Leukodystrophy

Definitions & Key takeaways

Leukodystrophy refers to a group of dysmyelinating diseases of the central and peripheral nervous system caused by genetic mutations in enzymes necessary for myelin production. The most common types are metachromatic leukodystrophy, Krabbe disease, and adrenoleukodystrophy. Symptoms are due to neurodegeneration, like decreased motor function, muscular rigidity, and later, blindness and hearing loss.

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Leukodystrophy can be broken down. Leuko- means “white”, -dys means “abnormal” and -troph means “growth”.
So, leukodystrophy means degeneration of the white matter of the brain, and that’s the part of the cerebral cortex that’s filled with myelinated axons.
Myelin refers to the electrical insulation sheath around axons which allows neurons to quickly send electrical impulses to one another.
Leukodystrophy is a dysmyelinating disease, meaning the structure of the myelin is abnormal, and it’s usually due to a genetic mutation.
In contrast, in a demyelinating diseases, previously normal myelin is damaged, like in multiple sclerosis where the immune cells attack the myelin.
There are many different kinds of leukodystrophy, but the most common ones are Krabbe disease, metachromatic leukodystrophy, and adrenoleukodystrophy.
The cerebral cortex is the largest region of the brain and it’s responsible for sensory and motor functions. The cerebral cortex has an outer grey area and an inner white area.
The grey area, referred to as grey matter, houses neuron cell bodies. And the white area, referred to as white matter, houses myelinated axons.
It is lighter because of the high fat content in myelin. Neurons are the key cells that transmit neural impulses to one another through synapses.
Each neuron has dendrites, a cell body, and an axon. Dendrites are the branches that first receive a neural impulse at a synapse with another neuron.
The neural impulse passes through the cell body and goes through an axon, which projects information away from the cell body to another cell.
Glial cells are support cells for neurons and they produce myelin to coat the axons. Myelin is a specialized membrane which helps insulate the axon to make neural impulses travel faster.
Glial cells in the central nervous system, are called oligodendrocytes, and glial cells in the peripheral nervous system are called Schwann cells.
Now the myelin is composed of certain fats, and the primary fat is called galactocerebroside. Galactocerebroside is also used to make another fat found in myelin called cerebroside sulfatide.
Over time, these fats are broken down by enzymes found within the lysosomes and peroxisomes of the glial cells. One enzyme that’s found in the lysosome is galactosylceramidase, which is encoded by the GALC gene.
Galactosylceramidase helps break down galactocerebroside as well as a cytotoxic metabolite called psychosine, which is a by-product of myelin production.
Another enzyme that’s in the lysosome is cerebroside-sulfatase, which is encoded by the arylsulfatase A gene, and helps break down cerebroside sulfatide.
An enzyme in the peroxisome is adrenoleukodystrophy, which is encoded by the ABCD1 gene, and helps break down very long chain fatty acids.
Most leukodystrophies are caused by genetic mutations and follow an autosomal recessive inheritance patterns, but some like Adrenoleukodystrophy are X-linked recessive.
Let’s go through three of the most common ones. First off, there’s Krabbe disease, named after the Danish neurologist Knud Krabbe, and it originates from a mutation in the GALC gene, which results in a shortage of galactosylceramidase.
That leads to a buildup of galactocerebroside and psychosine, which damages the glial cells in the central and peripheral nervous system.
Over time, dysmyelination occurs as the glial cells are no longer able to produce myelin. Special macrophages called globoid cells move in to clear out the damaged glial cells, and these globoid cells are a classic finding in Krabbe disease.
Typically, in Krabbe disease, symptoms begin in infancy. It can lead to feeding difficulties, stiffness, seizures, muscle weakness, deafness, and blindness.
Next up is metachromatic leukodystrophy, which is caused by a mutation in the arylsulfatase A gene, and results in a shortage of cerebroside-sulfatase.
That leads to a buildup of cerebroside sulfatide, which damages the glial cells in the central and peripheral nervous system.
Over time, dysmyelination occurs as the glial cells are no longer able to produce myelin. In metachromatic leukodystrophy, symptoms vary by the age of onset.
The late infantile form starts in children between age 1 and 2, and causes children to have severe muscle weakness, and causes difficulty walking, running, and climbing.
Over time it progresses to causing feeding difficulties, seizures, dementia, and blindness. If left untreated, it can cause death.
The juvenile form starts in children between age 3 and 10, and usually begins with a subtle cognitive decline like having difficulty in school, but then causes the same symptoms as infantile metachromatic dystrophy, including causing death.
Finally, the adult form begins in adulthood and can manifest as a psychiatric disorder or progressive dementia. Finally, there’s adrenoleukodystrophy, which is cause by a mutation in the ABCD1 gene, results in a shortage of adrenoleukodystrophy protein.
That leads to a buildup of very long chain fatty acids, which start to really build up in the adrenal glands and the brain.
These very long chain fatty acids trigger an inflammatory response, which damages the glial cells in the central and peripheral nervous system.
Like the other leukodystrophies, this leads to symptoms like feeding difficulties, stiffness, seizures, muscle weakness, deafness, and blindness.
The fatty acids also collect inside the adrenal glands, causing it to secrete less hormones like cortisol, and causes symptoms of Addison’s disease like vomiting, weight loss, and skin changes.
Diagnosis of leukodystrophies is done with an MRI that can help visualize degeneration of white matter. For metachromatic leukodystrophy, an arylsulfatase-A enzyme blood test in conjunction with a urinary sulfatide test can be done.
In adrenoleukodystrophy, blood levels of very long chain fatty acids can be obtained. Finally, genetic testing can help confirm the diagnosis.
Treatment of leukodystrophy starts with dietary changes to ensure that individuals avoid lipids that they cannot metabolize.
In addition, physical therapy may be helpful for motor difficulties. Finally, symptoms like seizures can be managed with antiepileptic medications.
Okay - so to recap, leukodystrophy is a dysmyelinating disease of the central and peripheral nervous system caused by genetic mutations in enzymes necessary for myelin production.
The most common types are metachromatic leukodystrophy, Krabbe disease, and adrenoleukodystrophy. Symptoms are due to neurodegeneration, like decreased motor function, muscular rigidity, and later, blindness and hearing loss.