The incidence of AMN is not exactly known, but some studies report it to be around 1 in 42,000 individuals. It affects males more than females, and affected males present symptoms at a younger age compared to affected females. The average age range for disease and symptom onset is between 20 and 40 years. There is no known racial predilection for adrenomyeloneuropathy.

Peroxisomes are structures within the cell that contain enzymes to break down various substances including VLCFAs. Because peroxisomes contain digestive enzymes, it is important that only the molecules that need to be digested can enter it to avoid breaking down essential components of the cell. Therefore, on the surface of peroxisomes, there are transport proteins, which act as gates to allow certain molecules to cross the peroxisomal membrane while leaving others out. One of these transport proteins is the adrenoleukodystrophy protein (ALDP). ALDP facilitates the transport of VLCFAs from the cytoplasm, or main body of the cell, into the peroxisome to be broken down.  AMN is caused by changes in the ABCD1 gene, which encodes ALDP. As a result, VLCFAs cannot be efficiently transported into the peroxisomes to be broken down, and therefore, accumulate in different tissues, particularly the nervous system, the adrenal glands, and the testes. This accumulation disrupts the function of these organs and causes the features of AMN. 

There is some evidence that increased oxidative stress also contributes to the disease process in AMN. Oxidative stress refers to an increased level of reactive oxygen species (ROS). ROS are highly reactive, oxygen-containing molecules that are produced naturally in the body as a byproduct or intermediate of many biological reactions. The body has intrinsic mechanisms to harvest these ROS and prevent them from reacting with and damaging cellular structures. However, if the balance between ROS production and removal is disturbed, the affected tissue experiences oxidative stress which can damage the tissue. 

The Nervous System

The nervous system is one of the main systems affected by AMN. Nerve cells or neurons are specialized cells that transmit nervous impulses in the form of electrical signals. They have a specialized structure called the axon. An axon is a long extension, or process, of the nerve cell that carries the signal some distance to another nerve or target cell. Many axons are wrapped in layers of a fatty substance known as myelin. This myelin “sheath” increases the speed at which nervous impulses are transmitted within the axon. The hallmark of AMN is axonal damage in a “dying back” pattern. This means that the most terminal, or farthest tip, of the longest axons are affected first, and the damage progresses backward along the axon toward the cell body until the nerve becomes unviable. Because they travel the greatest distances, from the brain to muscles,  spinal cord nerves are affected early and severely, with degeneration progressing backward along the nerve and then from longer nerves traversing the spinal cord to shorter neurons that form connections within the brain itself. This neuronal death is likely because VLCFA accumulates in cells that support and nourish the axons, hindering their ability to sustain the axons. AMN can also cause direct damage to the myelin sheath; however, the extent of this damage is highly variable among individuals. Over time, because of increased axon degeneration, the spinal cord shrinks in size, causing neurological symptoms.

The Adrenal Glands 

In addition to nerve damage, the adrenal glands and the testes can be significantly affected. The adrenal glands are small chemical-secreting structures that sit on top of the kidneys. They produce a number of chemicals, called hormones, that are essential to many bodily functions. The outer part of the adrenal gland is called the adrenal cortex, which consists of three layers, each of which is responsible for producing a certain hormone. 

The outermost layer of the adrenal cortex produces aldosterone, a hormone that regulates salt concentration and water volume, thereby controlling blood pressure. Specifically, aldosterone reduces the amount of salt and water excreted in the kidneys, increasing blood pressure. 

The second layer, which is most affected by AMN, is responsible for producing cortisol. Cortisol is known as the “stress hormone”, increasing blood sugar levels in times of crisis to ensure enough energy is available to the brain. 

The innermost layer of the adrenal gland produces androgens. Androgens are sex hormones that contribute to the development of certain secondary sexual characteristics such as pubic hair. Although their physiologic contribution is negligible in adult males, they continue to play a role in adult females.

Both cortisol and adrenal androgens are regulated by adrenocorticotropic hormone (ACTH), which is secreted into the blood from the pituitary gland in the brain to stimulate the production of cortisol or androgens when needed. In AMN, VLCFAs accumulate in adrenal glands and impair their ability to respond to ACTH. As a result, despite high ACTH levels, they are unable to produce enough cortisol in response to stress which leads to symptoms of adrenal insufficiency. 

The Testes

The testes are male sexual organs responsible for sperm and testosterone production. Testosterone is a male sex hormone that plays numerous roles, including stimulating sperm production, promoting sex drive, and maintaining bone and muscle mass. The accumulation of VLCFAs in testicular cells hinders their ability to produce testosterone and sperm.

