Adrenoleukodystrophy Causes, Symptoms, Diagnosis, Treatment

Adrenoleukodystrophy Causes, Symptoms, Diagnosis, Treatment


What is Adrenoleukodystrophy?


X-linked Adrenoleukodystrophy is one of a group of genetic disorders called the leukodystrophies that cause damage to the myelin sheath, an insulating membrane that surrounds nerve cells in the brain. Women have two X chromosomes and are the carriers of the disease, but since men only have one X chromosome and lack the protective effect of the extra X chromosome, they are more severely affected. People with X-Adrenoleukodystrophy accumulate high levels of saturated, very long chain fatty acids (VLCFA) in the brain and adrenal cortex. The loss of myelin and the progressive dysfunction of the adrenal gland are the primary characteristics of X-Adrenoleukodystrophy. While nearly all patients with X-Adrenoleukodystrophy suffer from adrenal insufficiency, also known as Addison's disease, the neurological symptoms can begin either in childhood or in adulthood. The childhood cerebral form is the most severe, with onset between ages 4 and 10. The most common symptoms are usually behavioral changes such as abnormal withdrawal or aggression, poor memory, and poor school performance. Other symptoms include visual loss, learning disabilities, seizures, poorly articulated speech, difficulty swallowing, deafness, disturbances of gait and coordination, fatigue, intermittent vomiting, increased skin pigmentation, and progressive dementia. The milder adult-onset form is also known as adrenomyeloneuropathy (AMN), which typically begins between ages 21 and 35. Symptoms may include progressive stiffness, weakness or paralysis of the lower limbs, and ataxia. Although adult-onset Adrenoleukodystrophy progresses more slowly than the classic childhood form, it can also result in deterioration of brain function. Almost half the women who are carriers of X-ALS will develop a milder form of AMN but almost never will develop symptoms seen in boys the X-Adrenoleukodystrophy. X-Adrenoleukodystrophy should not be confused with neonatal adrenoleukodystrophy, which is a disease of newborns and young infants and belongs to the group of peroxisomal biogenesis disorders.

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Types of Adrenoleukodystrophy


There are three types of Adrenoleukodystrophy.
  • Childhood cerebral Adrenoleukodystrophy mainly affects children who are between 4 and 10 years old. It can progress rapidly if the condition is not found early enough.
  • Adrenomyelopathy primarily affects male adults. It is milder than childhood cerebral Adrenoleukodystrophy. It also progresses slowly in comparison.
  • Addison’s disease is the third type of Adrenoleukodystrophy. It is also known adrenal insufficiency. Addison’s disease occurs when your adrenal glands don’t make enough hormones.

Causes and Risk Factors of Adrenoleukodystrophy


The adrenoleukodystrophy protein (ALDP) helps your body break down very long chain fatty acids (VLCFA). When this doesn’t happen, the fatty acids build up inside your body instead. This can harm the outer layer of the cells in your spinal cord, brain, adrenal glands, and testes.

People with Adrenoleukodystrophy have mutations in the gene that makes ALDP. Their bodies do not make enough ALDP.

Men are typically affected by Adrenoleukodystrophy at an earlier age than women and usually have more severe symptoms. 

Adrenoleukodystrophy affects males more than females because it is X-linked. This means that the gene mutation that causes it is on the X chromosome. Men only have one X chromosome, while women have two copies of it. That means that they can have one normal and one mutant copy of the gene.

Women with only one copy of the mutation have much milder symptoms than men. In some cases they don’t have symptoms at all. Their normal copy of the gene makes enough ALDP to help mask their symptoms. Most women with Adrenoleukodystrophy have adrenomyelopathy. Addison’s disease and childhood cerebral Adrenoleukodystrophy are less common.

Symptoms of Adrenoleukodystrophy


Childhood cerebral type:


  • Changes in muscle tone, especially muscle spasms and spasticity
  • Crossed eyes (strabismus)
  • Decreased understanding of verbal communication (aphasia)
  • Deterioration of handwriting
  • Difficulty at school
  • Difficulty understanding spoken material
  • Hearing loss
  • Hyperactivity
  • Worsening nervous system deterioration
  • Coma
  • Decreased fine motor control
  • Paralysis
  • Seizures
  • Swallowing difficulties
  • Visual impairment or blindness

Adrenomyelopathy:


  • Difficulty controlling urination
  • Possible worsening muscle weakness or leg stiffness
  • Problems with thinking speed and visual memory

Adrenal gland failure (Addison type):


  • Coma
  • Decreased appetite
  • Increased skin color (pigmentation)
  • Loss of weight, muscle mass (wasting)
  • Muscle weakness
  • Vomiting

Diagnosing Adrenoleukodystrophy


Adrenoleukodystrophy symptoms can mimic those of other illnesses. Therefore, tests are needed to distinguish it from other neurological conditions. Blood tests can:
  • look for abnormally high levels of VLCFAs
  • check your adrenal glands
  • find the genetic mutation that causes Adrenoleukodystrophy
Your doctor may also look for damage to your brain using magnetic resonance imaging (MRI). Skin samples or a biopsy and fibroblast cell culture can also be used to test for VLCFAs.

Children with suspected Adrenoleukodystrophy may need additional testing, including vision screens.

Treatment of Adrenoleukodystrophy


Treatment methods depend on the type of Adrenoleukodystrophy. Steroids can be used to treat Addison’s disease. There are no specific methods for treating the other types of Adrenoleukodystrophy.

Some people have been helped by:
  • switching to a diet that contains low levels of VLCFAs
  • taking Lorenzo’s oil to help lower elevated VLCFA levels
  • medications to relieve symptoms such as seizures
  • physical therapy to loosen muscles and reduce spasms
Doctors continue to look for new Adrenoleukodystrophy treatments. Some are experimenting with the use of bone marrow transplants. These may be able to help children with childhood cerebral Adrenoleukodystrophy when it is diagnosed early.

Possible Complications


  • Adrenal crisis
  • Vegetative state (long-term coma)

Prevention for Adrenoleukodystrophy


Genetic counseling is recommended for prospective parents with a family history of X-linked adrenoleukodystrophy. Female carriers can be diagnosed 85% of the time using a very-long-chain fatty acid test and a DNA probe study done by specialized laboratories.

Prenatal diagnosis of X-linked adrenoleukodystrophy is also available. It is done by evaluating cells from chorionic villus sampling or amniocentesis.

What is the prognosis?


Prognosis for patients with childhood cerebral X-Adrenoleukodystrophy is generally poor due to progressive neurological deterioration unless bone marrow transplantation is performed early. Death usually occurs within 1 to 10 years after the onset of symptoms. Adult-onset AMN will progress over decades.

What research is being done?


The NINDS supports research on genetic disorders such as ALD. The aim of this research is to find ways to prevent, treat, and cure these disorders. Studies are currently underway to identify new biomarkers of disease progression and to determine which patients will develop the childhood cerebral form of X-ALD. A recent case study in Europe demonstrated that the combination of gene therapy with bone marrow transplantation, using the patient's own bone marrow cells, may arrest disease progression in childhood cerebral X-ALD. A therapeutic trail in the United States is currently being discussed with the U.S. Food and Drug Administration.