Adrenomyeloneuropathy (AMN) is the second most common form of adrenoleukodystrophy (ALD) and is an adult-onset version of ALD. AMN is a genetically inherited x-linked condition which affects the myelin of the spinal cord. As with all forms of ALD, AMN affects predominantly males (1 in around 40,000) due to being inherited on the X chromosome.
There are two forms of AMN: AMN without cerebral involvement (just affecting the spinal cord) and is usually milder, or AMN with cerebral involvement (affecting both the spinal cord and brain) and is more severe.
What are the Clinical Characteristics/Symptoms of AMN?
AMN symptoms are later-onset than childhood cerebral ALD, which starts during infancy. Symptoms begin in the late 20s to anytime up to and during the early 40s. They also tend to be slower than in ALD progression.
As with ALD, symptoms can vary between affected individuals, as well as the severity. Most symptoms of AMN without cerebral involvement include features affecting movement and intrinsic somatic motor control:
- Progressive stiffness of the limbs which leads to progressive weakness (spastic paraparesis)
- Sexual dysfunction/impotence as well as bladder control issues
- Speech, language and swallowing difficulties (dysarthria and dysphagia)
- Difficulty in both walking ability and gait – sometime with ataxia present
- Adrenal insufficiency is seen in most cases of ALD/AMN – characterised by metabolic dysregulation leading to reduced hormonal levels in the body – these include adrenaline and cortisol dysregulation affecting blood pressure and sexual development.
AMN individuals with cerebral involvement tend to have additional neurological/psychiatric symptoms including:
- Behavioural changes e.g. attention-deficit hyperactivity disorder (ADHD)
- Sensory changes e.g. vision loss or hearing loss
- Neurological changes e.g. seizures and dementia
Symptoms tend to be progressive and prognosis depends on the severity and subtype of AMN. Generally, AMN with cerebral involvement is more severe and has a worse prognosis than AMN without cerebral involvement. Individuals with AMN without cerebral involvement can effectively live full-lives providing they have adequate physical therapy and counselling. Only 10-20% of individuals with AMN develop AMN with cerebral involvement that is progressively devastating, and can lead to long-term paralysis, coma and death.
ALD and AMN
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.
How is AMN Treated?
There is currently no cure for AMN (or for ALD in general), however, effective management and therapy can better the prognosis for some affected individuals.
Adrenal insufficiency (present in most cases of AMN) can be treated by steroid replacement therapy or by administration of corticosteroids. Replacing hormonal levels (adrenaline and cortisol), generally improves the quality of life in affected individuals.
Physical therapy can ameliorate muscle weakness and rigidity as well as maintain or improve motor function. However, as it is progressively deteriorating in nature, mobility aids may be needed in advanced stages of AMN.
As with ALD, gene therapy targeting mutated ABCD1 has been shown to be effective in recent clinical trials, compared to bone marrow stem cell transplants. This would only be effective in young age with early-stage AMN/ALD, however much more research is needed.
Further Reading