Adrenoleukodystrophy overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
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Overview
Adrenoleukodystrophy (ALD) is a degenerative disorder of myelin, a complex fatty neural tissue that insulates many nerves of the central and peripheral nervous systems. Without myelin, nerves are unable to conduct an impulse, leading to increasing disability as myelin destruction increases and intensifies. The victims of ALD are always male, and the disease begins its expression around the ages 5 to 10. The disease is due to an X-linked inheritance of peroxisomes that cannot properly process long chain fatty acids in the brain.
ALD is a type of leukodystrophy, disorders affecting the growth and/or development of myelin. Leukodystrophies are different from demyelinating disorders such as multiple sclerosis where myelin is formed normally but is lost by immunologic dysfunction or for other reasons.
Historical Perspective
Adrenoleukodystrophy was first described by Siemerling and Creutzfeld in 1923. The X-linked recessive inheritance phenomenon was clarified in 1963 by Fanconi et al. This was previously known as Schilder 's syndrome, but in 1970 Michael Blaw renamed it to "Adrenoleukodystrophy." Fanconi et al . discovered the X-linked recessive inheritance in 1963. In 1976, Igarashi et al identified the aggregation of concentrated, very long chain fatty acids (VLCFAs) in brain and adrenal tissue. In 1986, Lazo et al. indicated that incomplete oxidation of fatty acids is due to the deficiency of the peroxisome matrix enzyme lignoceroyl-CoA synthetase. Mosser et al. isolated the ALD gene in 1993.
Classification
Adrenoleukodystrophy may be classified based on different clinical presentations. There are seven male phenotypes i.e. Childhood cerebral adrenoleukodystrophy, Adolescent, Adrenomyeloneuropathy, Adult cerebral, Olivo-pontocerebellar, Addison-only , Asymptomatic and five female phenotypes i.e. Asymptomatic, Mild myelopathy, Moderate to severe myeloneuropathy, Cerebral involvement, Clinically evident adrenal insufficiency.
Pathophysiology
Adrenoleukodystrophy is an X-linked disease characterized by excessive accumulation of very long chain fatty acids (VLCFA), originally described by Moser et al in 1981. The gene (ABCD1 or "ATP-binding cassette, subfamily D, member 1") codes for a protein that transfers fatty acids into peroxisomes, the cellular organelles where the fatty acids undergo β-oxidation. A dysfunctional gene leads to the accumulation of very long chain fatty acids (VLCFA). However, VLCFA accumulation is necessary but not sufficient for the pathogenesis. Pathology in CNS shows distinct immunological features. A predominant Th1 cytokine response suggests the role of cell mediated immunity. Immunocytochemical analysis done on the CSF from the ALD patients showed IgG, B cells and the presence of cytoplasmic IgA in postmortem brain suggesting the role of the humoral immune process. There was increased expression of the antigen-presenting molecule, which presents foreign and self-lipid to MHC-unrestricted T cells, CD1 in cerebral lesions clearly showing that both VLCFA and a myelin component such as proteolipid protein serves as the antigen for the immune response. TNF-alpha also has an important role in the pathogenesis of ALD. On Gross Examination Adrenal glands show atrophy, Brain shows visible demyelination involving both cerebellar hemispheres, parts of the medulla oblongata, the pons and the midbrain and Spinal cord shows grayish white matter area. On microscopic examination adrenal medulla appears fine, but the cortex is atrophic. A substantial portion of it is replaced by clusters of extremely large cells, distinctly delimited from each other, with mildly granular eosinophilic cells and Cytoplasm and a nucleus moderately rich in chromatin shifted towards the cytoplasma membrane. Whereas nervous system shows Nearly complete demyelination affecting all white structures in the dorsal areas of the brain, Complete demyelination of the cerebellar hemispheres, prefrontal peduncles, pes pontis, pyramids and lateral pyramidal tract, Gliosis and macrophages are present, Glial cells are found in myelinated and unmyelinated regions, Abnormalities are found in the schwann cells of the peripheral nerve, Changes in the gray matter are less apparent than those in white matter but some of the pathological findings present include: Proximal Axonal Swellings in Purkinje cell axons, Ballooned nerve cells in the arcuate nucleus of the medulla oblongata and Granular cellular content and nucleus displaced towards the periphery.
