Understanding, Diagnosing and Treating CACNA1A Disorders

If you experience migraine headaches, mild to severe epilepsy, or related rapid eye movement that dramatically affects your wellbeing, you may be living with a gene variant known as CACNA1A — CAlcium voltage-gated ChaNnel subunit Alpha 1A — a gene that plays a crucial role in the communication between neurons in the brain.

Advances in gene mapping and gene-sequencing technology are empowering modern medicine to identify the root cause of numerous rare and mysterious medical conditions. We can now trace many illnesses to variants of one or more of the 20,000-plus genes that make up the human genome — the detailed set of instructions needed for a human being to develop and function.

We all have the same genes that make us human. Variations of these genes are what make each of us unique. For example, we all have genes that provide instructions for growing hair, but variations of these genes control whether that hair is straight, wavy, or curly and whether it is black, brown, blond, or red.

Unfortunately, some gene variants can cause disease or increase our susceptibility to developing a specific medical condition. Such is the case with certain variants of the CACNA1A gene — the gene that plays a vital role in a cell’s ability to generate and transmit electrical signals.

CACNA1A’s Role in Gain or Loss of Function

CACNA1A is part of a family of genes responsible for creating calcium channels, which transport positively charged calcium molecules (calcium ions) across cell membranes. What may be occurring in patients with CACNA1A disorders is that variants of the CACNA1A gene cause either gain of function (GOF) or loss of function (LOF) alterations in the CACNA1A protein.

For example:

• With GOF, too much calcium flows across the cell membrane causing increased neuron excitability.
• With LOF, insufficient calcium flows across the cell membrane resulting in decreased neuron firing.

Either situation can lead to neurological dysfunction, which can result in a range of illnesses, including epilepsy and seizures, ataxia, eye movement disorders, and neurodevelopmental differences, and hemiplegic migraines, as described in the following sections.

Epilepsy/Seizures

Certain variants of CACNA1A may be associated with the following conditions:

• Early infantile epileptic encephalopathy (EIEE), which is characterized by multiple seizure types and severe developmental delay.
• Lennox-Gastaut syndrome, which is characterized by multiple and concurrent seizure types, cognitive dysfunction, and slow spike waves on an electroencephalogram. Typically, it presents in children aged 3 to 5 years and can persist into adulthood.

Warning: Dravet syndrome — a genetic, treatment-resistant epilepsy characterized by temperature-sensitive/febrile seizures, that begins in the first year of life, and during differences in childhood development — is often misdiagnosed as being associated with CACNA1A, when often, once genetic testing is done, it turns out to be CACNA1A.

Seizure types associated with CACNA1A variants include the following:

• Absence seizures cause short periods of “blanking out” or staring into space.
• Focal motor seizures typically affect only part of the body (but may spread to others) and involve muscle activity, such as jerking, loss of muscle tone, or repeated movements.
• Generalized tonic-clonic (grand mal) seizures, which involve violent muscle contractions impacting the entire body and loss of consciousness.
• Myoclonic seizures that are characterized by brief, jerking spasms of a muscle or muscle group.
• Tonic seizures, which involve sudden tension or stiffness that may affect the arms, legs, or body.

Ataxia

Ataxia is a term used to describe a group of rare neuro-degenerative conditions characterized by involuntary movements, problems with balance and coordination, and lack of muscle control. CACNA1A variants have been associated with the following forms of ataxia:

• Congenital ataxia (onset before the age of two years) is characterized by poor muscle tone, poor balance and coordination, and developmental delay. The cerebellum (back part of the brain) may be smaller than normal.
• Episodic Ataxia Type 2 (EA2) is characterized by episodes of poor balance, vertigo, nausea, and headaches that last from hours to days. Episodes may be triggered by emotional stress, physical exercise, fever, alcohol, or caffeine.
• Spinocerebellar ataxia Type 6 (SCA6) (onset typically between the ages of 40 and 50 years) is a neurological disorder with gradual worsening of symptoms. Symptoms may include progressive loss of balance and coordination, tremors, slurred speech, and nystagmus (see the later section “Eye Movement Disorders”).

Eye Movement Disorders

As mentioned above, CACNA1A variants may cause abnormal eye movements, such as nystagmus or paroxysmal tonic upgaze. Here’s what you need to know about these types of eye movements

• Nystagmus — uncontrolled, rapid eye movement sometimes described as “dancing eyes” or “jiggling.” Eyes may move up and down, side-to-side, or in a circular pattern (rotary nystagmus).
• Paroxysmal tonic upgaze characterized by episodes of sustained upward staring (eyes rolled back while the chin is typically held low).

These abnormal eye movements may occur during a migraine attack or in association with ataxia. They’re not indicative of a seizure.

