Neurological Disorders Due to Lysosomal Dysfunction

Inner Workings of a Human Cell
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It is occasionally humbling to imagine what would happen to your neighborhood if all those in your profession were to stop working for a month.  For many “white-collar” workers, the answer is that the neighborhood might keep humming along quite nicely.  But what if all those in garbage disposal decided to strike for a month?  It wouldn’t take too long for things to get ugly.

While disposing waste isn’t the most glamorous job performed by the brain, it is absolutely essential.

  Within the cells of the brain, waste disposal is largely performed by microscopic structures called lysosomes.  Lysosomes break down cellular waste products into less harmful byproducts.  When the lysosome doesn’t work well, neurological abnormalities can result.

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is inherited in an autosomal recessive fashion, meaning not every generation may be impacted.  The core problem is a deficiency of arylsulfatase A, a lysosomal enzyme.  In metachromatic leukodystrophy, the problem is less in nerve cells than in the myelinating cells that normally surround and protect those nerves.  For example, in the peripheral nervous system Schwann cells wrap around the long axons through which nerve cells send their signals. In metachromatic leukodystrophy, Schwann cells prepared with methylene blue contain little red and black inclusions that are distinct from the light blue of the rest of the cell.

  Metachromatic means “many colored,” thus giving this leukodystrophy its name. 

Metachromatic leukodystrophy can come on either in childhood or adulthood, though early–onset disease is more common.  Younger ages of onset are usually associated with more aggressive disease progression.  Cognitive impairment, eye problems, and spastic limbs can result.

  The peripheral nervous system can also be involved, with a distal sensorimotor peripheral neuropathy. 

Testing may include an MRI of the brain, which shows plaques in the white matter of the brain as well as volume loss.  Nerve conduction studies may suggest myelin loss in the peripheral nervous system as well. 

Bone marrow transplantation may stabilize cognitive symptoms if the disease is detected soon enough.

Krabbe disease

Like most leukodystrophies, globoid cell leukodystrophy, also known as Krabbe disease, is inherited in an autosomal recessive fashion.  Like metachromatic leukodystrophy, Krabbe’s disease results from a deficiency in a lysosomal enzyme—in this case galactosylceramidase.  Symptoms can come on in childhood or adulthood, though the latter is less common.  The symptoms are similar to that of metachromatic leukodystrophy, with cognitive impairment, movement disorders, and a peripheral neuropathy. 

An MRI will show white matter changes in the brain, and electrophysiological testing will suggest a loss of myelin in peripheral nerves.

  If a nerve biopsy is done, clear tubular inclusions may be found in protective Schwann cells on electron microscopy.   While brain biopsies are not routinely done, under a microscope giant cells with several nuclei (globoid cells) can be found in the brain’s white matter.  Treatment is similar to metachromatic leukodystrophy—bone marrow transplantation early in the disease may be helpful. 

Fabry disease

Fabry disease is due to deficiency of alpha-galactosidase A (AGAL). The disease classically impacts males as it is inherited in an X-linked fashion.  As men only have one X chromosome, they experience the full brunt of the disease.  Women have two X chromosomes, and the more functional chromosome can alleviate the symptoms.  That said, up to 70% of women who carry the mutation also develop some clinical problems, though these are usually milder and occur at a later age than in men.   

Fabry disease goes beyond just impacting the brain.  Patients offer suffer from heart and kidney problems as well.   The peripheral nervous system is also impacted, with an unusually painful neuropathy.  The gastrointestinal tract and skin may also be involved.  Even in the brain, Fabry disease is not strictly a leukodystrophy, though brain MRIs of those with Fabry disease often show signal abnormalities.  Those with Fabry disease have approximately a 20-fold higher risk of cerebrovascular disease such as stroke compared to the general population. Nevertheless, cognitive problems are not usually a pronounced part of the syndrome. 

In short, the humble act of waste disposal is critical. Fabry disease, Krabbe disease, and metachromatic leukodystrophy are three examples of what can happen when the waste disposal system of brain cells goes awry.


Ropper AH, Samuels MA. Adams and Victor's Principles of Neurology, 9th ed: The McGraw-Hill Companies, Inc., 2009.

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