Adrenomyeloneuropathy

Adrenomyeloneuropathy (AMN) is a rare hereditary neurodegenerative disorder that primarily affects the spinal cord and peripheral nerves, occurring in less than 1 in 40,000 people.^[1] It is characterised by progressive motor dysfunction and adrenal insufficiency. AMN is a form of X-linked adrenoleukodystrophy, a peroxisomal disorder caused by mutations in the ABCD1 gene.^[1][2] Symptoms most commonly begin in a person's late twenties.^[3] AMN predominantly affects adult males but heterozygous females may develop symptoms later in life.^[4] Treatments mainly center around symptom-management.

Symptoms of AMN typically begin in adulthood, with the mean onset of symptoms for affected males occurring at 27.6 years of age.^[3] Common symptoms include:^[5][6][7]

• Spastic paraparesis (progressive stiffness and weakness of the legs)
• Ataxia (loss of coordination)
• Neurogenic bladder and bowel dysfunction
• Sexual dysfunction
• Adrenocortical insufficiency, leading to fatigue, weight loss, and low blood pressure
• Peripheral neuropathy, causing numbness or pain in the limbs

Approximately 46% of males with AMN also experience cerebral involvement, which can result in cognitive decline, behavioural changes, vision and hearing loss, and seizures.^[8][9]

Heterozygous females, though once thought to be asymptomatic carriers, tend to develop myelopathy and/or neuropathy before the age of 60, with the likelihood of symptoms increasing with age.^[10] While between 70-85% of males with AMN develop adrenocortical insufficiency, only 1% of symptomatic heterozygous females develop this condition.^[3][11] Only 2% of heterozygous females experience cerebral involvement.^[3]

AMN is caused by mutations in the ABCD1 gene located within the Xq28 region of the X chromosome.^[11] Over 1040 pathogenic variants of this gene have been identified.^[12] The ABCD1 gene encodes for the ATP-binding cassette (ABC) subfamily D member 1 protein, also known as the adrenoleukodystrophy protein (ALDP).^[3] ALDP facilitates the transport and subsequent degradation of very long-chain fatty acids (VLCFAs) via peroxisomal beta-oxidation.^[3] AMN is caused by a deficiency in ALDP, which precipitates the accumulation of VLCFAs within tissues that are typically ALDP-rich, namely the spinal cord, brain, adrenal glands, and testes.^[13] This results in a non-inflammatory myelopathy, primarily facilitated by microglial cells.^[14] AMN is primarily an axonopathy or neuronopathy, with the spinal cord being the most consistently affected structure.^[14] Spinal cord lesions typically occur in a bilateral, symmetrical manner and tend to severely impact the gracile and corticospinal tracts.^[14]

AMN can be detected via newborn screening tests.^[5] Blood tests may reveal elevated VLCFA levels, and genetic testing can be used to pinpoint mutations in the ABCD1 gene.^[8] Adrenocortical insufficiency can be identified by measuring plasma adrenocorticotropic hormone (ACTH) levels or conducting an ACTH stimulation test.^[15]

If AMN is diagnosed before the onset of symptoms, it is recommended that patients receive regular cerebral MRIs and adrenal insufficiency screening to monitor disease progression.^[16]

While there is no cure for AMN, treatments are available for symptom-management and to slow progression of the disease. Adrenal insufficiency can be treated with hormone replacement therapy, including the administration of glucocorticoids such as hydrocortisone and mineralocorticoids such as fludrocortisone.^[17] Cerebral AMN is typically treated with haematopoietic stem cell transplantation.^[18]

Lorenzo's oil has been proposed as method of reducing VLCFA levels within AMN patients, though the clinical efficacy of this treatment remains controversial.^[19] Immunosuppressive and immunomodulating drugs have been found to be ineffective in treating AMN.^[19]

The progression of AMN varies greatly among affected individuals. Clinical phenotype cannot be predicted from gene variants, and patient outcomes are suspected to be modulated by genetic and environmental factors.^[15] Early diagnosis and personalised interventions are thus crucial for managing AMN and addressing the specific needs of this population.^[18]