Causes
X-linked adrenoleukodystrophy (X-ALD) is a monogenic disease caused by mutations in the ABCD1 gene located on Xq28. It is passed down from parents to their children as an X-linked genetic trait. It therefore affects mostly males, although some women who are carriers can have milder forms of the disease. The condition results in the buildup of very-long-chain fatty acids in the nervous system, adrenal gland, and testes, which disrupts normal activity.
Differentiating Adrenoleukodystrophy from Other Diseases
Adrenoleukodystrophy must be differentiated from Leigh syndrome, Niemann-Pick disease type C, Infantile Refsum disease, Zellweger syndrome, Pyruvate dehydrogenase deficiency, Arginase deficiency, Holocarboxylase synthetase deficiency, Glutaric aciduria type 1, Ataxia telangiectasia, Pontocerebellar hypoplasias, Metachromatic leukodystrophy, Pelizaeus-Merzbacher, Angelman syndrome, Rett syndrome, Lesch-Nyhan syndrome, Miller-Dieker lissencephaly and Dopa-responsive dystonia.
Epidemiology and Demographics
Adrenoleukodystrophy is the most common peroxisomal disorder, with an estimated incidence of 1 in 17,000 births (male and female) and 1 in 21,000 males in the United States. The prevalence of X-linked adrenoleukodystrophy is approximately 1 in 20,000 individuals. This condition occurs at a similar frequency in all populations. The lifetime prevalence of adrenal insufficiency in ALD is ~80 percent. Childhood cerebral type is common in age 3-10 years. The median age of the AMN form is 28 years. Addison disease type occurs at 0 to (greater or equal to) 10 years of age. Cerebellar type can occur in childhood or adolescence. There is no race predilection for adrenoleukodystrophy. Men are more likely to be affected by adrenoleukodystrophy than women. Women can, however, be the carriers of the disease.
Risk Factors
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.
Screening
Adrenoleukodystrophy screening started in state of New York in December, 2013 followed by Connecticut, California, Minnesota and 14 other states. The first step in screening is to take newborn's dried blood spot and analyse it with tandem mass spectrometry for the elevated levels of C26:0-LPC. Samples with a high concentration of C26:0-LPC are then tested in the second step with a more sensitive but time consuming test, using High Performance Liquid Chromatography – MS / MS. The third step is the sequencing of the ABCD1 gene in those samples which still shows elevated C26:0-LPC.
Natural History, Complications, and Prognosis
Natural History
Adrenoleukodystrophy is a progressive disease as the risk of symptoms increases with age but its manifestations are highly variable. Most of the male patients presents with adrenal insufficiency (Addison disease) in childhood (80% prevalence) while those in adulthood presents with signs of myelopathy. Women with the ALD usually presents with myelopathy, other manifestations such as adrenal insufficiency are unusual. Childhood cerebral ALD is the most serious form of the disease. It typically occurs between the ages of 2.5 and 10 years, and is associated with rapid neurological decline and death or disability on average 3 years after initiation. Males who do not develop the disease in childhood, develops Adrenomyeloneuropathy (AMN) in 30s or 40s. ALD usually does not occur in heterogeneous women. Only 88 per cent of adult women can become symptomatic with myelopathy and peripheral neuropathy, but the symptoms are usually milder than those of men.
Complications
Common complications of Adrenoleukodystrophy include Adrenal crisis and Vegetative state (long-term coma).
Prognosis
The childhood form of X-linked adrenoleukodystrophy is a progressive disease that leads to a long-term coma (vegetative state) about 2 years after neurological symptoms develop. The child can live in this condition for as long as 10 years until death occurs. The other forms of this disease are milder.
