Introduction:
Adrenoleukodystrophy (ALD) is an inherited disorder that affects the myelin sheath of nerve fibers and adrenal glands. It occurs in one in 15,000 human beings, and males are more commonly affected than females. The genetic disorder is referred to as X-linked adrenoleukodystrophy or Schilder disease.
What Is Adrenoleukodystrophy?
In patients with adrenoleukodystrophy, the adrenal cortex (outer layer of the adrenal gland) and the protective layer (myelin sheath) of nerve fibers are affected. Adrenal glands are on top of the kidneys, and they secrete hormones to regulate blood pressure and the immune system. The deficiency of hormones occurs due to damage to the adrenal cortex. In addition, the nerve fibers in the brain and spinal cord are covered by a protective layer (myelin sheath), which is responsible for transmitting signals to the brain. Several neurological symptoms occur due to the deterioration of myelin sheath.
What Causes Adrenoleukodystrophy?
-
The leading cause of adrenoleukodystrophy is the changes or mutation in the ABCD1 gene on the X-chromosome. Males have one X and one Y chromosome, whereas females have a pair of X-chromosomes. The defect in the ABCD1 gene thus severely affects males, while females have fewer symptoms as one copy of the X-chromosome is affected.
-
The ABCD1 gene commands the synthesis of X-linked adrenoleukodystrophy protein (ALDP). The protein then carries fat molecules (very long-chain fatty acids) to the cells, which are later broken down. The alterations in the ABCD1 gene lead to the deficiency of ALDP, which disrupts the transmission and breakdown of fat molecules. The fat molecules then accumulate in the brain and adrenal cortex tissues and produce toxic effects.
What Are the Types of Adrenoleukodystrophy?
The distinct forms of adrenoleukodystrophy (ALD) are as follows:
1) Childhood Cerebral ALD - Most boy children are affected, and the symptoms appear between 3 to 10 years of age and worsen over time. It includes:
- Difficulty in reading, writing, and speech.
- Loss of previously acquired skills.
- Behavioral changes.
- Attention deficit hyperactivity disorder.
- Swallowing difficulties.
- Poor memory.
- Impaired vision.
- Hearing loss.
- Weakness and stiffness of limbs.
- Difficulty in walking.
- Seizures.
2) Adrenomyelopathy - The symptoms begin during early adolescence or adulthood. The males are manifested with:
- Spastic paraparesis (weakness in lower limbs).
- Abnormal gait.
- Urinary and gastrointestinal disorders are observed due to poor control of the bladder and gastrointestinal tract muscles.
- Erectile dysfunction.
- Pain and numbness along hands and feet.
- Behavioral changes.
- Balding and thinning of hair.
3) Adult Cerebral ALD - The men are affected with severe thinking, reasoning, and reading disabilities. The symptoms present in childhood ALD form worsen in affected men.
4) Addison's Disease - One in 10 people is only affected by Addison's disease in ALD form. The males are involved with a deficiency in adrenal hormones (adrenal insufficiency), and neurological disturbances do not usually occur. The symptoms are mild compared to other types, and it includes:
- Fatigue.
- Hyperpigmentation of skin.
- Nausea, vomiting.
- Decreased sugar and blood pressure levels.
5) Women With ALD - Women mainly remain carriers of the disease, with minor symptoms developing during adulthood. The severity of symptoms usually occurs after the age of 60. Rarely do neurological abnormalities arise.
6) In a few individuals, various symptoms develop during adolescence or mid-adulthood. For example, men can be affected by adrenal insufficiency, memory loss, and other psychological disturbances. It rarely occurs as a variation of the types mentioned above.
How Is Adrenoleukodystrophy Diagnosed?
-
Physical examination of the patient to assess the characteristic symptoms of ALD is done along with a detailed family and medical history as it is an inherited disorder.
-
A newborn screening test evaluates the risk of newborns developing severe disorders. The diagnosis is not confirmed with positive test results. It is usually followed by genetic testing to identify any mutations in the ABCD1 gene.
-
A blood test measures the level of very long-chain fatty acids (VLFA), which are not broken down. The levels are usually high in males with ALD, and genetic testing confirms it. In women, the levels of fatty molecules are normal.
-
Genetic testing is done for confirmatory diagnosis. It detects the alterations in the ABCD1 gene that causes adrenoleukodystrophy.
-
The magnetic resonance imaging (MRI) technique is used to visualize the damage to the brain’s structures and myelin sheath.
-
ACTH stimulation test measures adrenal glands' response to adrenocorticotropic hormone (ACTH) released by the pituitary gland. In Addison's disease, the response of adrenal glands and the level of adrenal hormones are low.
What Is the Differential Diagnosis?
The disorders that have similar characteristics to ALD are discussed below:
-
Krabbe Disease is an inherited disorder in which the myelin sheath is damaged. The symptoms develop at two to five months of age. The babies suffer from feeding difficulties, vomiting, muscle spasm, irritability, and developmental delay.
-
Multiple Sclerosis is a chronic auto-immune disorder. The immune system attacks the myelin sheath cells, thus causing damage. The symptoms can be mild or severe, consisting of fatigue, weakness, muscle spasm, blurred vision, and difficulty walking.
-
Hereditary Spastic Paraplegia is an inherited disorder characterized by weakening and stiffness of the legs.
How Is Adrenoleukodystrophy Treated?
There is no specific treatment for ALD, but the following measures are taken to prevent the worsening of the disease.
-
Hormone replacement therapy is the preferred treatment for Addison's disease. Hydrocortisone or Methylprednisolone is administered to replace the cortisol hormone, improving the symptoms.
-
Stem cell transplantation from a healthy donor to young boys with early stages of ALD has been shown to reduce the progression of neurological symptoms. It is done when the imaging studies of the brain show neurological involvement.
-
The use of Lorenzo's oil is still under study. But it is found to decrease the neurological symptoms if given before developing such symptoms.
-
Physical therapy is given to improve walking and muscle coordination.
-
Counseling of the parents is essential as a supportive therapy.
Conclusion:
Adrenoleukodystrophy is a rare disorder that causes severe symptoms in childhood and adulthood. Therefore, a multi-specialty approach is essential in diagnosing various types of ALD and planning for the necessary treatmnet to prevent disease progression.
