A New Use for Old Drugs

Written by Dr. Amy Smith-Dijak Edited by Logan Morrison

Basic biology helps identify a new treatment for ataxia

Drug design doesn’t always have to start with a blank slate. Sometimes understanding how existing drugs work can help researchers to design new ones, or even to recombine old drugs in new and more effective ways. That’s what the researchers behind this paper did. They investigated the basic biology of three existing drugs: chlorzoxazone, baclofen, and SKA-31.

Two of these – chlorzoxazone and baclofen – are already FDA-approved for use as muscle relaxants, and chlorzoxazone had previously been found to have a positive effect on eye movements in spinocerebellar ataxia type 6. Looking at the results of their experiments, they realized that a combination of chlorzoxazone and baclofen would probably be an effective treatment for ataxia over a long period. They offered this drug combination to patients, who had few adverse effects and showed improvement in their diseasesymptoms. Based on these findings, the researchers recommended that larger trials of this drug combination should be conducted and that people trying to design new drugs to treat ataxia should try to interact with the same targets as chlorzoxazone.

mutliple types of drugs in pill form scattered ac
Can old drugs have potential for new types of treatment? Photo by Anna Shvets on Pexels.com.

When this paper’s authors started their research, they wanted to know more about how ataxia changes the way that brain cells communicate with each other. Brain cells do this using a code made up of pulses of electricity. They create these pulses by controlling the movement of electrically charged atoms known as ions. The main ions that brain cells use are potassium, sodium, calcium and chloride. Cells control their movement through proteins on their surface called ion channels which allow specific types of ions to travel into or out of the cell at specific times. Different types of cells use different combinations of ion channels, which causes different types of ions to move into and out of the cell more or less easily and under different conditions. This affects how these cells communicate with each other.

For example, a cell’s “excitability” is a measure of how easy it is for that cell to send out electrical pulses. Creating these pulses depends on the right ions entering and exiting the cell at the right time in order to create one of these pulses. Multiple types of spinocerebellar ataxia seem to make it difficult for Purkinje cells, which send information out of the cerebellum, to properly control the pattern of electrical signals that they send out. This would interfere with the cerebellum’s ability to communicate with the rest of the brain. The cerebellum plays an important roll in balance, posture and general motor coordination, so miscommunication between it and the rest of the brain would account for many of the symptoms of spinocerebellar ataxias.

Earlier research had found a link between this disrupted communication and a decrease in the amount of some types of ion channels that let potassium ions into Purkinje cells. Thus, this paper’s authors wanted to see if drugs that made the remaining potassium channels work better would improve Purkinje cell communication.

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Snapshot: What does dominant ataxia mean?

Ataxias can occur due to a multitude of reasons. One way a patient might acquire ataxia is from an accident or an injury – not as a result of genetics. On the other hand, a patient could also inherit a specific mutation (a genetic defect, in other words) from one or both of their parents. In this case, the ataxia is called “hereditary.” Hereditary ataxias can be further classified as either “dominant” or “recessive.”

What is a dominantly-inherited disorder?

Most genes in our body have two copies: one that we inherit from our mother, and one that we inherit from our father. Dominantly-inherited disorders are diseases in which a mutation in just one copy of a gene is enough to cause disease. When both copies of a gene need to be mutated to cause symptoms, the disorder is known as “recessive” (learn more in the Snapshot on recessive ataxias). For a patient with a dominantly-inherited ataxia, this means that there is a 1-in-2 chance that their children will inherit the disease-causing mutation (assuming that their spouse is unaffected). If both spouses are affected by the same dominantly-inherited disease, this chance increases to 3-in-4. In cases where the child inherits both mutant copies of the gene, the symptoms are often more severe than when a single copy is inherited.

Visual depiction of paragraph above
How dominant disorders are inherited. Illustration by Larissa Nitschke, created with BioRender.

Which ataxias are dominantly-inherited?

