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Leukodystrophies

Last updated on Monday, April 20 2009 by gliageek

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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.