Diagnosis
History and Symptoms
The clinical manifestations of the disease are highly variable, with at least six different types ranging from childhood cerebral to asymptomatic.The most severe type is the childhood cerebral form, which normally occurs in males between the ages of 5 and 10 and is characterized by failure to develop, seizures, ataxia, adrenal insufficiency, as well as degeneration of visual and auditory function. Frequent initial symptoms include emotional lability, hyperactive behaviour, school failure, impaired auditory discrimination and difficulties in vision. The adolescent type usually starts between age 11 and 21 years. Adrenomyeloneuropathy usually presents with weakness and numbness of the limbs and problems with urination or defecation. Some patients may present with sole findings of primary adrenal insufficiency.
Physical Examination
Most males in childhood have adrenal insufficiency that can show orthostatic hypotension, hyperpigmentation and confusion. Females who are heterozygous and symptomatic can have sphincter disturbances, incoordination and paraparesis.The most aggressive one is Childhood cerebral type which can show behavioural changes, school failure, dementia, speech impairment, bulbar palsy, paralysis and audiovisual changes on examination. Some of the general examination findings which can occur in all phenotypes includes Strabismus, Swallowing difficulties, Aphasia, Deterioration of handwriting, Difficulty at school, Difficulty understanding spoken material, Hyperactivity,Coma, Decreased fine motor control,Paralysis, Seizures, Possible worsening muscle weakness or leg stiffness, Problems with thinking speed and visual memory.
Laboratory Findings
An elevated concentration of plasma levels of VLCFA suggests the presence of Adrenoleukodystrophy. DNA-based diagnosis can be obtained to look for mutations in the ABCD1 gene in the case of carriers and is particularly important in the diagnosis of the disease in women. Assessment of physical capabilities and measurements of walking speed, hip strength, vibration sense and nerve conductions studies has been used in assessing disease severity in AMN.
Imaging Findings
MRI
Brain MRI may be helpful in the diagnosis of Adrenoleukodystrophy. Findings on MRI suggestive of Adrenoleukodystrophy include Abnormal bright signal intensities on the T2-weighted MRI images, Involvement of Corticospinal tracts is the most common finding in male patients whereas in females there is mild diffuse increase of signal intensity in the parieto occipital or frontal lobe white matter. Spine MRI may also be helpful in the diagnosis of Adrenoleukodystrophy. Findings on MRI suggestive of Adrenoleukodystrophy include Magnetization transfer-weighted (MTw) images showing signal hyperintensities in the lateral and dorsal columns and Diffuse spinal cord atrophy, mainly in the thoracic and cervical regions.
CT Scan
Brain CT scan may be helpful in the diagnosis of Adrenoleukodystrophy but not used as it is less sensitive than MRI. Findings on CT scan suggestive of Adrenoleukodystrophy can include Contrast enhancement within or adjacent to the abnormally hypodense deep white matter of the parietal, occipital lobes and at the interface between this active demyelinating area and uninvolved normal brain, Asymmetric areas of diminished attenuation in occipital horns of the lateral ventricles and the splenium of the corpus callosum.
Proton Magnetic Resonance Spectroscopic (MRS) imaging
This imaging technique show changes in metabolic rates. MRS imaging was able to demonstrate low NAA and high choline levels in white matter as a first indicator of metabolic dysfunction, prior to MRI changes in ALD.
Diffusion Tensor Imaging (DTI)
This imaging technique show changes in water diffusion parameters. High directionality and structure of white matter, resulting from the directional morphology of myelinated axons, is quantified by a higher relative Fractional anisotropic (FA) with DTI. A decreased FA can be seen in central cALD lesion areas.
Other Diagnostic Studies
There are no other diagnostic studies associated with Adrenoleukodystrophy.
Treatment
Medical Therapy
The mainstay of treatment for adrenoleukodystrophy is Hematopoietic stem cell transplantation. Supportive therapy includes Lorenzo's oil and Lovastatin therapy. Antioxidant therapy has also shown some persuasive results demanding a larger study whereas treatment with Gene therapy including Ex vivo lentiviral gene correction and in vivo adeno-associated virus 9 (AAV9) based gene therapy is being pursued.
Surgery
Surgical intervention is not recommended for the management of adrenoleukodystrophy.
Prevention
Primary Prevention
There are no established measures for the primary prevention of adrenoleukodystrophy.