What are CACNA1A-Related Disorders?

Pathogenic variants (“mutations”) in the CACNA1A gene cause a range of neurological and developmental disorders, including epilepsy (mild to severe), episodic ataxia (periods of unsteadiness and poor balance), hemiplegic migraines (rare and severe type of migraine that involves weakness or paralysis on one side of the body), atypical eye movements, developmental delays, and autism spectrum disorder. The symptoms a child experiences and the severity of the disorder can vary widely and will depend on the particular CACNA1A-related disorder the child has.

Of note, another condition called spinocerebellar ataxia type 6 is an adult-onset disorder and caused by a very specific type of genetic change in CACNA1A. This condition is completely separate from the other types of CACNA1A-related disorders discussed on this page.

CACNA1A is not the name of a medical condition but is rather the name of the gene that is affected. When a disorder is traced back to a disease-causing (pathogenic) variant in the CACNA1A gene, it is called a CACNA1A-related disorder.

Signs and Symptoms of CACNA1A-Related Disorders

CACNA1A-related disorders, when present in multiple family members, fall into several broad categories, although some children have presentations that may overlap between these categories:

• Familial hemiplegic migraine (type 1)
• Episodic ataxia (type 2)
• Eye movement disorders, such as nystagmus or paroxysmal tonic upgaze
• Epilepsy (ranging from mild to severe)
• Early infantile epileptic encephalopathy
• Neurodevelopmental disorders (including developmental delay and/or autism spectrum disorder)
• Cerebellar atrophy
• Spinocerebellar ataxia (type 6) – separate genetic disorder from those above

Seizures beginning in the first year of life, not associated with a fever, may be the first indication of a CACNA1A-related disorder. Periods of ataxia, progressive ataxia, or a diagnosis of a hemiplegic migraine are also indications of a CACNA1A-related disorder. However, the associated symptoms and outcomes can vary widely, depending on the particular CACNA1A-related disorder the child has.

Familial hemiplegic migraine (type 1)

Hemiplegic migraine is a rare and severe type of migraine. Individuals will have temporary paralysis and/or weakness on one side of the body, often preceded by a migraine. They can range from relatively mild to very severe. These events can be triggered by a relatively minor head trauma, such as a child bumping his or her head. Hemiplegic migraines can be mistaken for a stroke, and in severe cases may involve brain swelling. Some people with a CACNA1A-related disorder can also have migraines without the associated one-sided weakness. Hemiplegic migraines are associated with particular types of genetic changes in the CACNA1A gene called “gain of function” variants. Some gain of function changes are known to be associated more or less severe hemiplegic migraines. These events are not known to be associated with “loss of function” variants.

Episodic ataxia (type 2)

Ataxia involves poor balance and unsteady movement, as well as dizziness, headache, and/or nausea. In episodic ataxia, a person has a sudden, temporary bout of ataxia. For example, a child that can normally walk without any problems may suddenly struggle to walk and keep his or her balance.

Eye movement disorders in CACNA1A-related disorders

CACNA1A-related eye movement disorders include nystagmus and paroxysmal tonic upgaze. Nystagmus refers to involuntary eye movements from side to side or up and down. Paroxysmal tonic upgaze refers to a sustained involuntary upward eye gaze.

CACNA1A-related epilepsy

Seizures in CACNA1A-related disorders can range from mild to severe. For some people, seizures can begin in the first days or weeks of life, while other may only have a few or no seizures during their life. Similarly, some people have easily treated seizures, while others have very difficult to treat seizures.

Epileptic Encephalopathy

Encephalopathy refers to a disease that affects the functioning of the brain. Children with CACNA1A-realted epileptic encephalopathy typically experience multiple daily seizures that begin within the first week of life. These seizures are often tonic (stiffening) seizures and may be associated with jerking movements and changes in breathing or heart rate. Seizures are often associated with characteristic patterns on EEG and may be difficult to control with anti-seizure medications initially. Children with CACNA1A-related epileptic encephalopathy have delays in reaching developmental milestones and associated cognitive impairment, ranging in severity from moderate to severe. This can include differences in muscle tone and features of autism spectrum disorder (see CACNA1A-related neurodevelopmental disorders for more information on these features).

In most children with CACNA1A-related epileptic encephalopathy, seizures disappear in childhood. However, cognitive impairment and other neurological complications persist.

CACNA1A-related neurodevelopmental disorders

There are several different neurodevelopmental features that can be seen in children with CACNA1A-related disorders, including:

• Hypotonia, or low core muscle tone. This can make it difficult for children to reach motor milestones on time.
• Spasticity, or increased muscle tone in the limbs. This can make it difficult for children to have full control over their arms and legs.
• Autism spectrum disorder. This involves changes in language development and social skills. Children with autism spectrum disorder often do not meet their language developmental milestones on time, and may not interact with other people like other children (for example, not making normal contact). They also have repetitive behaviors or restricted interested, such as repeating certain movements over and over or having a very strong fascination with a very limited number of topics.
• Global developmental delay (used before age 5)/intellectual disability (used after age 5). This refers to children that do not meet language or motor milestones on time, and have limited cognitive abilities compared to others that are the same age. In CACNA1A-related disorders, this can range from mild to severe.

