USMLE® Step 1 style questions USMLE
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A 3-year-old girl is brought to her pediatrician's office by her father because of difficulty talking and swallowing for the past month. She has an extensive history of seizures and developmental delay. Physical examination shows spasticity of the lower extremities. A magnetic resonance imaging study is done showing white matter changes and abnormalities within the brain stem and thalamus. Which of the following best explains this patient's symptoms?
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.
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.