Stem Cell Treatment for Ataxia

In order to delve into this treatment modality in ataxia, we first need to explain what exactly we mean when we say “ataxia”. Ataxia is when you have muscle coordination problems. It is basically when you lose control of coordinating your own voluntary muscles. You might see yourself as clumsy or ungraceful; but this might actually be one symptom of your ataxia presentation (1, 2).

Ataxia has numerous causes – with multiple classification systems being present. However, cause-wise, ataxia can be classified into (1,2):

Hereditary Ataxias These include different forms of ataxia that are inherited vertically along generations. They occur due to genetic mutations/aberrations transmitted from parents to children. Inherited ataxias are usually characterized by prolonged and slower disease progression compared to sporadic forms of ataxia. There are different modes of inheritance for ataxia; including:

• Autosomal dominant: Having one affected parent puts the child at risk of developing ataxia. One of the most widely known autosomal dominant ataxias includes Spinocerebellar Ataxia
• Autosomal recessive: This mode requires both parents to be disease carriers, or one carrier and one diseased, in order to transmit the disease to the offspring. Some of the widely autosomal recessive forms of ataxia include Friedreich’s Ataxia and Ataxia Telangectasia.
• Mitochondrial inheritance: This mode precludes a 100% risk of disease presentation if the mother is affected, and 0% if the father is the affected person. It occurs due to point mutations within the mother’s mitochondrial DNA which is exclusively transmitted to her offspring. Some ataxias in this category include Myoclonic Epilepsy with Ragged Red Fibers (MERRF) and Mitochondrial Encephalomyopathy.

Sporadic Ataxias These include different ataxia presentations in the absence of family history. This form is usually diagnosed preliminarily until a hereditary cause is found. It is usually due to affection of one of the three systems concerned with balance and coordination – namely the cerebellum, the vestibular system (within the inner ear), and the proprioceptive sensory pathway. According to whether or not we know the exact cause of this cause of ataxia, we can divide sporadic ataxias into either:

• Idiopathic ataxia (Also known as idiopathic late-onset cerebellar ataxia (ILOCA)): This form occurs due to reasons that are still unknown to us. It usually occurs in older ages ranging from 50s to 70s.
• Acquired ataxia: Acquired forms of ataxia usually occur due to diseases affecting the cerebellum – the main brain areas concerned with balance and proper coordination mentioned before. Some causes include:
• Strokes involving the cerebellum or brain stem
• Multiple Sclerosis
• Cerebellar tumors
• Cerebellar Infections
• Creutzfeldt–Jakob disease
• Vitamin deficiencies such as vitamin B1 and B12
• Hypothyroidism
• Excessive alcohol intake

When it comes to treating ataxia, treatment mainly depends on the exact cause of ataxia. For example, if one’s ataxia is due to stroke, then we manage the stroke and the ataxia consequently improves. If it is due to nutritional deficiency, then we supplement the deficient nutrient, and we see improvement in ataxia as well.

We still don’t have a “curative” treatment for hereditary or idiopathic ataxias (i.e. Primary ataxias). In hereditary ataxias, doctors usually recommend physiotherapy and occupational therapy for better muscle control and in coping with the condition. Symptomatic treatments are usually used as well to alleviate symptoms depending on the main complaint. For example, if you are complaining of urinary incontinence, bladder relaxants are prescribed, and so on. Sometimes, neuroprotective drugs are used as well to delay disease progression, similar to their use in other neurological disorders, such as:

• Riluzole: This drug is also commonly used in amyotrophic lateral sclerosis (ALS). It works by reducing the production of neuro-toxic substances and delaying disease progression.
• Varenicline: Commonly used for smoking cessation
• Amantadine: Also used in Parkinson’s disease
• Baclofen: This is a muscle relaxant that could help in muscle spasticity and pain associated with ataxia.

However, even with all the current medical advancements, there is still not a single curative treatment for hereditary ataxias, and the drugs listed above are merely supportive and still have limits to their efficacy as well as possible side effects due to the need for a life-long use (2,5,6).

Many are now probably thinking “So where does stem cell therapy come in all of this?” Well, to be honest, not all forms of ataxia could probably benefit from this form of therapy; however stem cell therapy has proven to have excellent results in people with primary forms of ataxia – i.e. those not due to a secondary/acquired cause. This is because primary forms of ataxia usually result from immune destruction, and degeneration, of brain areas concerned with equilibrium.

