1 gene that impairs the body’s ability to metabolize long-chain fatty acids. It is thought to affect roughly 1 in 17,000 people. These long-chain fatty acids build up in the adrenal glands, the long fibers of the spinal cord, and the brain.
ALD does not discriminate based on race, ethnicity, or geography and occurs worldwide. It is characterized as a brain disorder that destroys myelin, the protective barrier that surrounds the neurons in the brain. These neurons allow the body to think and control muscle movement. Without this protective sheath, the neurons lose the ability to conduct an impulse, resulting in the inability of the boys to perform their major, life-sustaining functions.
ALD Phenotypes
Childhood Cerebral ALD (CCALD)
The most severe and devastating form of ALD appears in childhood and most commonly occurs between the ages of 4 and 10. Some cases have been as early as two years old, and some have developed in adolescence, but these are not as common. It is thought that as many as 35-45 percent of boys will develop cerebral disease. CCALD destroys the brain, and boys lose the ability to see, hear, walk, eat, communicate, and control muscles until they deteriorate to a vegetative state, leading to death or suffering permanent, painful disability, usually within 2 to 5 years after diagnosis.
The only known treatments for CCALD are hematopoietic stem cell transplantation or gene therapy. Both of these treatments can only be initiated if the disease is identified within a very narrow time frame. Boys who are identified to late in disease progression do not qualify for treatment as it can exacerbate the condition, rather than halt progression.
Addison’s Disease
Most boys and men with ALD have Addison’s Disease. The adrenal glands are responsible for producing hormones that control the body’s sugar, sodium, and potassium levels. Approximately 10% of cases of ALD present as Addison’s being the only clinical manifestation of the disorder. In Addison’s disease, the body loses its ability to produce cortisone (the stress “fight or flight” hormone). This inhibits the body’s ability to respond to stress, and this condition can be fatal if left untreated. In fact, an “Addisonian Crisis” is one of the major ways boys and men who did not have the benefit of newborn screening are identified. ALD should always be considered in cases of unexplained adrenal insufficiency in boys and men. Fortunately, Addison’s Disease is easily treated by taking daily steroids and frequent blood monitoring. Some boys and men will also require aldosterone replacement as well.
Adrenomyeloneuropathy
ALD often does not present with any symptoms until adulthood. Beginning in their 20’s and 30s, men start to exhibit neurological symptoms, including gait problems, bowel/bladder/sexual dysfunction, and, in some instances, cerebral involvement.
Men who are affected can range from mild impairment to severe disability. The progression of the disease is slower. There is currently no effective treatment for the adult-onset form of ALD, but several promising clinical trials are currently underway.
It is critical for men with AMN to receive care from both a neurologist and endocrinologist as well as having annual MRIs to detect any changes signifying the onset of cerebral involvement.
ALD in Females
Females were initially thought to be the only carriers of ALD. This has been proven to be untrue, and women have been found to develop symptoms of the disorder older in life, such as progressive stiffness, generalized weakness, gait problems, paralysis of the lower limbs, pain in the joints, and urinary problems. Newborn screening would allow the ability for these women to effectively engage in family planning and, should they become symptomatic, to have an understanding of the cause of their symptoms so that they can seek out qualified treatment.
For information regarding X-Linked disease please visit Remember the Girls: Home To Females Impacted By X-Linked Conditions – Remember The Girls
Other Leukodystrophies
There are other leukodystrophies that have treatment options available that should also be added to the newborn screen panel. Efforts are underway to add these conditions to the Recommended Universal Screening Panel (RUSP) in the US.
Metachromatic Leukodystrophy
Metachromatic leukodystrophy is a rare hereditary (genetic) disorder that causes fatty substances (lipids) to build up in cells, particularly in the brain, spinal cord, and peripheral nerves. This buildup is caused by an enzyme deficiency that helps break down lipids called sulfatides. The brain and nervous system progressively lose function because the substance that covers and protects the nerve cells (myelin) is damaged.
There are three forms of metachromatic leukodystrophy, which involve different age ranges: late infantile form, juvenile form, and adult form. Signs and symptoms can vary. The infantile form is the most common and progresses more rapidly than the other forms.
There is no cure for metachromatic leukodystrophy yet. Depending on the form and age of onset, early identification, and treatment (stem cell transplant) may help manage some signs and symptoms and delay the progression of the disorder (Mayo Clinic).
Krabbe
Krabbe disease is a rare genetic disorder of the nervous system that usually results in death. People with Krabbe disease have a deficiency of galactosylceramidase production, which results in extensive degeneration of the myelin sheaths surrounding nerves in the brain. Without this myelin protection, cells in the brain will degenerate, and the body’s nervous system won’t work correctly.
About 85 to 90 percent of Krabbe disease cases begin in infancy (onset by age six months), but it can also develop later in life. There’s currently no cure for Krabbe disease, and most infants with this disease will die before age 2. Palliative and supportive care are the only treatments available for most cases of Krabbe disease.
However, patients diagnosed before symptoms begin or in later onset cases may be treated with a hematopoietic stem cell transplant (HSCT). The transplant may stabilize the disease progression and extend the life of the treated person. Bone marrow transplantation and stem cell therapy have been used in a small number of people with the disease. Gene therapy is also a treatment used in experimental trials (Healthline).
For information regarding efforts to add MLD and Krabbe to the RUSP, please see the Leukodystrophy Newborn Screening Action Network.
Every child with a rare disease that has a suitable treatment available deserves the chance to fight!
Advocacy
Advocacy to raise awareness, increase newborn screening, support research, and ensure equity of access to treatment.
Resources
Library of links to advocacy and treatment resources for ALD and other rare diseases in Canada and the U.S.
Remembering & Honouring Their Stories
We're keeping their memory alive by sharing stories of the children lost to ALD and other rare diseases.
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