Research Highlights

Research Rundown

What causes the symptoms of Warburg Micro Syndrome?

There are four genes known to cause Warburg Micro SPG69. These genes all cause RAB18 deficiency.

How exactly RAB18 deficiency causes the symptoms of Warburg Micro Syndrome still remains unclear, however research has suggested that RAB18 is involved in lipolysis, trafficking between the Golgi apparatus and ER, exocytosis, and autophagy. 

What do we know about what happens when RAB18 doesn't work?

One notable finding throughout studies, is that its loss of RAB18 leads to the build up of fewer, but larger lipid droplets. Lipid droplets play a role in energy homeostasis and ER stress. 

There are also adaptations in the autophagy pathway, which is the body’s way of cleaning out damaged cells.

How does this pathway relate to other forms of hereditary spastic paraplegia?

Lipid droplet size is also altered in other forms of hereditary spastic paraplegia like SPG31 and SPG3A.

Autophagy defects are also common in other forms of hereditary spastic paraplegia like SPG30, SPG47, SPG49, SPG50, SPG51, SPG52, SPG78 as well as in other motor neuron diseases like ALS and CMT implying neurons are particularly susceptible to disruption of the pathway.

RAB18 has many effectors- that is other proteins it interacts with to regulate activity in the body, and some of these may overlap with other HSPs.

Where can I read the latest studies about mechanisms and potential treatments?

Some important studies are still in prepublication. We will share those when available.

A characteristic and repeated finding in Warburg Micro is that lipid droplets are larger.
This study talks about one pathway that might be related- RAB18 binding to PLIN2 and ACSL3. PLIN2 has a role in cholesterol efflux.

This is an article about lipid droplets changes in hereditary spastic paraplegias.

This is an article about the specific association of RAB18 to lipid droplets
Another form of hereditary spastic paraplegia called SPG3a  (caused by a different gene) which begins around age 4, has found PLIN2 expression and cholesterol efflux are decreasedNerve cell degeneration was rescued in cortical neurons by applying a drug called an Liver X Receptor antagonist.
An experiment was done on another form of HSP, SPG61 (also caused by a different gene) which causes progressive spasticity beginning at birth.
In this case it was done in Drosophilia. L
iver X receptor-agonists again restored lipid droplet accumulation and improved locomotor function.

Tadepalle N and Rugarli EI (2021) Lipid Droplets in the Pathogenesis of Hereditary Spastic ParaplegiaFront. Mol. Biosci. 8:673977. doi: 10.3389/fmolb.2021.673977

Toupenet Marchesi L, Leblanc M, Stevanin G. Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia. Cells. 2021 Jul 2;10(7):1678. doi: 10.3390/cells10071678. PMID: 34359848; PMCID: PMC8307360.

Last Updated: June 28, 2022

Disclaimer: Families should consult a medical professional for genetic diagnosis, management and health concerns. We provide external links to help families and caregivers find additional information- this should not imply our endorsement or responsibility for their content. 

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