The most well-known ataxias with dominant inheritance patterns are the Spinocerebellar Ataxias (SCAs), such as SCA1, SCA2, SCA3, SCA6, and SCA7. Each disease is caused by defects in a different gene. Due to the high similarity in symptoms among all ataxias, genetic testing is often required to determine the exact gene mutation and type of ataxia a patient has.

How can a patient prevent passing on a dominantly-inherited disorder to their children?

There are multiple options to prevent passing on the disease to your child if you are affected by a hereditary ataxia. One potential option is to perform in vitro fertilization (IVF), a technology that is used the conceive embryos outside the human body. The embryos can be screened for genetic mutations, allowing only the healthy embryos to be implanted into the uterus.

If you are affected by a hereditary ataxia and want to prevent having a child with ataxia, it is recommended to talk to your physician and genetic counselor regarding reproductive options.

If you would like to learn more about in vitro fertilization and embryo screening, please take a look at these resources by the University of Pennsylvania. If you want to learn more about dominant ataxia, take a look at these resources by the National Organization for Rare Disorders and Ataxia Canada.

Snapshot written by Larissa Nitschke and edited by Dr. Marija Cvetanovic.

Les yeux, des fenêtres pour voir la fonction cérébrale dans les ataxies spinocérébelleuses

Écrit par Dr Sriram Jayabal, Édité par Dr David Bushart, Traduction française par: L’Association Alatax, Publication initiale: 20 décembre 2019 

Les déficits de mouvement oculaire se produisent de manière omniprésente dans les ataxies spinocérébelleuses, même aux premiers stades de la maladie, soulignant leur importance clinique.

Imaginez les différents mouvements moteurs que vous effectuez dans votre vie quotidienne. Beaucoup de gens pensent aux actions que nous effectuons en utilisant nos mains et nos jambes, comme atteindre des objets ou marcher. Zoomons sur une autre tâche : attraper une balle de baseball. Vous devez savoir où la balle va atterrir pour pouvoir courir jusqu’à cet endroit, puis guider vos bras pendant la plongée, si nécessaire, pour attraper la balle. Pour que cela fonctionne parfaitement, vous devez voir et suivre la balle. Vos yeux vous permettent de suivre la balle pendant qu’elle se déplace. Comment vos yeux peuvent-ils garder le ballon au point pendant que vous courez à pleine vitesse vers l’endroit où vous vous attendez à ce que le ballon atterrisse ? Vos yeux sont équipés de muscles qui permettent aux yeux de bouger afin de garder la scène visuelle au point. Ces mouvements oculaires, comme l’exigent les besoins du scénario actuel, dans ce cas, attraper une balle de baseball, nous sont indispensables pour voir le monde sans aucune entrave.

Woman with hand in a "C" shape in front of her face. She's focusing in on her eye.
Les yeux peuvent fournir une fenêtre sur l’ataxie spinocérébelleuse, avant même que d’autres symptômes n’apparaissent. Photo de fotografierende sur Pexels.com

Quelle région du cerveau nous donne le pouvoir de le faire?

C’est le cervelet qui permet de bouger les bras et les jambes avec précision, contrôle également la façon dont nous bougeons nos yeux. Par conséquent, il est logique d’affirmer que lorsque le cervelet tourne mal, cela peut entraîner des anomalies des mouvements oculaires. Plusieurs études antérieures ont montré que cela était vrai dans de nombreuses ataxies spinocérébelleuses (SCA), où des symptômes non liés à la marche tels que des anomalies des mouvements oculaires se sont avérés accompagner les déficits de la marche aux stades avancés de la maladie. Cependant, des travaux récents de pionniers de la recherche clinique sur l’ataxie à la Harvard Medical School ont montré que les anomalies des mouvements oculaires sont également couramment présentes dans les SCA, même dans les états pré-symptomatiques. Cette étude met l’accent sur la nécessité cruciale de mieux documenter l’historique des déficits des mouvements oculaires et de les suivre tout au long de la progression de la maladie. Cela aidera les chercheurs à développer de meilleures échelles d’évaluation de l’ataxie.

