Leukodystrophies

Last updated on Monday, April 20 2009 by gliageek

Leukodystrophies can be classified by their biochemical abnormalities into lipid disorders (e.g. adrenoleukodystrophy, globoid cell leukodystrophy, metachromatic leukodystrophy), protein disorders (e.g. Pelizaues-Merzbacher disease), organic acid disorders (e.g. Canavan’s disease), defects in energy metabolism (e.g. MELAS), and other disorders (e.g. Alexander’s disease).

Adrenoleukodystrophy (ALD)
This X-linked disease manifests as two markedly different phenotypes: an early onset cerebral inflammatory demyelinating process that is rapidly progressive and inevitably fatal (without early bone marrow transplant) and a slowly progressive axonal neuropathy that usually presents in young adults (including 10-15% of heterozygous females). The ALD protein is one of four ATP-binding cassette transporters that are localized in the peroxisomal membrane. While the exact functions of these proteins are not known, patients with ALD accumulate very long-chain fatty acids (which are normally degraded in peroxisomes) in their tissues and body fluids. Over 350 ALD mutations have been described, and so far no genotype-phenotype correlation has been identified. MRI findings are characteristic in cerebral ALD; contrast enhancement indicates a poor prognosis and aids in the selection of patients for bone marrow transplant, which results in stabilization and sometimes even partial improvement of the neurologic deficit.

Alexander’s disease
Similar to the other leukodystophies, Alexander’s disease presents most commonly as a rapidly progressive fatal disorder of early childhood, but may rarely be seen in milder form in older children and young adults. Along with Canavan’s disease, Alexander’s disease is unusual among leukodystrophies in that it presents with megelencephaly (along with developmental retardation and seizures typical for leukodystrophies). The pathologic hallmark of Alexander’s disease is the accumulation of partially degraded glial filaments within the cytoplasm of astrocytes (called Rosenthal fibers). In addition to glial filaments, Rosenthal fibers contain the stress (“heat-shock”) proteins alpha-crystalline and hsp27.

The first documentation of a genetic cause for Alexander’s disease came in 2001, with the demonstration of heterozygous GFAP missense mutations in 12 of 13 unrelated patients with various forms of the disease, 0 of 53 control patients, and none of the parental DNA samples. Thus, mutations in this astrocytic protein arise de novo, result in a dominant gain of function, and give rise to a disorder of myelination. Among the reasons given for this are affectation of a common precursor cell (the O2A cell) and defective blood-brain barrier function consequent to the astrocyte dysfunction, with secondary impairment of myelination and axonal metabolism.

Acquired, non-inflammatory leukoencephalopathies
The major causes for this category of white matter disease are toxic, metabolic, vascular, and traumatic. We will focus on toxic leukoencephalopathy, as recognition of this class of disorders is on the rise. As with other forms of diffuse white matter damage, patients with toxic leukoencephalopathy tends to present with abnormalities of higher cerebral functioning (‘mental status changes”). In contrast to grey matter disorders that present with mental status changes, language is characteristically preserved in leukoencephalopathies. Four general categories of agents are implicated in the genesis of toxic leukoencephalopathy: 1. Therapeutic agents (including chemotherapeutic agents and radiation therapy), 2. Drugs of abuse (e.g. heroin, ecstasy/MDMA, glue/toluene), 3. Environmental toxins (e.g. carbon monoxide), and 4. Organic solvents (e.g. toluene.) A variety of pathogenic mechanisms have been postulated for the damage caused by these agents, and much more study is needed before successful therapies can be developed.

Related images:

Adrenoleukodystrophy, horizontal section
Diffuse loss of subcortical and deep white matter with a posterior -- anterior gradient and no preservation of subcortical U-fibers

Alexander disease, coronal section, close-up view
Diffuse loss of white matter without sparing of subcortical U fibers

Cockayne syndrome, ventral surface of brain
Microencephaly, with preferential atrophy of posterior fossa contents. Fibrous thickening of meninges with consequent communicating hydrocephalus.

Cockayne syndrome, multiple coronal sections of brain
Relatively normal appearing cerebral cortex accompanied by decreased white matter volume with dilated lateral ventricles. Basal ganglia appear dark, perhaps secondary to extensive microcalcification. Compare to the section of normal brain, below.

Krabbe disease, H&E stained section, high power
Vasculocentric accumulation of globoid microglia/macrophages.

Krabbe disease, coronal section, close-up
Diffuse white matter loss with sparing of subcortical U-fibers

Krabbe disease, ventral surface of brain
Discolored, but markedly enlarged olfactory and optic nerves.

Krabbe disease, H&E stain x 100
Diffuse reactive astrocytosis with globoid cells in various stages of development

Pelizaeus Merzbacher disease, Coronal section, Close Up
Tigroid demyelination with preservation of subcortical U fibers

Vanishing white matter disease
Chromatolytic appearing neurons within cerebral cortex

Vanishing White matter disease, H&E stain, high power
Axonal spheroids within subcortical white matter.

Vanishing white matter disease, H&E stain, 200 X magnification
Rarefaction of cerebral white matter with axonal spheroids

Vanishing white matter disease, cerebral cortex and white matter, H&E stain x 40
Diffuse rarefaction of subcortical white matter

Vanishing White matter disease, mid sagittal section
Preservation of brainstem and cerebellar white matter

Vanishing White matter disease, thalamus, H&E stain section
Spongiosis within thalamic nuclei

Adrenoleukodystrophy
Adrenoleukodystrophy

Alexander Disease, H&E stained section of cerebral cortex, 200 X magnification
Abundant Rosenthal fiber formation demonstrating subpial and perivascular accentuation

Alexander Disease, cerebral cortex and white matter, H&E stained section, 20X magnification
Abundant Rosenthal fiber formation within both gray and white matter, giving rise to macroencephaly in the early stages of the disease process

Canavan Disease, gray white junction, PAS stained section
Spongiform degeneration of the white matter

Canavan disease, high powered PAS stained section of cerebral cortex
Spongiform degeneration involving superficial layers of cerebral cortex.

Methotrexate neurotoxicity, H&E stained section x 100
Multi-Focal necrotizing leukoencephalopathy with axonal spheroids

Methotrexate neurotoxicity, H&E stain section, high power
Necrotizing leukoencephalopathy with prominent axonal spheroids

Pelizaus-Merzbacher disease, H&E stained section of white matter
Patchy (tigroid) myelin loss

Pelizaus-Merzbacher disease, Crimbring stained section of white matter
Patchy (tigroid) myelin loss

Alexander Disease on T2-weighted MRI
The findings in this MRI are typical for Alexander disease. MRI criteria for the diagnosis of Alexander disease include: 1. Extensive, frontally-predominant cerebral white matter changes 2. A periventricular rim which is bright on T1 and dark on T2 3...