Adrenoleukodystrophy (ALD) is caused by a mutation in an gene called ABCD1, which normally transports very long chain fatty acids (VLCFA) into a compartment in the cell called the peroxisome where they are normally broken down. Due to this mutation, patients with ALD accumulate high levels of VLCFA in the blood and in body tissues, such as the brain.
ALD has two subtypes: X-linked ALD and neonatal ALD.
X-lined ALD: X-linked ALD occurs when the patient inherits the abnormal gene from one or both parents. Since males only have one X chromosome, they will have the disease if they inherit one copy of the mutated X chromosome. Since females have two X chromosomes, they must inherit two copies of the mutated chromosome in order to have the disease. If females have just one copy of the mutated gene, they are called carriers. Carriers of ALD may experience mild symptoms of ALD. This is because the normal copy of the gene can partially compensate for the abnormal one in females.
Neonatal ALD: Neonatal ALD is also an inherited condition. Unlike X-linked ALD, the mutated gene that causes neonatal ALD is not located on the X-chromosome. This means that neonatal ALD affects both males and females equally. Mutations in the gene PEX5 have been shown to cause neonatal ALD. PEX5 is a receptor that functions in protein import into the peroxisome. Both copies of PEX5 need to be mutated for an individual to develop ALD.
VLCFA testing: A blood test or skin test can be used to check for increased levels of very long chain fatty acids (VLCFA).
MRI: A magnetic resonance imaging (MRI) scan may be performed to take pictures of the brain. MRI is a noninvasive imaging technique that uses magnetic waves and radio waves to take an image of tissues within the body. If brain damage has occurred in a patient with ALD, the damaged tissue will appear as white regions in the MRI image. These damaged regions are called white matter.
Genetic testing: A genetic test may be performed to diagnosis neonatal adrenoleukodystrophy (ALD). During the procedure, a sample of the patient's blood is taken and sent to a laboratory. If a mutation is found in specific genes that have been implicated in ALD, the patient is diagnosed with the condition.
signs and symptoms
In patients with adrenoleukodystrophy (ALD), there is a buildup of VLCFAs (because they do not get broken down), which leads to the breakdown of the myelin sheath (a fatty membrane that surrounds and protects nerves in the brain and spinal cord) and to a dysfunction in the adrenal glands. Breakdown of the myelin sheath is thought to be due to solubilization of the sheath by VLCFAs, and adrenal gland dysfunction may be caused because normal VLCFA metabolism is needed by the adrenal gland to produce steroids. Patients with ALD have reduced levels of cortisol, which is a hormone released by the adrenal gland. Cortisol regulates blood pressure, and ensures proper glucose metabolism and maintenance by regulating insulin release.
Childhood ALD: Symptoms of X-linked ALD may develop in childhood or adulthood. The childhood form usually develops between the ages of four and 10. The most common symptoms are behavioral changes (such as abnormal withdrawal or aggression), poor memory, and poor performance at school. Other symptoms may include vision loss, learning disabilities, seizures, poorly articulated speech, difficulty swallowing, deafness, difficulty walking, poor coordination, fatigue, intermittent vomiting, darkening of the skin tone, and progressive dementia.
Adult ALD: Symptoms of X-linked ALD are usually milder if they develop during adulthood. Adult-onset symptoms, which usually develop between the ages of 21 and 35, may include progressive stiffness, weakness or paralysis of the lower limbs, and loss of coordination. Although adult-onset ALD generally progresses more slowly than the childhood form, it may also cause brain function to progressively deteriorate.
Carriers of X-linked ALD may experience mild symptoms, including weakness of the legs, loss of coordination, excessive muscle tone, urinary problems, and numbness or tingling sensations in the hands or feet (called peripheral neuropathy). This is a result of minor VLCFA buildup in these patients.
Neonatal ALD: Symptoms of neonatal ALD develop during infancy. Common symptoms include mental retardation, facial abnormalities, seizures, weak muscle tone, enlarged liver, and adrenal dysfunction. Symptoms of adrenal dysfunction typically include muscle weakness and fatigue, weight loss and decreased appetite, darkening of the skin, low blood pressure, fainting, cravings for salt, low blood sugar levels, irritability, depression, diarrhea, nausea, and vomiting. This form of ALD usually progresses rapidly, causes neurodegeneration, and results in death in infancy or young childhood.
Adrenal dysfunction: Patients with adrenoleukodystrophy (ALD) often exhibit defects in the adrenal glands, which normally produce the hormone cortisol. Cortisol regulates proper glucose metabolism, blood pressure, and insulin release for blood sugar regulation. The adrenal glands in patients with ALD often produce insufficient amounts of cortisol, which may lead to muscle weakness and fatigue, weight loss and decreased appetite, darkening of the skin, low blood pressure, fainting, cravings for salt, low blood sugar levels, irritability, depression, diarrhea, nausea, and vomiting.
Neurological dysfunction: If loss of brain function becomes severe, patients with ALD may enter into a vegetative state. A vegetative state is a condition of unconsciousness in which an individual is alive, but can't move or respond to his or her surroundings.
Due to the progressive loss of neurological function, patients with ALD generally only survive one to 10 years after the onset of symptoms.
Adrenoleukodystrophy (ALD) is an inherited genetic condition, and a mutation on the X chromosome has been linked to the development of ALD. Therefore, families in which at least one parent has this X chromosome mutation are at greater risk for having a child with ALD.
Males are at higher risk for developing X-linked ALD than females. This is because females have two copies of the X chromosome, but males only have one copy. Females must have the mutation on both X chromosomes, while males, who have an X and a Y chromosome, only need to have the mutation on the one X chromosome. This is a form of inheritance called recessive X-linked inheritance.
Unlike X-linked ALD, the mutated gene that causes neonatal ALD is not located on the X-chromosome. This means that both male and female babies are affected equally. Neonatal ALD is inherited in an autosomal recessive pattern. In an autosomal recessive genetic disorder, both copies of a certain gene need to be defective for the condition to manifest itself. People who only have one mutated gene are called "carriers." If only one parent is a carrier, none of the children will have ALD, but each child has a 50% risk of being a carrier; if both parents are carriers, then there is a 50% chance that a child will be a carrier, and a 25% chance that a child will have ALD.