Dans cette étude, une population de patients SCA (134 individus) qui présentaient différents types de SCA (y compris SCA1, SCA2, SCA3, SCA5, SCA6, SCA7, SCA8 et SCA17) ont été évalués pour les anomalies des mouvements oculaires à différents stades de la maladie, du stade pré-symptomatique (sans déficit de marche) au stade avancé (ceux qui utilisent un fauteuil roulant). Premièrement, il a été constaté que ~ 78% de tous les individus pré-symptomatiques présentaient des déficits de mouvement oculaire, et ces déficits sont devenus encore plus courants à mesure que la maladie progressait, où chaque personne à un stade avancé présentait des déficits de mouvement oculaire.

Deuxièmement, lorsque les chercheurs ont examiné de près les mouvements oculaires, ils ont constaté que différents types d’ataxie pouvaient provoquer différents types de déficits des mouvements oculaires.

Cependant, ces résultats ne sont que suggestifs en raison de la faible population d’individus SCA à un stade précoce dans cette étude et des types d’évaluations utilisées. Par conséquent, les études futures nécessiteront une plus grande taille de la population et une analyse quantitative approfondie des types spécifiques de déficits de mouvement oculaire pour aider à caractériser les anomalies du mouvement oculaire dans les SCA. Enfin, la Brief Ataxia Rating Scale (BARS), un test clinique simple récemment conçu pour l’ataxie, a été encore améliorée dans cette étude pour tenir compte des déficits de mouvement oculaire cliniquement observés dans les SCA. Avec une métrique aussi nuancée, un score BARS amélioré s’est révélé corrélé avec le stade, la gravité et la durée de la maladie, quel que soit le type d’ataxie.

Continue reading “Les yeux, des fenêtres pour voir la fonction cérébrale dans les ataxies spinocérébelleuses”

Snapshot: How does CAG tract length affect ataxia symptom onset?

The instructions our bodies need to grow and function are contained in our genes. These instructions are made up of tiny structures called nucleobases. There are four types of nucleobases in DNA: adenine (A), cytosine (C), guanine (G), thymine (T). By putting these four nucleobases in different orders and patterns, this writes the instructions for our body.

artists drawing of a blue DNA molecule
A cartoon strand of DNA. Image by PublicDomainPictures from Pixabay

Some of the genes contain long sections of repeating ‘CAG” instructions, called CAG tracts. Everyone has repeating CAG tracts in these genes, but once they are over a certain length they can lead to disease. Some ataxias are caused by this type of mutation, including SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. These are often called polyglutamine expansion disorders. This is because “CAG” gives the body instructions to make the amino acid glutamine. You can read more about what is polyglutamine expansion in our past Snapshot about that subject.

For each disorder caused by a CAG expansion mutation, the number of times the CAG is repeated in a particular gene will determine whether someone will develop the disease. Repeat lengths under this number will not cause symptoms and repeat lengths over the threshold will usually lead to ataxia. When someone undergoes genetic testing for ataxia, doctors will be able to tell them the length of these CAG tracts and whether they have a CAG repeat number in one of these genes that is over the threshold. This table gives a summary of different CAG expansion mutations that can lead to ataxia and how the length of the repeat affects age of onset.

 Affected Gene Normal
Repeat Size
Disease
Repeat Size
SCA1ATXN16-4439-88
SCA2ATXN215-3136-77
SCA3ATXN312-4055-86
SCA6CACNA1A 4-1821-33
SCA7ATXN74-3537-306
SCA12PPP2R2B4-3266-78
SCA17TBP25-4246-63

For SCA1, SCA2, SCA3, SCA6, and SCA7; longer CAG tracts are associated with earlier onset.

For SCA12, it is hard to predict the age of onset based on repeat length as SCA12 is so rare. Some individuals with long repeats don’t develop ataxia. One study found that longer CAG tract lengths are associated with earlier onset but that it does not affect the severity of symptoms.

