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]
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]
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