Adrenoleukodystrophy pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
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, transfers fatty acids into peroxisomes to undergo [[beta oxidation|β-oxidation]]. However, VLCFA accumulation is necessary but not sufficient for the pathogenesis. The CNS pathology suggests the role of cellular and humoral immune processes. | |||
==Pathophysiology== | ==Pathophysiology== | ||
===Physiology=== | |||
The most common form of ALD is [[X-linked]] (the defective gene is on the X chromosome, location Xq28), and is characterized by excessive accumulation of very long chain [[fatty acids]] (VLCFA) — fatty acids chains with 24–30 [[carbon]] atoms (particularly hexacosanoate, C26) in length. This was originally described by Moser ''et al'' in 1981.<ref>Moser HW, Moser AB, Frayer KK, Chen W, Schulman JD, O'Neill BP, Kishimoto Y. ''Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids.'' Neurology 1981;31:1241-9. PMID 7202134.</ref> So, when the ALD gene was discovered in 1993, it was a surprise that the corresponding protein was in fact a member of a family of transporter proteins, not an enzyme. It is still a mystery as to how the transporter affects the function of the fatty acid enzyme and, for that matter, how high levels of very long chain fatty acids cause the loss of myelin on nerve fibers. | The most common form of ALD is [[X-linked]] (the defective gene is on the X chromosome, location Xq28), and is characterized by excessive accumulation of very long chain [[fatty acids]] (VLCFA) — fatty acids chains with 24–30 [[carbon]] atoms (particularly hexacosanoate, C26) in length. This was originally described by Moser ''et al'' in 1981.<ref>Moser HW, Moser AB, Frayer KK, Chen W, Schulman JD, O'Neill BP, Kishimoto Y. ''Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids.'' Neurology 1981;31:1241-9. PMID 7202134.</ref> So, when the ALD gene was discovered in 1993, it was a surprise that the corresponding protein was in fact a member of a family of transporter proteins, not an enzyme. It is still a mystery as to how the transporter affects the function of the fatty acid enzyme and, for that matter, how high levels of very long chain fatty acids cause the loss of myelin on nerve fibers. | ||
===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. <ref name="HudspethRaymond2007">{{cite journal|last1=Hudspeth|first1=Michelle P.|last2=Raymond|first2=Gerald V.|title=Immunopathogenesis of adrenoleukodystrophy: Current understanding|journal=Journal of Neuroimmunology|volume=182|issue=1-2|year=2007|pages=5–12|issn=01655728|doi=10.1016/j.jneuroim.2006.10.009}}</ref> | |||
TNF-alpha also has an important role in the pathogenesis of ALD. | |||
==Genetics== | |||
The gene (''[[ABCD1]]'' or "ATP-binding cassette, subfamily D, member 1") codes for a protein that transfers fatty acids into [[peroxisome]]s, the cellular [[organelle]]s where the fatty acids undergo [[beta oxidation|β-oxidation]].<ref>Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, Poustka AM, Mandel JL, Aubourg P. ''Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters.'' [[Nature (journal)|Nature]] 1993;361:726-30. PMID 8441467.</ref> A dysfunctional gene leads to the accumulation of very long chain fatty acids (VLCFA). | The gene (''[[ABCD1]]'' or "ATP-binding cassette, subfamily D, member 1") codes for a protein that transfers fatty acids into [[peroxisome]]s, the cellular [[organelle]]s where the fatty acids undergo [[beta oxidation|β-oxidation]].<ref>Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, Poustka AM, Mandel JL, Aubourg P. ''Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters.'' [[Nature (journal)|Nature]] 1993;361:726-30. PMID 8441467.</ref> A dysfunctional gene leads to the accumulation of very long chain fatty acids (VLCFA). | ||
==Gross pathology== | |||
*Adrenal glands show atrophy. | |||