Autosomal dominant and autosomal recessive ataxias are hereditary ataxias, and spinocerebellar ataxia (SCA) and Friedreich’s ataxia (FRDA) are the most common forms of hereditary ataxia. Autosomal dominant genes express themselves when present. Autosomal recessive genes will only express themselves when in the homozygous state — i.e., both genes in the gene pair are the recessive gene form. Thus, recessive genes can be “carried” by those whose phenotype does not exhibit the gene characteristic, while dominant genes cannot be “carried”. Therefore, generally autosomal dominant ataxias are easier to express and at a higher morbidity than autosomal recessive ataxias.

However, it is important to note that the presence of a specific gene does not guarantee the development of the associated ataxia. Other factors, such as environmental influences and genetic modifiers, can also play a role in the manifestation of the disease. Additionally, the severity and progression of ataxias can vary widely among individuals, even within the same genetic subtype. Therefore, a comprehensive understanding of the underlying genetic mechanisms and individualized management approaches are crucial for effectively addressing hereditary ataxias.

Purkinje cells are a type of neuron found in the cerebellar cortex, at the base of the brain. They are among the largest neurons and are responsible for most of the electrochemical signaling in the cerebellum.

The Purkinje cells and the cerebellum are essential to the body’s motor function. Disorders involving the Purkinje cells usually negatively affect the patient’s movements.

Ataxia might be a solitary presentation or might be part of a larger set of symptom presentations. Therefore, good awareness of different etiologies and syndromes of ataxia is quite important for proper diagnosis and management. Most types of ataxia have these symptoms in common (2,4):

• Poor movement coordination
• Regression of fine motor skills (such as buttoning your shirt or using cutlery)
• Loss of balance while walking and adopting a wide-based gait to compensate for this lack of balance and due to fear of falling
• Speech and swallowing problems
• Eye muscle coordination problem (ex. Nystagmus which is involuntary eye movement)

Most people don’t know what cerebellar ataxia is and may overlook the early symptoms. Anyone with progressive gait disorder or imbalance should be evaluated by a neurologist. MRI is recommended in all cases. If a treatable cause is not discovered, a gene test should be done. In about 60 percent of the cases, the gene test will determine the type of ataxia.

As previously mentioned, there are multiple classifications for different forms of ataxias according to how exactly we look at it. For example, ataxia can be classified according to (1):

• Etiology/Cause: As we discussed, it can be hereditary or sporadic.
• Disease onset: Acute (progresses over hours to days), sub-acute (progresses over weeks), or chronic (progresses over months to years).
• Brain distribution: There might be a focal (localized) cause such as ataxias due to strokes or tumors; or symmetric/generalized affection such as in case of cerebellar infection, drug-intoxication, metabolic causes (such as vitamin deficiencies and hypothyroidism), or hereditary ataxias.

There are many diseases manifesting with ataxia, either as a primary symptom or as part of a larger syndrome. However for the sake of being concise, we will briefly mention some of the most commonly encountered diseases associated with ataxia. Other forms of ataxias are present of course; yet most of them are due to a primary cause, i.e.  Acquired ataxia, and treating that cause usually leads to improvement of ataxia (2,3).

Spinocerebellar Ataxia (Previously known as dominantly-inherited ataxias): This type is the most common dominantly inherited ataxia. In this type, an affected family member is usually present on taking family history and people with this form usually present during adulthood. There are more than 40 types of spinocerebellar ataxias, each presenting with a unique predominant symptom depending on the affected gene. For example, in addition to the previously mentioned symptoms, people with spinocerebellar ataxia could have additional muscle stiffness and pain, loss of hand and feet sensation, reduced bladder control, and problems with memory and language.

Friedreich’s Ataxia: This is the most common type of recessively inherited ataxias, i.e. needing at least both parents to be carriers of the genetic mutation responsible for this disease. It typically manifests prior to the age of 25, and we most commonly see it in older children – older than 5 – and adolescents younger than 15. People with this form of ataxia usually have additional findings including slurred speech, diabetes, reduced hearing or vision, abnormal spine curvature (scoliosis), and progressive leg weakness. If not treated early, this type could cause the affected person to become wheel-chair ridden by the age of adulthood.

Ataxia-telangectasia: Similar to Friedreich’s ataxia, but rarer in incidence, this type is another autosomal recessive hereditary ataxia. It typically begins manifesting during childhood and it commonly has rapidly deteriorating symptoms with people with this condition often having shorter life spans. People with this type often have characteristic telangectasias – i.e. visible clusters of blood vessels on the skin – and often have higher risk of developing cancers.