What doesn't work (and why)

In the first post, I described what it's like to live with myoclonus-dystonia on a daily basis. Now, I'd like to explain what actually happens in the body and in the brain, what malfunctions, and why conventional treatments can't do much about it. Not to play doctor, but because when you live with this disease, understanding what's going on inside helps you accept what's going on outside.

One gene, one protein, one grain of sand

It all starts with a gene called SGCE, located on chromosome 7. This gene has a specific role: it produces a protein called epsilon-sarcoglycan. This protein belongs to a family of proteins, the sarcoglycans, that serve as anchor points between the inside of cells and their external environment. You can think of them as small hooks that keep the cell firmly attached to the structure surrounding it.

Epsilon-sarcoglycan is present throughout the body -- in the liver, lungs, kidneys -- but it is particularly abundant in two places that matter to us: muscle fibers and neurons. And that's where things get complicated.

In my case, the SGCE gene carries a mutation. This mutation causes the protein it produces to be truncated, incomplete, and therefore non-functional. The cell detects it as defective and destroys it. The result: there isn't enough epsilon-sarcoglycan where it's needed, particularly in the brain.

An important genetic detail: this gene is subject to what is called parental imprinting. In concrete terms, only the copy inherited from the father is expressed. The mother's copy is naturally silenced. This means that if the mutation comes from the father, the disease is fully expressed, since the only active copy of the gene is defective. This is the case in the vast majority of patients with DYT11.

In my case, the mutation is called de novo. This means it was not inherited from either of my parents: it appeared spontaneously, probably during the formation of reproductive cells or at the very beginning of embryonic development. Both my parents were tested, and neither carries the mutation. I am the first in my lineage to have it. It's a genetic accident, a copying error in the DNA that occurred only once, in me, with no family history and no explanation. There is no one to trace it back to, no carrier grandparent, no affected cousin. The mutation was born with me.

To give a sense of scale: DYT11 affects roughly one person in 500,000, and de novo mutations represent only a fraction of those cases. In other words, not only did I hit the jackpot of a rare genetic disease, but I hit it without even having a ticket: no carrier parent, no heredity, no known predisposition. I won the genetic lottery without playing, and the grand prize was a de novo myoclonus-dystonia. If I'd had the same astronomical odds of landing the right numbers on the EuroMillions, I'd be on a yacht. Instead, I shake. That's pretty representative of my luck in life, which operates on a simple and constant principle: a lot of bad luck and a lot of good luck, all the time, as if the universe couldn't make up its mind. But in the end, I'm fairly content, because it balances out. Sometimes it hurts, that's true. But in every case, it lets me taste incredible events and things, and I often meet extraordinary people. As for the scumbags, they don't deserve a paragraph.

The basal ganglia: the silent conductor

To understand why this missing protein causes involuntary movements, you have to look at a deep region of the brain called the basal ganglia.

These nuclei form a set of interconnected structures that play an essential role in movement control. They don't initiate movement themselves -- that's not their function. Their role is more that of a filter, a regulator, a silent conductor. They decide which movements should go through and which should be inhibited. When you want to grab a glass of water, it's the motor cortex that commands the gesture, but it's the basal ganglia that make sure only the right movement is executed, that unnecessary muscles stay quiet, that the gesture is smooth and proportionate.

Among these structures, there is one that plays a central role in dystonia: the globus pallidus internus, abbreviated GPi. The GPi is a kind of exit gate of the basal ganglia. It sends a permanent inhibitory signal to the thalamus, which in turn transmits commands to the motor cortex. This inhibitory signal is the system's brake. When the GPi is working properly, it prevents unwanted movements from occurring. When it malfunctions, this brake releases intermittently, and involuntary movements escape.

The cerebellum: the other player

For a long time, dystonia was thought to be exclusively a problem of the basal ganglia. But recent research has shown that the cerebellum plays an equally important role in DYT11.

The cerebellum, located at the back of the skull, is the center for fine motor coordination. It adjusts movements in real time, corrects errors, and ensures the smoothness of gestures. It turns out that epsilon-sarcoglycan is particularly abundant in Purkinje cells, which are the principal neurons of the cerebellum. When this protein is missing, these neurons no longer function normally: their firing pattern becomes irregular, their frequency decreases, and motor coordination is disrupted.

Studies on animal models have shown that deactivating the SGCE gene in the cerebellum alone is enough to produce symptoms of dystonia and myoclonus, whereas the same deactivation in the basal ganglia produces only mild motor impairment. This suggests that in DYT11, the starting point of the dysfunction may well be the cerebellum, and that the basal ganglia are disrupted downstream, through a network effect.

