Below are the most common symptoms that can be caused by differences within CACNA1A. It is important to know that not everyone with CACNA1A will develop the symptoms below, but these are some symptoms you could expect to see:

Neurodevelopmental differences can include global developmental delays, intellectual disability, autism spectrum disorder, and learning differences. Children with CACNA1A can have difficulty with language and motor development due to hypotonia (weak muscle tone), making it more difficult for them to meet their motor milestones. Intellectual disability that is caused by CACNA1A can range from mild to severe.

Epilepsy and seizures can occur in people with CACNA1A and can range from mild to severe. Seizures can occur shortly after birth or in the first weeks of life in the earliest cases, while others experience very few to no seizures during their lifetimes. Seizures fall on a continuum between being easily managed to extremely challenging to control.

Early Infantile Epileptic Encephalopathy is a seizure disorder characterized by infantile spasms that typically appear before the age of one. Type 42 is associated with CACNA1A and is a form of epileptic encephalopathy. It is characterized by multiple seizure types, epileptiform activity and severe developmental delay.1 Some people with severe CACNA1A-related epilepsy may be diagnosed with Lennox-Gastaut Syndrome or Dravet Syndrome. ⁴

Episodic ataxia consists of episodes of unsteadiness of movement and poor balance, vertigo (dizziness), nausea, and headache. People with episodic ataxia may typically walk without any problems, but suddenly struggle to keep their balance and move as they usually would. These attacks can be triggered by physical stress, fevers, exercise, and alcohol or caffeine, among others.

Hemiplegic migraine is a rare and severe type of migraine with an aura that is associated with weakness and/or temporary paralysis on one side of the body. People who have hemiplegic migraine can lose consciousness or even enter a state of coma due to minor head trauma. Sometimes, these attacks can be mistaken for a stroke because of the severity and symptom overlap, but they are not strokes. In addition, people with CACNA1A can have frequent or chronic migraines that are not followed by weakness of one side of the body. (Jen et al., 2015; Ophoff et al., 1996)

Eye movement differences can include nystagmus and paroxysmal tonic upgaze. Nystagmus is an uncontrolled movement of the eyes from side-to-side or up-and-down. Paroxysmal tonic upward gaze involves periods where a person’s eyes uncontrollably stare upwards. These are not seizures. The events can sometimes occur during episodes of ataxia or migraine.

Cerebellar Atrophy can be related to CACNA1A, which can sometimes be progressive. This affects muscle coordination and balance and, as a result, can more rarely affect other parts of the central nervous system to include thinning of the corpus callosum. Symptoms include uncoordinated movement of the arms and legs, wide-based uncoordinated walk, back and forth tremor in the trunk of the body, slow and slurred speech and nystagmus.²

Spinocerebellar ataxia type 6 is a degenerative neurological disorder in which individuals develop progressive ataxia and issues with balance, as well as tremor, dysarthria (difficulty with speech), and nystagmus, that usually onsets between the ages of 40 to 50. It is important to note that this disorder is caused by a unique genetic difference within CACNA1A, due to an increase in something called “CAG repeats” in the CACNA1A gene. The increased number of repeats results in the creation of an abnormal protein that can lead to loss of Purkinje cells in the cerebellum, which are essential for balance and speech. This syndrome is different than CACNA1A-related migraine, episodic ataxia, epilepsy, and neurodevelopmental differences.

Patients with GOF mutations might respond to calcium channel antagonists (such as Verapamil), whereas patients carrying LOF mutations might respond to peptide inhibitors or chaperones designed to enhance trafficking of the channels to the cell membrane. Ultimately, clarifying the mechanisms by which specific mutations affect the function and localization of CACNA1A channels will improve therapeutic interventions for patients with CACNA1A‐associated DEEs.⁴

In some reported cases, acetazolamide (more frequently used) and verapamil have shown positive responses in preventing the recurrence of the acute phenotype (migraine, sporadic/familial hemiplegic migraine, or acute coma); however, there are no clinical trials evidencing this benefit.³ Patients with EA2 and LOF alleles are often responsive to acetazolamide, while patients with GOF alleles and FHM may respond, but generally tend to be less responsive. It can be predicted that calcium channel blockers might be more effective for gain-of-function alleles.⁷

There is some early evidence that calcium channel blockers (such as Verapamil) may be an effective prophylactic agent for the severe hemiplegic migraine episodes.⁶ Specialized therapies to address various areas of development may be beneficial and can include speech therapy, physical therapy and occupational therapy. Behavioral phenotypes might be overlooked in patients when epilepsy or ataxia are predominant, but careful consideration of potential cognitive and behavioral consequences in these patients might allow for an earlier instauration of cognitive-behavioral interventions and improve long-term outcome.³