Neurodevelopmental Differences

CACNA1A variants may cause various developmental, learning, or behavioral disorders, including the following:

• Global developmental delays — delays in language development and delays in the development of fine and gross motor skills due to poor muscle tone and coordination
• Mild to severe intellectual disability
• Autism spectrum disorder
• Learning differences

Hemiplegic Migraines

Hemiplegic migraine is a rare form of migraine accompanied by weakness or paralysis on one side of the body, which may last for hours, days, or even weeks. Attacks are often mistaken for strokes, but they differ from strokes because the weakness/paralysis is temporary.

People who experience hemiplegic migraines often also experience auras — sensory or motor disturbances just prior to a migraine attack, such as seeing dots, sparks, or zigzags; feeling dizzy; being unable to speak clearly; or hearing ringing in the ears (tinnitus).

According to the CACNA1A Foundation — a parent-led not-for-profit organization dedicated to creating awareness and finding a cure for CACNA1A genetic variants — a CACNA1A-related Severe Hemiplegic Migraine (CSHM) can be progressive and severe, resulting in uncontrolled seizures and potentially life-threatening brain swelling. Similar to more traditional hemiplegic migraine, the dysfunction of the calcium channels leads to cortical spreading depression — a wave that spreads across the surface of the brain that first activates and then briefly inactivates the nerve cells and then leads to an inflammatory response.

Pro Tip: Learn more about CACNA1A-related Severe Hemiplegic Migraines by visiting the CACNA1A Foundation website. The CACNA1A Foundation is the leading organization on the identification of CSHMs and so much more!

During activation, one may experience “positive” symptoms such as seeing sparkles/waves or feeling a tingling. During deactivation, one may experience “negative” symptoms such as a blind spot or numbness. When the wave hits the part of the brain that controls movement, one may struggle with physical movement.

Some patients may also experience changes in the blood vessels of the brain, causing narrowing and reducing blood flow to certain regions of the brain as well as swelling that may lead to longer lasting weakness, a change in level of awareness, and seizures.

A CSHM may be triggered by any of the following (or have no identifiable trigger):

• Minor head trauma
• Seizure
• Emotional or physical stress
• Viral infection
• Lack of sleep
• Menstrual period

Symptoms of CSHM include the following:

• Eye deviation
• Increased nystagmus
• Decreased responsiveness and/or altered consciousness
• Vomiting
• Fever

A CSHM can lead to cerebral edema and stroke, so it is important to evaluate for these conditions.

In addition to genetic testing when a CACNA1A variant is suspected, head imaging should also be ordered. This is especially important after the first suspected CSHM attack, but not necessarily for every episode. Imaging may include:

• A computerized tomography (CT) scan
• A magnetic resonance imaging (MRI) scan, even if the CT is normal
• An MR or CT angiogram (to check blood vessels in the brain)
• An electroencephalogram (EEG) and bloodwork to check for infection

It is recommended that observation be considered at least overnight in the hospital because prior history of mild attacks cannot fully predict severity of current attack.

Diagnosing CACNA1A Variants

CACNA1A variants can be identified only by genetic testing, which is usually ordered when someone is experiencing one or more of the conditions described in this post. Epilepsy gene panels, which involve testing of multiple epilepsy-associated genes, and whole exome sequencing (WES) will detect CACNA1A variants.

Treatment for CACNA1A-Variant Medical Conditions

CACNA1A variants cannot be corrected, so related medical conditions have no “cure.” However, treatments can help reduce the frequency and severity of the condition, reduce some of the collateral physical damage to the body, and support overall health and fitness. Here are a few examples of treatment options:

• Anti-seizure medications for patients with epilepsy
• Diet modification to support overall health, gut health specifically, and reduce inflammation
• Nutritional supplements to address deficiencies
• Supplements to support brain and nerve health and function
• Medication review and modifications, if necessary, to avoid/reduce medications that may be counterproductive
• Fitness coaching to support muscle tone and coordination and overall health and fitness without overdoing it

Here at Restoration Healthcare, we develop a personalized treatment option based on results from detailed and comprehensive testing, along with each patient’s medical and family history and input on treatment preferences. No two patients are identical.

The specific CACNA1A variants are only one factor that differs between one patient and another. Other genetic variations — along with a host of other health conditions, lifestyle choices, environmental factors, and more — can impact a patient’s health and fitness profile and must be taken into consideration.

If you or a loved one has been diagnosed with a CACNA1A disorder or is experiencing any of the symptoms described in this post, we encourage you to consult with a functional medicine practice near you for testing, diagnosis, and a personalized treatment plan. If you are in or near Southern California, contact us to schedule an initial consultation.

And for the latest news and information about CACNA1A, please visit the CACNA1A Foundation website.

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Disclaimer: The information in this blog post about CACNA1A disorders is provided for general informational purposes only and may not reflect current medical thinking or practices. No information contained in this post should be construed as medical advice from the medical staff at Restoration Healthcare, Inc., nor is this post intended to be a substitute for medical counsel on any subject matter. No reader of this post should act or refrain from acting on the basis of any information included in, or accessible through, this post without seeking the appropriate medical advice on the particular facts and circumstances at issue from a licensed medical professional in the recipient’s state, country or other appropriate licensing jurisdiction.