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Phenotypes of Adrenoleukodystrophy.[edit]

Adrenoleukodystrophy (ALD) as a genetic disorder has several phenotypes that appear during it's development in an individual.[1] These phenotypes are age related and as a progressive disease these often lead to a degeneration of function across the lifetime.[2] While these phenotypes are not in any way heterogeneous across individuals, with some being asymptomatic and others not, these designations are helpful in determining the nature of the condition and it's pathophysiology.[1]

Male adrenoleukodystrophy phenotypes[edit]

Childhood cerebral[edit]

Childhood cerebral ALD is a potentially deadly stage of the condition that affects both the adrenal glands and central nervous system. Usually appearing between the ages of 3-10 in symptomatic patient and generally appears in about 30-40% of those diagnosed with ALD, for such symptomatic patients the prognosis is generally poor.[1] The condition manifests as the result of inflammatory brain demyelination. During this stage the treatments are generally either the use of bone marrow transplants, which can stabilise the degenerative effects of this stage of the condition, though the exact mechanisms of this improvement are not exactly understood. In addition, the use of therapeutic treatments such as Lorenzo's oil are more often used due to the reduced risk of the treatments.[3]

Adolescent[edit]

This stage of the condition often progresses down very similar paths to the earlier childhood cerebral stage, though often at a slower pace. The onset of this stage usually occurs between the ages of 15-21 and follows a path similar to the earlier stage.[1] The similarities in both phenotypes extend to the treatments, with Lorenzo's oil and bone marrow transplant being the main sources of therapy.[3]

Adrenomyeloneuropathy (AMN)[edit]

AMN is a common later onset phenotype of ALD that is characterised by the axonopathy in the spinal cord.[4] It is further characterised by a lack of any lesions or lymphocytic infiltrations that characterise the childhood and adolescent phenotypes.[1] About 15% of males with AMN do not develop any type of adrenal insufficiency Instead there are many microglia and macrophages.[5] This phenotype is usually appears in the third decade of life and results in slow degeneration over the next several decades, this often results in limb stiffness which eventually results in the individual become wheelchair bound. Chronic AMN sufferers are often treated through the use of hydrocortisone replacement. During development, it is expected that roughly 40-50% of AMN sufferers will develop some sort of white matter lesion in T1 and T2 weighted images for MR studies. Such individuals are often characterised under the label of cerebral AMD. Local MR spectroscopy can identify myelin breakdown and axonal loss in such individuals usually after the changes in such structures have already begun. This is generally why such individuals are given regular MR spectroscopy in order to track its progression.[4]

Adult cerebral[edit]

This stage appears well into adulthood and often runs parallel to the AMN phenotype in terms of age. It varies however in the fact that it involves cerebral demyelination and neuro-inflammation that eventually results in white matter degeneration. This demyelination leads to neurocognitive functions, resulting in dementia and behavioural changes. This stage also results in a rapid loss of motor and sensory functions.[6] The ultimate result of this degeneration is the individual falling into a vegetative coma and eventually neurological death. Detection of this cerebral demyelination has thus far proved elusive, and predicting it's onset s currently difficult before symptoms appear. Due to the quick progression from appearance to death, the use of haematopoietic stem cell transplantation which is used for the treatment of earlier onset cerebral ALD is less able to be effectively. Despite this it has been shown that this type of treatment may be feasible, but further study is needed.

Olvio-Pento-Cerebellar[edit]

This form of ALD coincides with a degeneration in nerve cells located in the cerebral and brain cell damage. This stage is also characterised by X-linked glyceryl kinase deficiency and central pontine myelinolysis.[7] This stage typical appears in adolescence or adulthood, and usually first presents as a gait disturbance which later develops into cerebellar ataxia at around a year after first onset. The treatment for this phenotype is usually the reduction in plasma VLCFA.[3]

Addison's-Disease Only[edit]

Addison's disease, also known as adrenal insufficiency (AI) is a condition that also affects many boys born with X-ALD. Addison's disease is primarily represented by an inability to synthesise glucocorticoid and mineralocorticoid which are both primary the cortisol and aldosterone hormones respectively, this results in the pituitary corticotropes increase secretion of adrenocorticotropin (ACTH), this was in order to increase the stimulation of the adrenal glands.[8][9] This results in Addison's disease also featuring a reduction in ACTH levels. Symptoms of Addison's disease may present before the appearance of the symptoms associated in X-ALD. Addison's disease is usually present in about 43% of asymptomatic cases. In industrialised countries Autoimmune degeneration is the most common example of Addison's disease degeneration. In order to diagnose the presence of this condition it is usually the case that biochemical measures of cortisol levels must be conducted in order to establish whether there is a deficiency. This is usually conducted through either adrenal insufficiency in the setting of hypotension or through a test of morning serum cortisol. Treatment for Addison's disease is usually in the form of 12-15mg of hydrocortisone and 0.05 and 0.3mg of fludrocortisone, both taken orally.[3]

Asymptomatic[edit]