Pattern of Inheritance

Human cells contain 23 pairs of chromosomes, including sex chromosomes, which can be X or Y. An individual is genetically male if they have an X chromosome and Y chromosome and female if they have two X chromosomes. One copy of each chromosome pair is inherited from the mother and one copy from the father. The offspring becomes genetically male if they happen to inherit a Y chromosome from their father and female if they inherit an X chromosome from their father. While the other 22 pairs of chromosomes have very similar content, the X chromosome is much larger than the Y chromosome, and therefore, contains many more genes.

AMN is inherited in an X-linked manner, as the responsible gene is located on the X chromosome. Therefore, it affects males (XY) more than females because one of the female’s X chromosomes still contains a healthy copy and can compensate for the defective copy. Females need to have two defective copies, one on each X chromosome, to be fully affected, whereas females who only have one mutated copy of the gene are either not affected or have a milder form of the condition. Males who have one defective copy of the gene on their X chromosome, on the other hand, do not have another copy to compensate and exhibit the full presentation of the condition. 

Another implication of an X-linked pattern of inheritance is that females can be carriers, meaning they can pass on a defective copy of the gene to their male and female children (50% chance per child) without being affected themselves. However, males cannot be asymptomatic carriers of X-linked conditions because if they have a defective copy, the condition will present either at birth or later in life or even adulthood. Affected males will pass it on to all their female offspring but none of their male offspring. 

While the vast majority of AMN cases are inherited from parents, a small number (about 4%) are not inherited, due to random mutation in the egg or sperm that lead to a new genetic change (de novo) in the offspring that was absent in the parents.

AMN symptoms typically onset in the late twenties in males and later forties in females. While almost all males with defective ABCD1 will develop AMN, only one-fifth of females with the same defect will develop AMN and usually a milder form with only some neurological symptoms and no adrenal insufficiency. 

The milder forms of AMN only affect the spinal cord while the more severe forms affect both the spinal cord and the brain. Neurological symptoms typically begin as stiffness and weakness in the legs that progress over time. This may present as difficulty walking or changes in walking form (gait). Symptoms tend to appear in the legs years before the arms and the hands are affected. Other early symptoms are impaired vibration sensation, difficulty with balancing and coordination, and slurred speech. Problems with bladder control are also seen early in the disease.  In more severe cases in which the brain is affected, vision problems and blindness, hearing problems, seizures, attention deficit hyperactivity disorder (ADHD), and behavioral problems may occur.

Most male patients (but almost none of the affected females) develop adrenal insufficiency, causing long-term fatigue, weight loss, nausea and vomiting, abdominal pain, and joint pain. Other symptoms that are more specific to adrenal insufficiency include changes in skin color where patches of skin become darker, low blood pressure that worsens and can cause lightheadedness when standing up, and craving salty foods. These signs may present before, simultaneous to, or after neurological symptoms, or they may never occur. Furthermore, the severity of neurological symptoms and adrenal insufficiency symptoms are independent of one another. While most affected males develop testicular insufficiency, this typically does not have any significant clinical manifestations. 

Individuals affected by AMN also tend to have thin and sparse hair and may begin balding at a young age. 

AMN is usually diagnosed in, but not limited to, young men who display weakness and numbness of the limbs and urination or defecation problems. Women may be asymptomatic or may, like men, have problems with mobility and bladder and bowel control. 

If AMN is suspected based on signs and symptoms, family history, or a positive newborn screen, the first step is to assess VLCFA levels by a blood test. If VLCFA levels are elevated, diagnosis can be confirmed by genetic testing. While the majority of affected males have elevated VLCFA , many females may have normal levels, making it a less useful diagnostic measure. Genetic testing is the only definitive diagnostic test in females. 

If genetic testing confirms the diagnosis, further tests are needed to assess the degree of brain involvement and adrenal involvement.

If a blood test shows elevated VLCFA levels, genetic testing is undertaken to detect any abnormalities in the ABCD1 gene to confirm the diagnosis. In females, if there is clinical suspicion of AMN, genetic testing may be done despite normal VLCFA levels. 

Once an AMN diagnosis is confirmed, a brain imaging test, often MRI, is performed to assess whether there is any brain involvement.

