Genetic Discoveries

Essential tremor may have a strong genetic component affecting multiple generations of families. NINDS researchers are building on previous genetics work to identify genes that make people more susceptible to familial early-onset (before age 40) essential tremor.  Researchers are focusing on multigenerational, early tremor onset families to better detect connections. Additionally, NINDS scientists are researching the impact of genetic changes on the development of essential tremor.  

2020 Stanford Scientists Uncover Genetic Basis of a Common Tremor Disease
Researchers expand knowledge of the genetic basis of Essential tremor -- the most common adult-onset movement disorder -- whose causes are unknown.BY ERIKA HUNTING

Today, trembling hands seem to be a hallmark of aging. This is just one of the symptoms of Essential Tremor (ET), the most common adult-onset movement disorder characterized by involuntary trembling of one or more body parts.  However, it turns out that for many people, ET starts at an earlier age than we realize.  

Although the causes of essential tremor are unknown, many studies involving families and individuals have shown that genes may play a role. However, it has proven quite challenging to identify the specific genes involved. But, in a paper published on Oct. 1 in PLOS Genetics, researchers in the lab of Michael Snyder, Stanford B. Ascherman Professor and Chair of Genetics and Director of Genomics and Personalized Medicine at Stanford University School of Medicine, discovered that TUB -- a gene previously implicated in obesity -- is associated with familial ET. 

"Essential tremor is a common condition, but the genetics part is still not well understood,” explained Postdoctoral Fellow Reza Sailani, the lead researcher on this study. “Unlike tremor related to aging, essential tremor starts much earlier in life. Our study identified a new candidate gene associated with this condition.” 

Correlation between TUB and Essential Tremor
A genetic variant is a specific region of the genome which differs between genomes i.e. people. Although many studies have shown that genes may play a role in families and individuals affected with ET, it has proven quite challenging to identify the specific genetic variants involved. Researchers in the Snyder Lab showed that rare variants of the TUB gene that are not present in healthy individuals are present in many individuals impacted by ET. Stanford scientists hope that understanding the TUB gene and its variants will expand our knowledge of the genetic basis of ET.

To look for genetic variants associated with ET, Dr. Sailani and his team began by analyzing the genomes of a large family, many of whom were affected by ET. By analyzing the genetic similarities and differences between the 10 affected and 6 un-affected family members, the scientists identified a genetic variant of the  TUB gene associated with ET. 

After these exciting initial findings, the researchers performed a follow-up study in an even larger cohort to make sure that their findings could generalize to more than just one family. Analysis of 820 unrelated individuals with ET and 630 healthy people revealed significant presence of rare TUB variants (including the variant identified in the family) in the individuals affected by ET. “This gene called TUB, is a transcription factor that turns on/off  many other genes,” explained Dr. Sailani. “It turned out that this gene mainly plays a role in the cerebellum part of the brain. In alignment with this condition, TUB  regulates the expression of neurotransmitters, such as those involved in the dopaminergic and cholinergic synapses. Defects in these pathways are known causes of tremor disorders. TUB is a new identified player for essential tremor and requires further investigations to understand its exact role in pathology of tremor."

Insights into Disease and Drug Targets
Expressed predominantly in neuronal cells, the TUB transcription factor “turns on/off  many other genes,” and modulates a broad spectrum of pathways in the brain. The pathways associated with ET, such as those involved in neurotransmission may have implications for diseases beyond ET.

To begin, mouse studies revealed that TUB regulates the pathways responsible for neurotransmitter production as well as thyroid hormone signaling. For example, TUB regulates pathways associated with acetylcholine, a neurotransmitter which facilitates many processes of the central nervous system, including learning, memory, attention and motor control. Additionally, Sailini’s study data shows that TUB regulates thyroid hormone signaling in the brain, suggesting interactions between TUB and thyroid hormone, and other studies have shown that TUB expression is lower in rats with hypothyroidism. Given that the thyroid regulates metabolism and that TUB seems to also be associated with obesity and insulin resistance, there may be promise in studying the TUB’s role in both pathways in developing a single treatment for both conditions.

Promising research continues at Stanford, as others in the Snyder Lab use stem cells to search for drugs that will alleviate ET. "The researchers plan to generate stem cells (iPS cells) from blood cells of tremor patients with TUB mutation,” explained Dr. Sailani. “They then turn these stem cells to brain cells in a petri dish where they can screen thousands of different drugs for therapeutic purposes". 

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Children's Educational Initiative

Children's Educational Initiative ​is dedicated to advocating for parents and children, empowering them to navigate the educational system so that children with Essential Tremor can achieve their full academic potential.
Children & ET
Essential Tremor is caused by overactive cells in the area of the brain called the thalamus. The thalamus is about the size of a walnut, and there are two within the brain. If there are overactive cells in the right thalamus, the person will have signs of tremor on the left side and vice versa. Some patients suffer from tremor on both sides.

The Point of onset can be similarly challenging, as tremor starts as on the is subtle.​
​As is the case with other degenerative conditions such as Parkinson’s disease, SCA, or dementia, the onset of ET is similarly insidious, as has been well-documented. Indeed, age of onset can be difficult to determine because patients can have difficulty appreciating their tremor early on.

Retrospectively recalling the point of onset can be similarly challenging, as tremor starts as subtle, of low-amplitude, and difficult to distinguish from medication-induced tremor, anxiety-related tremor or other para-normal and/or situational forms of tremor. As with other forms of neurodegeneration, the worsening of tremor in ET follows a gradual yet progressive clinical course, albeit the pattern of progression differs across patients; there have never been any documented cases of reversion of tremor or cessation of disease once set in motion.

There is a marked and continued rise in disease occurrence (both incidence and prevalence), which is exponential in advanced ages, and which is yet another feature of the neurodegenerative conditions. Furthermore, ET itself has been associated with other neurodegenerative disorders. For example, there is a longstanding association between ET and PD; indeed, having ET increases the risk of developing incident PD four to five-fold. ET & the Cerebellum
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Despite its prevalence, it wasn't until 2013 that essential tremor was given its own specific diagnostic code, one that's distinct from other tremors, in the 10th edition of the World Health Organization's International Statistical Classification of Disease and Related Health Problems (ICD) code book. ICD-10-CM Code for Essential tremor G25.0

ICD-10 code G25.0 for Essential tremor is a medical classification as listed by WHO under the range - Diseases of the nervous system.  
​In medicine, the word "essential" means there's no known underlying cause for a symptom, which is the case for essential tremor. 
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Diann Shaddox Foundation for Essential Tremor