For SCA17, Longer CAG tracts have separately been associated with an earlier age of onset and more severe cerebellar atrophy.

In general, people with longer repeat lengths in ataxia genes are likely to present with ataxia symptoms earlier in life. However, it is important to remember that there are many other factors involved. Other genes may have mutations that either worsen the progression of ataxia or protect against more severe symptoms. Therefore, in individual people, the length of the repeat is not always enough information to determine when that person will start showing symptoms, or how severe these symptoms will be.

If you would like more information about the genetic causes of SCAs, including information about genetic testing and what CAG repeat length might mean, take a look at these resources by the National Ataxia Foundation.

Snapshot written by Anna Cook and edited by Larissa Nitschke.

Continue reading “Snapshot: How does CAG tract length affect ataxia symptom onset?”

Eyes: Windows to peek at brain function in spinocerebellar ataxias

Written by Dr. Sriram Jayabal Edited by Dr. David Bushart

Eye movement deficits occur ubiquitously in spinocerebellar ataxias, even at early disease states, highlighting their clinical importance.

Imagine the different motor movements that you make in your everyday life. Many people think of actions that we perform using our hands and legs, such as reaching for objects or walking. Let’s zoom in on a different task: catching a baseball. You need to know where the ball is going to land so you can run to that spot, then guide your arms while diving, if need be, to catch the ball. For this to work perfectly, you need to see and follow the ball. Your eyes enable you to track the ball while it is moving. How can your eyes keep the ball in focus while you are running at full speed towards the spot where you expect the ball to land? Your eyes are equipped with muscles which enable the eyes to move so as to keep the visual scene in focus. These eye movements, as demanded by the needs of the current scenario, in this case, catching a baseball, are indispensable for us to see the world without any hindrance.

Woman with hand in a "C" shape in front of her face. She's focusing in on her eye.
The eyes may provide a window into spinocerebellar ataxia, even before other symptoms show up. Photo by fotografierende on Pexels.com

Which brain region gives us the power to do this?

The cerebellum, or “little brain”, which enables one to move their arms and legs precisely, also controls the way we move our eyes. Therefore, it is logical to posit that when cerebellum goes awry, it may lead to eye movement abnormalities. Several previous studies have shown this to be true in many spinocerebellar ataxias (SCAs), where non-gait symptoms such as eye movement abnormalities have been found to accompany gait deficits in advanced stages of the disease. However, recent work from pioneers in clinical ataxia research at the Harvard Medical School have shown that eye movement abnormalities are also commonly present in SCAs even in pre-symptomatic states. This study emphasizes the critical need to better document the history of eye movement deficits and track them throughout the progression of the disease. This will help researchers to develop better rating scales for ataxia.

In this study, a population of SCA patients (134 individuals) who exhibited different types of SCA (including SCA1, SCA2, SCA3, SCA5, SCA6, SCA7, SCA8 and SCA17) were assessed for eye movement abnormalities at different stages of the disease, from pre-symptomatic (with no gait deficits) to advanced stages (those who use a wheel-chair). First, it was found that ~78% of all pre-symptomatic individuals exhibited eye movement deficits, and these deficits became even more common as the disease progressed, where every single person in advanced stages exhibited eye movement deficits. Second, when researchers examined the eye movements closely, they found that different types of ataxia might cause different kinds of eye movement deficits. However, these results are only suggestive because of the small population size of early-stage SCA individuals in this study, and the types of assessments used. Therefore, future studies will require a larger population size and a thorough quantitative analysis of specific types of eye movement deficits to help characterize eye movement abnormalities in SCAs. Finally, the Brief Ataxia Rating Scale (BARS), a recently designed simple clinical test for ataxia, was further improved in this study to account for the clinically observed eye movement deficits in SCAs. With such a nuanced metric, an improved BARS score was found to correlate with the stage, severity and duration of the disease irrespective of the type of ataxia.

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