Because these two structures do not operate in isolation. The cerebellum and the basal ganglia are connected to each other through direct pathways, and they communicate constantly via the thalamus and the motor cortex. We speak of a circuit: the cerebello-thalamo-cortical and striato-pallido-thalamo-cortical circuit. When one link in this circuit malfunctions, the entire system goes haywire.

GABA: the chemical brake that gives way

At the heart of this dysregulation is a fundamental neurotransmitter: GABA, or gamma-aminobutyric acid. GABA is the brain's main inhibitory messenger. Its role is to calm neuronal activity, to slow down excessive signals, to maintain the balance between excitation and inhibition. Without GABA, the brain would be in permanent overdrive.

In DYT11, several studies have shown that the GABAergic system is impaired. Neurons that use GABA as their messenger, particularly in the striatum (a part of the basal ganglia) and in the cerebellum, operate below capacity. Research on neurons derived from DYT11 patients has revealed that these cells have fewer GABAergic synapses than normal, that they produce weaker and less frequent inhibitory signals, and that their spontaneous activity is reduced.

In simple terms, the brain's chemical brake no longer brakes enough. Motor signals that should be suppressed get through. Movements that should remain in the planning stage execute anyway. That is what a myoclonus is: a movement that escapes because the inhibition system failed to hold it back.

Why alcohol helps (and why it's not a solution)

This is a well-known fact among neurologists and experienced by many DYT11 patients: alcohol reduces symptoms, sometimes dramatically. One glass of wine, and the myoclonias calm down, the muscles relax, the gestures become smoother. This is no coincidence.

Alcohol acts, among other things, on GABA-A receptors, and in particular on a specific type of receptor located outside the synapses, in the cerebellum, that maintains a background inhibitory current in the neurons. By stimulating these receptors, alcohol temporarily restores part of the inhibition that is lacking. It compensates, for a few hours, for what the mutation prevents permanently.

But it's a trap. Alcohol creates dependency, and DYT11 patients are particularly vulnerable to it, precisely because the effect is real and immediate. This isn't weakness of character -- it's biology: when your brain discovers a substance that corrects its own malfunction, it asks for more. The psychiatric disorders associated with DYT11 -- notably anxiety, depression, and obsessive-compulsive behaviors -- don't help matters. Alcohol as treatment is therefore a known and documented dead end. For my part, I made the choice not to drink, precisely so as not to open that door. When you know your brain is wired to respond to alcohol better than average, the best strategy is to never give it the chance to remember.

What you try, and what disappoints

Faced with such a complex disease, medicine offers several pharmacological approaches. None is truly satisfactory.

Benzodiazepines, like clonazepam, also act on GABA receptors and can reduce myoclonias. But they cause significant drowsiness, tolerance builds up, and their effect diminishes over time.

Antiepileptics, like valproate, levetiracetam, or zonisamide, have been tested with variable results. Zonisamide is the only one to have shown efficacy in a controlled clinical trial, but the benefits remain modest and the side effects can be bothersome.

Anticholinergics can improve the dystonic component, but have no effect on the myoclonias, which are often the most disabling symptom.

Botulinum toxin can relieve localized dystonia, such as cervical dystonia, but it treats only one muscle at a time and does not address the core problem.

Sodium oxybate, a GABA derivative that acts similarly to alcohol on certain receptors, has shown promising effects in a few patients, but its use remains marginal and its safety profile is questionable, particularly in patients at risk for addiction.

The fundamental problem is the same for all these medications: they try to compensate for a chemical imbalance by acting diffusely across the entire brain, when the dysfunction is tied to a specific circuit. It's like trying to adjust the volume of a single instrument in an orchestra by turning the master volume knob. You get a partial effect, often accompanied by side effects, because the medication also acts where it isn't needed.

So, what's left?

What's left is an approach that doesn't correct the chemistry globally, but intervenes directly where the circuit malfunctions. An approach that consists of sending a continuous electrical signal into the GPi -- that exit gate of the basal ganglia I mentioned earlier -- to restore the brake that gave way. That approach is deep brain stimulation.

But before talking about that surgery, there's something else to tell. Because between the diagnosis and the operating room, there are years. Years during which you don't just sit still waiting for a solution. You build a life despite everything, with the dystonia, on top of the dystonia. That's the subject of the next post.

To be continued.