Thread by @spinacademics

🧵 SPIN TWEETORIAL WEDNESDAY

LBSL — The tract-selective mitochondrial leukodystrophy
(DARS2-related)

There are leukodystrophies that blur the brain.
And then there are leukodystrophies that trace pathways with intention.
LBSL belongs to the latter.

Back to basics!

1/ Clinically, think slowly progressive:

Ataxia

Spastic paraparesis

Loss of vibration/position sense

Legs more affected than arms.
Reflexes are often preserved — and that alone is a beautiful clue.
Speech may become slurred with time.

Seizures can occur but are usually mild

2/ It’s caused by biallelic mutations in DARS2, a mitochondrial aspartyl-tRNA synthetase.
This isn’t a “global mitochondrial meltdown.”
It’s a selective energy failure in long, heavily myelinated tracts.

These tracts have:

Long axonal projections

Dense mitochondrial demand

Vulnerability when mitochondrial translation falters

So: the imaging pattern reflects the cell biology.

3/ The MRI pattern is the story.

LBSL doesn’t just affect white matter.
It chooses tracts.
With precision.

Start at the cerebral white matter:
Patchy or confluent deep white matter involvement,
but the subcortical U-fibers are spared.

This U-fiber sparing consistently distinguishes it from more diffuse leukodystrophies.

4/ Drop into the brainstem, and the diagnosis becomes unmistakable.

Look for signal changes in:

The pyramids (corticospinal tracts)

The decussation of the medial lemniscus (dorsal column pathway)

The superior and inferior cerebellar peduncles

And the most elegant giveaway:
The intraparenchymal trigeminal nerve fascicles.

Once you’ve seen this pattern,
you never unsee it.

5/ Now the spinal cord—the clincher.

The dorsal columns and the lateral corticospinal tracts light up,
beautifully symmetric, often from cervical cord down.

If you’re unsure in the brain,
go straight to the cervical cord.

If the cord is normal, reconsider your diagnosis.

6/ Lactate may or may not appear on MRS.
Its absence does not exclude LBSL.
The diagnosis is MRI-driven.
Molecular confirmation: DARS2.

7/ Important learning contrast:

Vitamin B12 deficiency also targets posterior columns,
but without this ruthless tract-specific brainstem signature.

Mitochondrial leukodystrophies may involve the brainstem,
but they don’t trace the pathways like this.

LBSL is tract art.

8/ Management is supportive.
No curative therapy yet.
But this is the exact category of disease being targeted in emerging mitochondrial translation therapies.

Avoid head trauma — episodes of sudden worsening are known.

9/ The one-line teaching pearl:

If both the dorsal columns and corticospinal tracts are involved in the brainstem AND spinal cord, with subcortical U-fiber sparing — think LBSL.

Say it while scrolling.
It works.

Image courtesy: GeneReviews, 2021 update on LBSL

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