*Brain shows visible demyelination involving both cerebellar hemispheres, parts of the medulla oblongata, the pons and the midbrain. | |||
*Spinal cord shows grayish white matter area. | |||
==Microscopic Pathology== | |||
===Adrenals=== | |||
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. Cytoplasm and a nucleus moderately rich in chromatin shifted towards the cytoplasma membrane.<ref name="UlrichHerschkowitz1978">{{cite journal|last1=Ulrich|first1=J.|last2=Herschkowitz|first2=N.|last3=Heitz|first3=Ph.|last4=Sigrist|first4=Th.|last5=Baerlocher|first5=P.|title=Adrenoleukodystrophy|journal=Acta Neuropathologica|volume=43|issue=1-2|year=1978|pages=77–83|issn=0001-6322|doi=10.1007/BF00685001}}</ref> | |||
===Nervous System<ref name="UlrichHerschkowitz1978">{{cite journal|last1=Ulrich|first1=J.|last2=Herschkowitz|first2=N.|last3=Heitz|first3=Ph.|last4=Sigrist|first4=Th.|last5=Baerlocher|first5=P.|title=Adrenoleukodystrophy|journal=Acta Neuropathologica|volume=43|issue=1-2|year=1978|pages=77–83|issn=0001-6322|doi=10.1007/BF00685001}}</ref>=== | |||
*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 | |||
**Granular cellular content and nucleus displaced towards the periphery | |||
==References== | ==References== | ||
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Overview
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, transfers fatty acids into peroxisomes to undergo β-oxidation. However, VLCFA accumulation is necessary but not sufficient for the pathogenesis. The CNS pathology suggests the role of cellular and humoral immune processes.
Pathophysiology
Physiology
The most common form of ALD is X-linked (the defective gene is on the X chromosome, location Xq28), and is characterized by excessive accumulation of very long chain fatty acids (VLCFA) — fatty acids chains with 24–30 carbon atoms (particularly hexacosanoate, C26) in length. This was originally described by Moser et al in 1981.[1] So, when the ALD gene was discovered in 1993, it was a surprise that the corresponding protein was in fact a member of a family of transporter proteins, not an enzyme. It is still a mystery as to how the transporter affects the function of the fatty acid enzyme and, for that matter, how high levels of very long chain fatty acids cause the loss of myelin on nerve fibers.
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. [2] TNF-alpha also has an important role in the pathogenesis of ALD.
Genetics
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.[3] A dysfunctional gene leads to the accumulation of very long chain fatty acids (VLCFA).
Gross pathology
- Adrenal glands show atrophy.
- Brain shows visible demyelination involving both cerebellar hemispheres, parts of the medulla oblongata, the pons and the midbrain.
- Spinal cord shows grayish white matter area.
Microscopic Pathology
Adrenals
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. Cytoplasm and a nucleus moderately rich in chromatin shifted towards the cytoplasma membrane.[4]
Nervous System[4]
- 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
- Granular cellular content and nucleus displaced towards the periphery
References
- ↑ Moser HW, Moser AB, Frayer KK, Chen W, Schulman JD, O'Neill BP, Kishimoto Y. Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. Neurology 1981;31:1241-9. PMID 7202134.
- ↑ Hudspeth, Michelle P.; Raymond, Gerald V. (2007). "Immunopathogenesis of adrenoleukodystrophy: Current understanding". Journal of Neuroimmunology. 182 (1–2): 5–12. doi:10.1016/j.jneuroim.2006.10.009. ISSN 0165-5728.
- ↑ Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, Poustka AM, Mandel JL, Aubourg P. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 1993;361:726-30. PMID 8441467.
- ↑ 4.0 4.1 Ulrich, J.; Herschkowitz, N.; Heitz, Ph.; Sigrist, Th.; Baerlocher, P. (1978). "Adrenoleukodystrophy". Acta Neuropathologica. 43 (1–2): 77–83. doi:10.1007/BF00685001. ISSN 0001-6322.