Asymptomatic ALD in male individuals is characterised by those who posses all of the biochemical markers of the condition but do not have the neurological degeneration that is associated with traditional ALD suffers as observed through MRI of affected areas, these MRI projections usually appear before the age of 7[2]. In addition, these individuals do not have the adrenal insufficiency that appears in other sufferers. However, specialist tests for ALD such as the plasma very long chain fatty-acids (VCLFA) assay may reveal some weakness of the adrenal system. These types of analysis are useful in that they reveal biochemical evidence that would otherwise be clinically silent. As individuals age the presence of asymptomatic cases tend to drop with the chances of cerebral onset reducing to it's lowest point after the age of 13. It should be noted however that the chances of developing cerebral symptoms never entirely disappears.[10]

Female Phenotypes[edit]

Asymptomatic[edit]

The vast majority of female individuals that possess the genetic markers of X-ALD do not develop any type of adrenal or neurological deficiencies before their third decade. The only seeming marker of the condition being that they carry the condition and can pass it on to any children they may have.[8]

Mild myelopathy[edit]

This phenotype usually involves the loss of sensitivity in the lower extremities. This can lead too mild disability in some individuals, but can also develop no obvious disability in many other individuals.[8]

Moderate to severe myelopathy[edit]

In this phenotype stage the loss of lower extremities is more pronounced and in many ways mirrors the AMN phenotype that appears in males. Due to the rarity of this condition in women it may often be mis-diagnosed as multiple sclerosis.[8]

Cerebral Involvement[edit]

In this phenotype, neurological demyelination is far more pronounced ad as a result can often feature more noticeable and severe symptoms, this includes dementia, severe spasticity, spastic paraparesis and seizures. Even in individuals with no obvious physical symptoms can have markers of atrophy, such a lesions and evidence of demyelination This can lead to individuals dropping into a state of stupor, followed by death.[8]

Adrenal Involvement[edit]

Adrenal insufficiency is incredibly rare among female carriers. Theses symptoms typically mirror those of the male phenotypes, though with a typically later onset, usually appearing during the fifth decade.[8]

[1] [2] [3] [4] [5] [10] [6] [7] [9] [8]

  1. ^ a b c d e f Moser, Hugo W; Smith, Kirby D; Watkins, Paul A; Powers, James; Moser, Ann (2001). The metabolic & molecular bases of inherited disease (8th ed.). New York: McGraw-Hill. pp. 412–419. ISBN 978-0-07-136320-4.
  2. ^ a b c Geel, Björn M. van; Bezman, Lena; Loes, Daniel J.; Moser, Hugo W.; Raymond, Gerald V. (2001). "Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy". Annals of Neurology. 49 (2): 186–194. doi:10.1002/1531-8249(20010201)49:23.0.CO;2-R. ISSN 1531-8249.
  3. ^ a b c d e Mahmood, Asif; Dubey, Prachi; Moser, Hugo W.; Moser, Ann (2005). "X-linked adrenoleukodystrophy: Therapeutic approaches to distinct phenotypes". Pediatric Transplantation. 9 (s7): 55–62. doi:10.1111/j.1399-3046.2005.00447.x. ISSN 1399-3046.
  4. ^ a b c Powers, James M.; DeCiero, David P.; Ito, Masumi; Moser, Ann B.; Moser, Hugo W. (February 2000). "Adrenomyeloneuropathy". Journal of Neuropathology & Experimental Neurology. 59 (2): 89–102. doi:https://doi.org/10.1093/jnen/59.2.89. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  5. ^ a b Gong, Yi; Sasidharan, Nikhil; Laheji, Fiza; Frosch, Matthew; Musolino, Patricia; Tanzi, Rudy; Kim, Doo Yeon; Biffi, Alessandra; Khoury, Joseph El; Eichler, Florian (2017). "Microglial dysfunction as a key pathological change in adrenomyeloneuropathy". Annals of Neurology. 82 (5): 813–827. doi:10.1002/ana.25085. ISSN 1531-8249.
  6. ^ a b Berger, J; Forss-Petter, S; Eichler, F.S. (1 March 2014). "Pathophysiology of X-linked adrenoleukodystrophy". Biochimie. 98: 135–142. doi:10.1016/j.biochi.2013.11.023. ISSN 0300-9084.
  7. ^ a b Vianello, M.; Manara, R.; Betterle, C.; Tavolato, B.; Mariniello, B.; Giometto, B. (2005). "X-linked adrenoleukodystrophy with olivopontocerebellar atrophy". European Journal of Neurology. 12 (11): 912–914. doi:10.1111/j.1468-1331.2005.01134.x. ISSN 1468-1331.
  8. ^ a b c d e f g Jangouk, Parastoo; Zackowski, Kathleen M.; Naidu, Sakkubai; Raymond, Gerald V. (1 February 2012). "Adrenoleukodystrophy in female heterozygotes: Underrecognized and undertreated". Molecular Genetics and Metabolism. 105 (2): 180–185. doi:10.1016/j.ymgme.2011.11.001. ISSN 1096-7192.
  9. ^ a b Nieman, Lynnette K.; Chanco Turner, Maria L. (1 July 2006). "Addison's disease". Clinics in Dermatology. 24 (4): 276–280. doi:10.1016/j.clindermatol.2006.04.006. ISSN 0738-081X.
  10. ^ a b Dubey, Prachi; Raymond, Gerald V.; Moser, Ann B.; Kharkar, Sidharth; Bezman, Lena; Moser, Hugo W. (1 April 2005). "Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening". The Journal of Pediatrics. 146 (4): 528–532. doi:10.1016/j.jpeds.2004.10.067. ISSN 0022-3476.
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