cacna1a related epilepsy graphic

What is CACNA1A?

The CACNA1A gene belongs to a family of genes that provide instructions for making calcium channels. These channels, which transport positively charged calcium (calcium ions) across cell membranes, play a key role in a cell's ability to generate and transmit electrical signals.

Changes in the DNA sequence of the gene may result in a variant alters the way that the CACNA1A protein functions. Broadly speaking, there are “Gain of Function” (GOF) or “Loss of Function” (LOF) changes; these terms reflect different types of effects seen when the CACNA1A gene changes are studied in cells in vitro (in the laboratory in a ‘dish’).

When there is a GOF change, too much calcium flows across the cell membrane, causing increased neuron excitability. When there is a LOF variant, the opposite occurs, with is improper channel opening, resulting in less calcium entering the cells and decreased neuronal firing.

Both types of variants may lead to epilepsy, and scientists have acknowledged that the GOF and LOF distinctions may be an oversimplification.

Seizures & Epilepsies Associated with CACNA1A

Seizures and epilepsy may occur shortly after birth in an individual with a CACNA1A gene variant. Seizures may range from mild and easily managed to severe and drug-resistant.

Multiple types of seizures may occur, including:

Pathogenic variants in CACNA1A may be associated with early infantile epileptic encephalopathy (EIEE), which is characterized by multiple seizure types, epileptiform activity, and severe developmental delay. Some individuals with variants in CACNA1A may be diagnosed with Lennox-Gastaut syndrome and may have some features overlapping with Dravet syndrome.

Non-seizure Symptoms of CACNA1A Variants

Note - these non-seizure symptoms can be seen in different individuals and not all in the same individuals.

Ataxia

Ataxia refers to a group of rare, degenerative neurological conditions of the nervous system commonly caused by damage to the cerebellum. It is characterized by involuntary movements, problems with balance and coordination, and lack of muscle control. The following forms of ataxia can be seen in individuals with CACNA1A variants:

  • Congenital ataxia – Onset before age of 2, characterized by low muscle tone, poor balance and coordination and developmental delay; on brain imaging, the back part of the brain, called the cerebellum, may be smaller than normal.
  • Episodic Ataxia Type 2 (EA2) – Episodes of poor balance, vertigo, nausea and headaches that last from hours to days and are triggered by emotional stress, physical exercise, fever, alcohol and caffeine.
  • Spinocerebellar Ataxia Type 6 (SCA6) – Neurological disorder in which there is gradual worsening of symptoms which include progressive loss of balance and coordination, tremors, slurred speech, and nystagmus (jiggling of the eyes) with onset typically between ages 40-50 years.

Hemiplegic Migraine

Hemiplegic migraine is a rare form of migraine associated with temporary weakness or paralysis on one side of the body. These attacks are often mistaken for stroke because of the severity and symptom overlap. However, they differ from stroke as the weakness is reversible.

Eye Movement Disorders

Eye movement disorders include nystagmus and paroxysmal tonic upgaze.

  • Nystagmus is an uncontrolled movement (beating or jiggling) of the eyes from side to side or up and down.
  • In paroxysmal tonic upgaze, the eyes uncontrollably stare upwards.

These are not seizures. These abnormal eye movements may occur during periods of ataxia or migraine headache.

Cerebellar Atrophy

The cerebellum is a structure that is present in the back part of the brain and is important for coordination. In CACNA1A, this structure is often found to be smaller than normal on imaging of the brain (MRI or CT), a pattern called cerebellar atrophy. There can be progressive loss of size of the cerebellum, although the pattern and rate vary. Patients with cerebellar atrophy often present with poor balance, uncoordinated movements, slurred speech, and nystagmus. They are also at a higher risk of cognitive impairment.

Developmental, Learning, and Behavioral Disorders

  • Global developmental delays
  • Mild to severe intellectual disability
  • Autism spectrum disorder
  • Learning differences

Children have language, fine and gross motor delays due to low muscle tone and coordination problems, making it difficult to meet their milestones.

How are variants in CACNA1A diagnosed?

CACNA1A variants can only be identified by genetic testing. Targeted testing of the CACNA1A gene specifically is the most direct method of testing an individual when there is a high degree of confidence that a variant in the CACNA1A gene is likely to be the underlying cause, for example when individuals have symptoms like those above and a family member with a known CACNA1A variant. Epilepsy gene panels, which involve testing of multiple epilepsy-associated genes, and whole exome sequencing (WES) will also detect CACNA1A variants.

Genetic counseling prior to genetic testing is an important step in making sure that the best testing strategy is selected, and that patients and families understand the risks, benefits, limitations, and outcomes of testing.

How are CACNA1A-related epilepsies treated?

There is currently no cure and no gene-specific treatments for CACNA1A-related epilepsies. Doctors may attempt to manage symptoms by prescribing anti-seizure medications and special diets, such as the ketogenic and modified Atkins diet.

Understanding if a specific variant is gain of function or loss of function will likely play a role in treatment selection, though formal trials have not been undertaken yet. Acetazolamide has been shown to decrease episodes of ataxia and hemiplegic migraine for patients with loss of function variants, but its role in treating epilepsy requires further study. Likewise, it is hypothesized that calcium channel blockers may help treat patients with gain of function variants, but this possibility requires further study.

How common is CACNA1A-related epilepsy?

We do not have adequate data to know how common CACNA1A-related epilepsy is. However, CACNA1A variants currently account for up to 1 of every 100 (1%) individuals among large cohorts of children with epilepsy. In persons with episodic ataxia type 2 (EA2), 30% also have epilepsy and another 30% have febrile seizures.

What is the outlook for CACNA1A-related epilepsy?

The long-term seizure outcome varies considerably, with some people having seizures that are easily controlled, and others having drug-resistant epilepsy. Those with cognitive impairment, or learning and intellectual disabilities, will likely require support, although living an independent life is possible. As cerebellar atrophy progresses, there may be an increase in difficulties with balance and coordination, behavior, personality disorder, and memory.


For more information:

CACNA1A Foundation

 

With special thanks to Lisa Manaster, president of CACNA1A Foundation.

 

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Authored By: 
Lisa Manaster
Authored Date: 
06/2021
Reviewed By: 
Sookyong Koh MD, PhD
Beth Sheidley MS, CGC
Annapurna Poduri MD, MPH
on: 
Wednesday, June 16, 2021