Cerebellar atrophy

Cerebellar atrophy can affect movement, balance, and coordination. People may have slow and slurred speech, involuntary eye movements (nystagmus), wide-based and poorly coordinated walking pattern, and tremor in the body’s trunk. This is not a common feature of CACNA1A-related disorder. If present, it can sometimes be progressive, and in rare cases affect other parts of the brain.

Spinocerebellar ataxia (type 6)

Spinocerebellar ataxia is a progressive disorder that involves increasingly severe problems with movement, coordination, and balance. It can also involve problems with speech and eye movements due to lack of coordination of mouth, tongue, and eye movements. Symptoms typically start around 40-50 years of age.

This disorder is caused by a specific type of change in the CACNA1A gene, in which a certain patterned section (called a CAG repeat) increases in size. This is a different type of change that seen in other types of CACNA1A-related disorders and requires a different kind of genetic test to be diagnosed.

Diagnosis of CACNA1A-Related Disorder

Suggestive features of a CACNA1A-related disorder include a severe hemiplegic migraine event, ataxia and eye movement disorders in an individual with seizures or developmental delay, or a positive family history of familial hemiplegic migraine. However, a diagnosis of a CACNA1A-related disorder cannot be made based on clinical features alone.

Genetic testing is required to confirm a diagnosis.

Additional tests may also be done, including:

• Electroencephalogram (EEG) to look for evidence of abnormal brain activity and seizures
• Magnetic resonance imaging (MRI) to look for structural brain abnormalities

Genetics of CACNA1A-Related Disorders

All children with CACNA1A-related disorder have a pathogenic variant (“mutation”) in the gene CACNA1A, which encodes the instructions to make a protein in the brain called a calcium channel. Pathogenic variants that affect the CACNA1A calcium channel impair the flow of calcium ions in the brain.

In children with CACNA1A-related disorders, the pathogenic variant may affect the CACNA1A potassium channel in different ways. In most cases (especially if episodic ataxia or neurodevelopmental differences are most prominent), the CACNA1A mutation leads to decreased activity of the ion channel. In other cases (especially if hemiplegic migraine is present), the mutation leads to over activity of the ion channel.

In most children with CACNA1A-related disorders, the pathogenic CACNA1A variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic CACNA1A variant has been passed on from an asymptomatic parent due to parental mosaicism. Just like a mosaic piece of art, in which each tile is different, a mosaic parent has distinct cell types. Most cells of a mosaic parent do not carry the pathogenic CACNA1A variant. However, a small proportion of cells do carry the pathogenic CACNA1A variant in very low levels that may be difficult or impossible to detect.

Cases of mild hemiplegic migraine or spinocerebellar atrophy may be inherited from affected parents, especially if a family history of the respective disorder. However, these conditions can also occur de novo, or brand new, in a child.

Treatment for CACNA1A-Related Disorder

Treatment for CACNA1A-related disorder will depend on the type and severity of the seizures.

• A combination of seizure medications is typically used to control the different seizure types. No particular anti-seizure medication has been shown to be more effective than others.
• A different set of medications, known as rescue therapies, may be given to help stop or shorten clusters of seizures when they occur.
• Implantable devices such as vagus nerve stimulation (VNS) or responsive neurostimulation (RNS) may be considered when medications are not effective in controlling seizures.
• Dietary therapy, such as the ketogenic diet, may be helpful in some cases.
• For individuals at risk for hemiplegic migraine, an action plan should be in place for medical staff to reference if a hemiplegic migraine event occurs. This includes suggested medications and procedures that should be started in the hospital or ambulance.

Family training and support is a key element in a successful epilepsy treatment plan. Parents and caregivers must know how to watch for and respond to seizures.

Cognitive and developmental delays or autism spectrum disorder associated with CACNA1A-developmental and epileptic encephalopathy are treated with physical, occupational and speech therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.

Why Choose CHOP for Treatment of CACNA1A-Related Disorders?

Families come to our ENGIN Clinic from all over the world. Children with CACNA1A-related disorder who are cared for at CHOP will receive cutting-edge genetic testing to confirm the underlying cause of their condition, as well as parental testing to confirm the diagnosis and inform recurrence risk with a subsequent pregnancy. Through ENGIN, your child will have access to any other medical specialists they may need. They will also have access to the full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including epilepsy management, dietary treatment and epilepsy surgery, as well as cutting edge research, clinical trials and ongoing follow-up care.

All individuals seen in the ENGIN Clinic are offered the opportunity to participate in research studies. ENGIN providers are collaborators on the NIH-funded Channelopathy-Associated Epilepsy Research Center, the goal of which is to understand how variation in ion channel genes including CACNA1A leads to epilepsy and to advance the development of novel therapeutics. Our clinic is also heavily involved in several research efforts to better understand CACNA1A-related disorders, especially CACNA1A-related hemiplegic migraines.

ENGIN integrates genetic testing into the diagnosis and treatment of children with difficult-to-treat or unexplained epilepsies, genetic epilepsy syndromes and other genetic neurodevelopmental disorders. We combine cutting-edge clinical care and advanced genetic testing with innovative research to identify the underlying cause of a child’s epilepsy and develop an individualized approach to treatment and management.

Resources for CACNA1A-related disorder

• CACNA1A Foundation
• Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission