What is myelin (white matter) and why is it so important in the nervous system?
Myelin constitutes the “white matter” of the brain. It consists of fatty acid molecules, and provides the protective covering of the nerve cells, similar to insulation surrounding an electric wire. Myelin is required for the rapid, precise transmission of information to and from neurons throughout the brain and spinal cord. Demyelination is the stripping away of the fatty coating (white matter) that keeps nerve pulses confined and maintains the integrity of nerve signals. This process inhibits the nerves ability to conduct properly, thereby causing neurological deficits. In childhood cerebral ALD, not only do cells undergo demyelination, but there is also an inflammatory response, all of which destroy the brain.
When myelin is damaged, communication is lost during transmission. This results in the loss of voluntary and involuntary functions in the body.
Currently there is no known treatment to reverse damaged myelin, although there are options to manage symptoms. Proactive, comprehensive medical care will allow families and caregivers to give the affected individual the best quality of life possible. Furthermore, through ALD Newborn Screening, affected children have the opportunity to benefit from lifesaving treatment, which can halt the disease (see Treatment Section).
What causes ALD? And why does the disease typically impact boys?
ALD is caused by mutations in ABCD1, a gene located on the X chromosome that codes for ALD, Protein (ALDP), which functions as a peroxisomal membrane transporter. The transporter is required for the normal turn over, or metabolism, of fatty acids in the brain and spinal cord. Without the transporter, the normal metabolism of fatty acids does not occur. Therefore, the brain and spinal cord undergo demyelination. Biochemically, individuals with ALD show very high levels of unbranched, saturated, very long chain fatty acids, particularlycerotic acid (26:0).
The damaged gene that causes ALD resides on the X Chromosome. Boys inherit only one X Chromosome, which is passed to them from their mothers. Because girls inherit two X Chromosomes, one from each parent, the functional copy inherited from their father usually protects female children from the disease. However, females with the mutation are carriers who can pass the disease on to their male offspring. It is possible – but rare for girls to inherit 2 copies of the mutation from both parents.
How do you get ALD?
ALD disease is a genetic, or inherited, disorder. If a mother is a carrier of ALD, there is a 50% chance of passing this on to her children. If a father is a carrier of ALD, he will pass this on to his daughter
Spontaneous mutations are another way a baby can inherit ALD. This means that the mother and father are not carriers of ALD, but the mutation of the gene causing ALD happens in utero. Spontaneous mutations arise from a variety of sources, including errors in DNA replication, spontaneous lesions, and transposable genetic elements.uu
How does ALD affect the individual?
ALD is a multisystem disease, but most prominently affects both the central and peripheral nervous systems, which are responsible for all of the body’s voluntary and involuntary functions.
Damage to the brain results in blindness, seizures and hyperactivity. Other effects include problems with speaking, listening, and understanding verbal instructions.
Damage to the spinal cord results in the loss of the ability to walk and maintain normal breathing.
The most severely affected tissues outside of the nervous system are the adrenal cortex, and the Leydig cells in the testes. Damage to the adrenal cortex results in adrenal insufficiency or Addison’s Disease. Damage to the testes results in infertility.
The rate of progression depends on what form of the disease the individual has.
With proactive, comprehensive medical care the symptoms of ALD can be managed and give the individual the best quality of life possible. Furthermore, through ALD newborn screening, affected children have the opportunity to benefit from lifesaving treatment.
Who else in my family needs to be tested for ALD?
If a mother has ALD, there is a 50% chance of each of her other children also having ALD. This is crucial if the child is male and they should be tested immediately. If there are other female children, they can be tested when they are of childbearing age. Extended family – sisters, brothers, aunts, uncles, nieces, and nephews of the affected parent should also be tested for ALD.
To determine if other children in the family are affected by or carriers of ALD disease, it is best to consult with your genetic counselor or your child’s primary care physician.
You can also request a blood spot card from the Kennedy Krieger Institute.
The requisition form may be downloaded at http://genetics.kennedykrieger.org/forms/pero1.pdf.
Results are available within 7 to 10 days, unless there are special circumstances.
Contact information related to testing:
Kennedy Krieger Institute Genetics Laboratory - Peroxisomal Diseases Section
707 North Broadway
Baltimore, MD 21205 USA
How is ALD diagnosed?
ALD is diagnosed through a blood test, which analyzes the amount of very long chain fatty acids, which are elevated in ALD.
An MRI diagnoses cerebral ALD.
Although newborn screening for ALD is available in some states it is NOT a diagnostic test. Newborn screening can, however, lead to a proper and early diagnosis upon confirmatory testing.
ALD Newborn Screening is currently active in 9 states: New York, Connecticut, California, Minnesota, Pennsylvania, Washington, Tennessee, Florida and Nebraska. More states are slated to come on board in late 2018/2019. If you currently live in a state which is not testing or have extended family living in a state that is not testing, please contact the Kennedy Krieger Laboratory, listed above, for a blood spot card.
What are the different forms of ALD?
Adrenoleukodystrophy, or ALD, is an x-linked metabolic disorder, characterized by progressive neurologic deterioration due to demyelination of the cerebral white matter. ALD takes several forms, which can vary widely in their severity and progression. Unfortunately, there is no clear correlation of genotype (the type of mutation a patient has) and phenotype (the clinical presentation or subtype).
Childhood Cerebral Demyelinating ALD
This is the most common form of ALD, representing about 45% of all ALD cases. It is characterized by an inflammatory process that destroys the myelin, causing relentless progressive deterioration to a vegetative state or death, usually within five years.
The AMN phenotype occurs in 45% of people with ALD and generally develops in adults. AMN affects the longest nerve fibers of the spinal cord. These fibers conduct signals from the brain to the legs and the bladder and back to the brain.
Some people experience some of the following symptoms:
- Walking and balance problems
These problems can begin as general leg weakness and stiffness and progress to walking difficulty. Some people have more problems with their balance. Leg weakness and balance problems can change the way a person walks. Mobility devices, such as canes, walkers, and wheelchairs may be needed over time.
- Pain, numbness, or tingling in the legs
- Mild to moderate weakness of the arms/hands
- Urinary disturbances or incontinence and bowel urgency or incontinence
- Sexual dysfunction, or the inability to obtain or maintain an erection
The majority of other cases of the disease occur as the adult form, known as AMN. In about half of the sons who inherit the mutated ALD gene, symptoms of the disease do not develop until young adulthood, and in general, they progress more slowly. Beginning in their 20s and 30s, these young men exhibit neurological based motor lesions in their extremities. These lesions progress over many years and are inevitably accompanied by moderate to severe handicap. In approximately one third of these patients the central nervous system also becomes involved. These young men undergo the same mental and physical deterioration as the previously described boys. The progress of the disease is slower, usually declining to a vegetative state and/or death in 5 years or longer.
Addison’s Disease (Hypoadrenocorticism)
90% of boys and men with ALD/AMN have Addison’s disease, a disorder of the adrenal gland; in about 10% of ALD cases, this is the only clinical sign of the disorder. The adrenal glands produce a variety of hormones that control levels of sugar, sodium, and potassium in the body, and help it respond to stress. In Addison’s disease, the body produces insufficient levels of the adrenal hormone, which can be life threatening. Fortunately, this aspect of ALD is easily treated, simply by taking a steroid pill daily (and adjusting the dose in times of stress or illness).
Although women who carry the ALD gene mutation do not generally develop the brain disease itself, some display mild symptoms of the disorder. These symptoms usually develop after age 35, and primarily include progressive stiffness, weakness, or paralysis of the lower limbs, numbness, pain in the joints, and urinary problems.