Additionally, another blood test called ACTH stimulation testing is done to determine whether there is adrenal insufficiency. For this test, the individual’s blood is drawn to measure baseline cortisol levels. This is followed by an ACTH injection. After a given period of time, blood is drawn again. Since ACTH is the hormone that stimulates the adrenal glands to produce cortisol, healthy individuals would have higher cortisol levels in their second blood sample compared to their first (baseline). However, in an individual with adrenal insufficiency, cortisol levels do not increase as expected. 

Currently, there are very limited treatment options for AMN. Treatment mostly targets symptom progression or complication prevention such as improving bladder control, managing sexual dysfunction, etc. 

Dietary modifications have been considered as a treatment option for AMN to reduce VLCFA levels in the blood, but subsequent studies did not show any significant improvement. One example is the use of Lorenzo’s oil, a mixture of two fatty molecules: glycerol trioleate and glycerol trierucate. Lorenzo’s oil reduces the formation of VLCFA in the body and has been found to reduce VLCFA levels in the blood. Despite this finding, there was no neurological or adrenal symptom improvement associated with the use of Lorenzo’s oil. This treatment is considered experimental by the FDA and can cost approximately $440 per month. Because of its experimental status, most insurance companies will not cover this treatment. If despite the lack of supporting evidence, Lorenzo’s oil is used, blood platelet count and liver function should be monitored to avoid associated complications. Restricting the dietary intake of VLCFAs does not lower blood VLCFA levels because they are naturally synthesized in the body. One biotechnology company working to develop a treatment for AMN is ReceptoPharm, Inc., a subsidiary of Nutra Pharma Corporation. This treatment just completed its Phase IIb/IIIa clinical trial in London, England. 

Hematopoietic stem-cell transplantation (HSCT) has been suggested to benefit individuals affected by AMN with mild brain involvement. This, however, is based on very limited data. HSCT is a surgical procedure in which stem cells, which are special undifferentiated cells that can develop into many different cell types, are harvested from a blood-related source such as the bone marrow or the blood itself and infused into the recipient. HSCT is not believed to be beneficial for individuals affected by AMN with no brain involvement and may even worsen some neurological symptoms. This procedure also has a high mortality rate in those with severe brain involvement. Therefore, those with mild brain involvement are the best candidates for HSCT. Those with no brain involvement should be monitored closely in order to detect any potential brain involvement before it becomes severe.

If there is adrenal insufficiency, corticosteroid replacement therapy is essential. This therapy usually involves taking tablets to replace cortisol and aldosterone which the adrenal glands cannot produce in adequate amounts.  

The prognosis of AMN varies significantly among individuals and can range from severe, early disability to mild disability late in life. Typically, those with no brain involvement have a better prognosis than those with brain involvement. Less than half of men with AMN develop brain abnormalities. In some of these cases, severe symptoms such as behavioral issues and cognitive decline develop.

Genetic and Rare Diseases Information Center. Adrenomyeloneuropathy. 2015. Available from https://rarediseases.info.nih.gov/diseases/10614/adrenomyeloneuropathy

James M. Powers, MD, David P. DeCiero, BS, Masumi Ito, MD, Ann B. Moser, BS, Hugo W. Moser, MD, Adrenomyeloneuropathy: A Neuropathologic Review Featuring Its Noninflammatory Myelopathy, Journal of Neuropathology & Experimental Neurology, Volume 59, Issue 2, February 2000, Pages 89–102, https://doi.org/10.1093/jnen/59.2.89

Walterfang MA, O'Donovan J, Fahey MC, Velakoulis D. The neuropsychiatry of adrenomyeloneuropathy. CNS Spectr. 2007 Sep;12(9):696-701. doi: 10.1017/s1092852900021532. PMID: 17805216.

Moser, H. & (1995). Clinical and Therapeutic Aspects of Adrenoleukodystrophy and Adrenomyeloneuropathy. Journal of Neuropathology and Experimental Neurology, 54 (5), 740-745.

Engelen, M., Kemp, S. & Poll-The, BT. X-Linked Adrenoleukodystrophy: Pathogenesis and Treatment. Curr Neurol Neurosci Rep 14, 486 (2014). https://doi.org/10.1007/s11910-014-0486-0

Berger J, Forss-Petter S, Eichler FS. Pathophysiology of X-linked adrenoleukodystrophy. Biochimie. 2014;98(100):135-142. doi:10.1016/j.biochi.2013.11.023

Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012 Aug 13;7:51. doi: 10.1186/1750-1172-7-51. PMID: 22889154; PMCID: PMC3503704.