CACNA1A – this is what you need to know (2022)

CACNA1A. A lot has happened in the world of CACNA1A since our last blog post in 2015, including the formation of a family foundation, a natural history study, and a major multicenter research project. This post summarizes what we now know about CACNA1A in 2022.

Here are the most recent blog posts that mention CACNA1A

In a nutshell. CACNA1A codes for a neuronal ion channel, the alpha-1a subunit of a voltage-dependent P/Q calcium channel, which is expressed widely throughout the CNS. It was originally known as a gene for familial ataxias and hemiplegic migraines with little connection to epilepsy, but its story has quickly changed. We now know that both mild and severe forms of epilepsy are relatively common features. Our understanding of CACNA1A-related hemiplegic migraine has also evolved, from a primarily mild, familial phenotype to a spectrum that frequently includes de novo variants and severe, even life-threatening events. While the “original” presentations still exist and come up in our clinic, the mounting evidence for these severe phenotypes has caused us to change our approach to treatment and counseling for patients with a new CACNA1A diagnosis, and broaden what we think of as a “typical” CACNA1A presentation.

Below, we’ll review the classical phenotypes associated with CACNA1A as well as the phenotypes that have become more apparent since 2015 

Phenotypes | Genetics | Mechanism | Community

Figure 1. An overview of various disease-causing variants in CACNA1A, including several of the most common recurrent variants.

Phenotypes

Summary. In brief, CACNA1A has traditionally been associated with three main familial phenotypes: familial episodic ataxias, familial spinocerebellar ataxias, and familial hemiplegic migraines. The reason why I am distinguishing episodic and spinocerebellar ataxias is due to the fact that the disease presentation in these conditions is entirely different. Episodic ataxias lead to brief, recurrent, non-progressive episodes of lack of balance, whereas spinocerebellar ataxias are chronic, progressive diseases that are often associated with imaging findings (cerebellar atrophy). Historically, CACNA1A was identified in familial hemiplegic migraine and episodic ataxia at the same time in 1996. The discovery in spinocerebellar ataxia followed soon afterwards in 1997.

CACNA1A patients can present with considerable variability both in the severity of individual features and in the combination of specific phenotypes. In addition, patients may initially come to neurological attention because of one feature (e.g. developmental delay) but later present with another feature (e.g. hemiplegic migraine) that quickly overshadows the one first identified. Some genotype-phenotype correlations exist, as described in more detail below, but more work is needed to fully understand the phenotypic spectrum of each variant.

Familial hemiplegic migraine 1 (FHM1). Familial hemiplegic migraine was one of the first phenotypes to be associated with mutations in CACNA1A. FHM is characterized by migraines with aura that is associated with weakness on one side of the body. As the name implies, this phenotype is often present in multiple family members, and as with most familial phenotypes, can be mild. However, more severe presentations of hemiplegic migraine can be seen in association with CACNA1A, which we will separate here since the treatment implications are different.

CACNA1A-related severe hemiplegic migraine. Severe hemiplegic migraines are typically caused by de novo variants as opposed to the inherited variants seem in FHM1. Individuals experiencing one of these events are usually hospitalized and worked up for a stroke given the severity of the hemiplegia. In some cases, events are triggered by mild head trauma. In the most severe cases, patients can have loss of consciousness, coma, and brain swelling. In rare cases, the brain swelling can become fatal. Diffusion restriction is often seen on MRI during severe events, with resolution after the patient returns to baseline. Most patients are able to recover most if not all functioning, but this may take anywhere from days to months, and intense rehabilitation is often required. These events can co-occur with seizures and status epilepticus, which is not seen in classic FHM1.

Episodic ataxia 2 (EA2). Episodic ataxia type is characterized by attacks of gait ataxia, poor balance, nausea, vomiting, and sometimes particular eye movement disorders that is referred to as oscillopsia. Patient with episodic ataxia can present in childhood or adolescence and the attacks can last between hours and a few days. Sometimes, attacks are set off by triggers such as stress, infection, fever, heat, exertion, caffeine, or alcohol. The attacks can be associated with various neurological symptoms, occasionally even with the hemiplegic symptoms seen in FHM. Between the attacks, patients usually do not have symptoms. However, more recent studies suggest that up to 50% of patients may eventually develop chronic neurological features such as nystagmus or cerebellar atrophy. Of note, care should be taken to distinguish episodic ataxia from developmental ataxia that occasionally becomes more prominent during times of illness or fatigue. For example, a patient with an underlying developmental ataxia may have a harder time compensating for the congenital deficiency when tired, and become more ataxic than normal. This is distinct from an otherwise motorically typical child who has a sudden onset of ataxia.

Eye movement disorders. The classic CACNA1A-related eye movement disorder is paroxysmal tonic upgaze (PTU). Individuals with this experience brief period in which their eyes are essentially stuck looking upwards. Individuals may tilt their heads downwards to compensate. In these instances, the eyes are fixed in the upwards position. In contrast, individuals with nystagmus, another common eye movement disorder in CACNA1A, will have drifting eye movements in one direction with quick saccades back to center. This can at first appear to be PTU, as eyes may appear stuck in a position, but closer examination can reveal the drifting and saccades of nystagmus.  In some cases, the nystagmus may become more prominent when looking down, so individuals with this will avoid looking down in order to maintain control. Looking up is a compensatory measure in these cases, rather than true PTU.

Epilepsy. CACNA1A variants can cause a variety of seizure phenotypes, from no seizures or EEG features only, to absence epilepsy, to intractable generalized epilepsy. Some patients experience status epilepticus the first time they ever present with a seizure. Patients with severe epilepsy may be at higher risk to also have severe hemiplegic migraines.

Developmental differences. Patients with CACNA1A can present with typical development or mild to severe developmental delay/intellectual disability. In familial cases, development is generally typical or very mildly affected. In de novo cases, development can vary but is often in the range of mild to moderate impairment. Autism spectrum disorder is also a fairly common feature, though many children with CACNA1A are very friendly. Finally, other neurodevelopmental features such as ADHD and anxiety are fairly common.

 

Spinocerebellar ataxia 6 (SCA6). Spinocerebellar ataxia is a slowly progressive neurological disorder that is characterized by progressive limb and gait cerebellar ataxia. Often, patients also develop other neurological symptoms such as dysmetria in the upper extremities, intention tremor, dysarthria, and various oculomotor symptoms such as nystagmus or diplopia. The bulbar signs especially dysarthria can be the presenting sign in up to 10% of patients. Patients usually present with symptoms in adulthood, usually in their 40s and 50s.

SCA6 is associated with CAG repeat expansions in CACNA1A. The CAG repeats, or “poly-Q” or “poly-glutamine” tract, are located in the last exome of the gene (exon 47). Eighteen or fewer CAG repeats is considered non-pathogenic, and 20 to 33 CAG repeats are considered disease-causing. 19 repeats is considered an “allele of questionable significance” and may or may not result in symptoms. Typically, individuals with more repeats will have an earlier age of onset. Because of anticipation, it is possible to have childhood onset of SCA6 if an individual has a very high number of CAG repeats, but this is rare. There is some variability in age of onset among siblings carrying the same amount of CAG repeats. Trinucleotide repeats cannot be ascertained through sequencing or traditional tests for copy number variants, so SCA6 cannot be diagnosed through sequencing, microarray, or MLPA. Targeted testing of repeat number is the typical testing method, though some ataxia panels exist that can test for multiple types of spinocerebellar ataxia.

It is important to keep in mind that SCA6 is distinct from other CACNA1A-related disorders, in three primary ways: 1) SCA6 is a progressive, adult-onset disorder, not a developmental phenotype that becomes apparent in childhood. 2) SCA6 is caused by trinucleotide repeat expansions only. It is not caused by loss of function variants, copy number variants, or single nucleotide variants, which are the types of variants that can cause the other phenotypes on this page. Individuals that have any type of variant in CACNA1A besides a repeat expansion should not be considered at higher risk for SCA6 because of their CACNA1A variant. 3) The molecular mechanism of SCA6 and the neurodevelopmental phenotypes associated with CACNA1A are distinct and do not overlap. The CACNA1A gene actually codes for two separate proteins: α1A, a P/Q calcium channel subunit (involved in the rest of the CACNA1A-related disorders on this page), and α1ACT, a transcription factor. The neurodevelopmental phenotypes, on the other hand, are caused by a reduction in α1A or a change to how the resulting calcium channels work. SCA6, on the other hand, results from a toxic buildup of abnormal α1ACT protein.

Genotype

Genotype vs. phenotype. There is some degree of genotype-phenotype correlation in CACNA1A, even though the correlation between subphenotypes and variability within families is large. There can be incomplete penetrance, and especially in FHM families, up to one third of patients can be unaffected. FHM has been associated with missense alterations in CACNA1A that code for functional regions of the protein, typically either the pore lining or voltage sensor region. Most EA2-associated CACNA1A alterations result in premature protein truncation, but missense alterations have also been reported. For some EA2-related missense mutations, functional studies have demonstrated that lead to loss of P/Q channel function.

Severe epilepsy, including status epilepticus, is associated with gain of function mutations and is not expected with loss of function mutations. The same is generally thought to be true of hemiplegic migraine. A recent paper by Lipman and colleagues (2022) suggests that loss of function variants may cause hemiplegic migraines, though additional research may be needed to confirm that these variants are indeed loss of function and patients presented with hemiplegic migraine and not a different neurological feature.

Recurring variants. There is emerging data on recurrent variants for some of the CACNA1A-related phenotypes, such as the familial hemiplegic migraines. Therefore, the p.R192Q or the p.S218L variant have been reported in multiple families with FHM, the p.R583Q or p.T666M variant has been found in several families with FHM and ataxia. The p.R1349Q variant has been found recurrently in patients with ataxia, intellectual disability and paroxysmal tonic upward gaze. Episodic ataxia and epilepsy phenotypes are often associated with truncating mutations or deletions.

Segregation. CACNA1A-associated disorders are inherited in a dominant fashion and segregation data (testing parents and families) may help figure out whether a variant is pathogenic. Severe, early onset childhood phenotypes in otherwise unaffected families may be de novo. Alternatively, the variant can be inherited from a parent with a milder phenotype.

Transcripts. One of the things that makes CACNA1A particularly complex is the presence of multiple transcripts, with different ones favored historically and by certain labs. After a careful review of expression data, the Center Without Walls selected transcript 3 (NM_001127221) as our transcript of choice. However, lab reports and literature may use a handful of others as their reference, which can change the number position given for a base pair or amino acid. For example, the same variant could be listed as c.6796C>G, Q2266E (NM_023035.3); c.6781C>G, Q2261E (NM_001127221.2); or c.6778C>G, Q2260E (NM_001127222.2). Adding to the complexity is that certain motifs repeat. For example, in exon 25, there is a section where the amino acid sequence is LRVLRVLR. Two common transcripts, NM_023035.3 and NM_001127221.2, are 3 amino acids different. This makes it impossible to know which variant is being referenced by R1349Q if a transcript is not given – both NM_023035.3 and NM_001127221.2 contain an R1349Q, but at different positions (in NM_001127222.2, this is R1345Q and R1348Q, respectively).

 

My patient has a mutation in CACNA1A – what does this mean? Assessing CACNA1A variants is difficult in many cases. This gene is included in many gene panels and clinicians may be faced with the problem to interpret milder symptoms in transmitting carriers correctly. For example, when looking at the segregation of CACNA1A variants, does the presence of migraine without aura in a parent of child with absence epilepsy suggest that the variant is causative? CACNA1A is a large gene and with the advent of widespread genetic testing, both causative and rare population variants in this gene are identified. Here are three criteria that may help you interpret CACNA1A mutations in your patient.

1 – Variant. There is some emerging data on recurrent variants for some of the CACNA1A-related phenotypes, such as the familial hemiplegic migraines. Therefore, the p.R192Q or the p.S218L variant have been reported in multiple families with FHM, the p.R583Q or p.T666M variant has been found in several families with FHM and ataxia. CAG repeat expansions larger than 20 repeats are associated with SCA6. The p.R1349Q variant has been found recurrently in patients with ataxia, intellectual disability and paroxysmal tonic upward gaze. Episodic ataxia and epilepsy phenotypes are often associated with truncating mutations or deletions. Therefore, either known recurrent variants or truncation mutations/deletions may be considered explanatory for the patient’s phenotype in the absence of segregation data or the precise phenotype. Functional data suggesting a gain of function for a particular variant may also suggest a possibility of hemiplegic migraine or epilepsy.

2 – Segregation. CACNA1A-associated disorders are inherited in a dominant fashion and segregation data (testing parents and families) may help figure out whether a variant is pathogenic. Severe, early onset childhood phenotypes in otherwise unaffected families may be de novo. Alternatively, the variant can be inherited from a parent with a milder phenotype.

3 – Phenotype. The phenotypic spectrum of CACNA1A is large and the question may arise, which phenotype would be considered incompatible with CACNA1A as the underlying gene, suggesting that an identified variant may be considered non-causal based on the phenotype alone. Based on the currently available data on the epilepsy phenotype, most epilepsies have a generalized component. The spectrum of the phenotypes is broad and expanding, and future studies will help us figure out the associated epilepsies better.

Mechanism

Ion channels. CACNA1A codes for a neuronal ion channel, the alpha-1a subunit of a voltage-dependent P/Q calcium channel, which is expressed widely throughout the CNS. Kraus and collaborators have found that missense mutations in the alpha-1a subunit associated with FHM introduce issues in channel gating, including both faster and slower recovery from channel inactivation than wildtype.  Further studies of FHM mutations in human cells found that the functional effects of the studied CACNA1A mutations were a decrease of maximal Ca(v)2.1 current density in neurons and an increase in single-channel calcium ion influx. Hemiplegic migraines are caused by gain of function mutations that allow for excessive, coordinated neuronal firing and cortical spreading, which in turn can lead to brain swelling due to overactivity of neurons.

Community

The CACNA1A Foundation is a non-profit organization for CACNA1A families and researchers. They have various resources and educational videos for families and host an annual conference. They are currently working with Columbia University to conduct a natural history study, and several different partners to coordinate variant functional studies and a centralized phenotypic database.