Adrenomyeloneuropathy – Symptoms, Diagnosis, and Prevention.

Definition

Adrenomyeloneuropathy (AMN) is an inherited condition that affects the spinal cord. It is a form of X-linked adrenoleukodystrophy. On average, people with AMN begin to develop features in the late twenties. Signs and symptoms may include progressive stiffness and weakness of the legs; ataxia; speech difficulties; adrenal insufficiency; sexual dysfunction; and bladder control issues. Some people with AMN also have brain involvement which can lead to behavioral abnormalities, vision loss, hearing problems, and/or seizures. AMN is caused by changes (mutations) in the ABCD1 gene and is inherited in an X-linked manner. Treatment addresses the symptoms in each person and may include steroid replacement therapy for adrenal insufficiency.

Inheritance

Adrenomyeloneuropathy (AMN) is inherited in an X-linked manner.[4] A condition is considered X-linked if the responsible gene is located on the X chromosome, one of the two sex chromosomes. The Y chromosome is the other sex chromosome. Women have two X chromosomes and men have an X and a Y chromosome.

Because men have one copy of the X chromosome, a mutated copy of the responsible gene in each cell is enough to cause signs or symptoms of the condition. A man with an X-linked condition will pass the mutation to all of his daughters and none of his sons.

Because women have two X chromosomes, the effect of the mutation may be masked by the other, normal copy of the gene, on the other X chromosome. Women with one mutation are often referred to as “carriers” of an X-linked condition. In most cases, carrier women have no symptoms or are mildly affected. However, some may be just as severely affected as males with the condition. Women who carry an X-linked condition have a 50% chance of passing the mutation on with each pregnancy.

In AMN approximately 20% of women who carry one ABCD1 mutation will develop progressive stiffness and weakness in their legs, often in middle age or later. These women typically have normal adrenal function.

What Causes AMN?

As with ALD, AMN is caused by genetically inherited mutations to the gene ABCD1. ABCD1 normally encodes the protein adrenoleukodystrophy protein (ALDP) which is involve in the transport of very long chain fatty acids (VLCFA) into cells to be degraded by peroxisomes or lysosomes.

Genetic mutations to ABCD1 result in a deficiency of ALDP, therefore causing a build-up of VLCFAs within the blood and body tissues. The accumulation of VLCFAs is thought to be toxic to myelin in the spinal cord (and brain) as well as the adrenal glands and testes.

Risk Factors of Adrenomyeloneuropathy

Adrenoleukodystrophy is a inherited disease, and someone with a family history of illness is at risk. Because the disorder is passed by parents to their offspring as an X-linked genetic mutation, males are mainly affected, while some females may have signs of the disease but are mostly asymptomatic carriers.

What are the symptoms of AMN?

Like all of the categories of X-ALD, the symptoms of AMN can be quite variable. Below we have listed some of the symptoms that could be present, along with definitions as necessary.

• Difficulty in walking/change in walking pattern: this is the most common initial symptom of patients with AMN
• Spastic paraparesis: gradual, progressive weakness and stiffness of the legs; in AMN this is often specific to the lower limbs
• Ataxia: loss of the ability to coordinate muscle movement
• Hypertonia: excessive muscle tone
• Visual defects
• Dysarthria: Difficulty in articulating words, caused by impairment of the muscles used in speech
• Seizures: sudden convulsions/attacks/spasms
• Adrenal insufficiency: The adrenal glands are located above the kidneys, and are responsible for releasing certain hormones such as adrenaline and cortisol. These hormones are important in the control of blood pressure, heart rate, and sexual development and reproduction. In adrenal insufficiency, these hormones are not produced at the appropriate levels and so these processes are not properly controlled. Adrenal insufficiency occurs in approximately 70% of men with AMN.
• Sexual dysfunction/impotence – This may be related either to involvement of the spinal cord or the testes themselves. The latter is relatively uncommon. It can be diagnosed by measuring testosterone levels in plasma.
• Bulbar palsy

• Behavioral changes
• Bladder dysfunction
• Mild peripheral neuropathy
• Weight loss
• Nausea

Possible Complications

These complications can occur:

• Adrenal crisis
• Vegetative state
• Erectile dysfunction
• Problems with bowel and bladder control due to sphincter dysfunction
• Urinary dysfunction
• Balding and thinning of hair

Diagnosis

AMN can be diagnosed by a simple blood test that analyzes the amount of very long chain fatty acids; the levels of these molecules are elevated in X-ALD (see our general fact sheet on X-ALD). A DNA-based blood test is also available.

If the blood test suggests X-ALD, then generally an MRI will be performed in order to assess cerebral involvement. Additionally, the patient will be evaluated for adrenal insufficiency (by another blood test), as this is a common symptom of the disease that can be corrected.

Treatment for Adrenomyeloneuropathy

Currently there is no cure for AMN; however, there are some clinical and dietary treatments that patients are using to help alleviate some of the symptoms of the disease.

One of the possible symptoms of patients with AMN is adrenal insufficiency. The adrenal glands are located above the kidneys, and are responsible for releasing certain hormones such as adrenaline and cortisol. These hormones are important in the control of blood pressure, heart rate, and sexual development and reproduction. In adrenal insufficiency, these hormones are not produced at the appropriate levels and so these processes are not properly controlled. Adrenal insufficiency can be corrected by steroid replacement therapy, which generally will improve the quality of life of the patient. Failure to test for and treat adrenal insufficiency can lead to a fatal outcome. Only replacement dosage of steroids, which do not cause the side effects of “pharmacologic” doses, are required.

Prognosis

The long-term outlook (prognosis) for people with adrenomyeloneuropathy (AMN) varies depending on the subtype. In general, AMN with cerebral involvement (both brain and spinal cord affected) has a worse prognosis than AMN without cerebral involvement (only spinal cord affected). Many people without cerebral involvement are able to maintain successful personal and professional lives with physical therapy, management of bladder control issues, and counseling.

Prevention of Adrenomyeloneuropathy

Genetic counseling is recommended for couples with a family history of X-linked adrenoleukodystrophy. Mothers of affected sons have an 85% chance of being a carrier for this condition.

Prenatal diagnosis of X-linked adrenoleukodystrophy is also available. It is done by testing cells from chorionic villus sampling or amniocentesis. These tests look for either a known genetic change in the family or for very long chain fatty acid levels.