Written by Dr. Judit Pérez Edited by Dr. David Bushart
A new case report describes how a new mutation in the CACNA1A gene causes ataxia with seizures.
Genes and their diseases
Hereditary ataxias are caused by mutations in different genes that affect how different parts of the brain and spinal cord work. Usually, the affected genes predict how one would expect the patient’s clinical signs and symptoms to look. The reverse can also be true. For example, a set of clinical signs and symptoms may raise suspicion of a known genetic disease, which allows doctors to perform focused genetic testing to confirm the diagnosis. These correlations are helpful for doctors and patients in understanding the diagnostic process and disease outlook.
New mutation, new disease
A study by Stendel and colleagues was inspired by a patient who developed ataxia in mid-adulthood that slowly worsened over the next decades of his life. The progression resembled that of spinocerebellar ataxias with repeat expansions in their genes as the culprits. However, when doctors performed the usual genetic testing for ataxia genes, they did not find a match. Nevertheless, suspicion for an ataxia gene playing a role remained high. The patient had experienced seizures as a child (called “absence seizures”), which didn’t entirely fit the picture of known SCAs. Where to go from here? The scientists next broadened their search to include 118 genes that are known to cause ataxia or other diseases that include ataxia symptoms. To their surprise, they found a previously unidentified mutation in a well-known ataxia gene called CACNA1A.
CACNA1A – three birds with one stone
CACNA1A is a gene that instructs brain cells to make a calcium channel protein, called Cav2.1, whose task is important to help neurons communicate. Three different mutation types are already known to disrupt and derail the work of Cav2.1 and lead to three distinct neurological diseases. These are Spinocerebellar ataxia type 6 (SCA6), Episodic Ataxia type 2 (EA2), and Familial Hemiplegic Migraine type 1 (FHM1). Although CACNA1A is their common link, the three diseases show distinct clinical features (Table 1).
SCA6 is an adult disease that usually presents in the fifth decade of life as coordination difficulties (ataxia) that gradually worsen over time. In contrast, EA2 is a childhood disease. It consists of transient episodes of coordination difficulties without symptoms between those episodes. In FHM1, patients experience migraines that are so severe they result in temporary paralysis of one side of their body. Clinically, SCA6, EA2, and FHM1 are distinguishable neurological diseases that would seem to have distinct genetic entities, but have CACNA1A as their cause. The distinction is in the details.
|CACNA1A mutation||CAG expansion (polyglutamine)||Point mutations; small deletions/insertions||Point mutations; small deletions/insertions||Exon 14 deletion|
|Effects of mutation on protein function||Faulty protein, and harmful effects on cells||Faulty protein||harmful effects on cells||Completely inactive protein|
|Symptoms||Progressive ataxia. Starts in late adulthood.||Sudden attacks of ataxia symptoms and imbalance that lasts minutes to days, occurring a few times a week or year. Starts in childhood. 50% may have migraines.||Migraines that result in paralysis of half of the body, May also have ataxia.||Absence seizures in childhood. Progressive non-episodic ataxia in adulthood.|
|Treatment||N/a||Avoid triggers. Drug: acetazolamide||N/a||N/a|
Like some other spinocerebellar ataxias, SCA6 is caused by CAG expansion mutations making abnormally long polyglutamine portions in the Cav2.1 protein it produces. CAG expansion in CACNA1A affects how well Cav2.1 functions, but also confers damaging effects. In the case of EA2 and FHM1, the genetic mutations are not CAG expansions. Instead, the mutations can either be “typos” in the DNA or tiny insertions/deletions “pieces” of genetic material that affect the quality and function of Cav2.1. If the genetic alteration affects how well Cav2.1 works, the disease is EA2. However, if the genetic alteration causes Cav2.1 to have damaging effects in cells, the disease is FMH1. The nuance and complexity of the CACNA1A gene is perplexing, and its enigmatic nature continues to grow.
Why is it important to recognize the genetic distinctions between these three diseases? The reasoning is that knowing the underlying cause may influence how best to treat these patients. For instance, EA2 ataxic episodes have recognized triggers that may be avoided if the disease is accurately diagnosed. We also know that a drug called acetazolamide can help lower the severity of symptoms in EA2 and how frequently they occur. These interventions are not helpful in SCA6 or FHM1 and would be unnecessary in those patients.
CACNA1A – (four?) birds with one stone
Let’s return to the case report. What did the new genetic testing reveal in this patient? Was it informative? It turns out that this patient has a novel variant of the CACNA1A gene! But, how is it different from the mutations that in the same gene can cause SCA6, EA2, FHM1? To answer this, the investigators went on to test how it affects the function of Cav2.1 protein. First, they grew patient skin cells in the laboratory (fibroblasts), and analyzed what portion of the gene created the protein. They found that the mutation results in the loss of an entire piece of Cav2.1 ion channel protein. Then they introduced the mutant genetic material into frog eggs and tested how well this ion channel protein conducts currents. They found that the mutation completely blocks the ability of the channel to function!
Expanding our genetic diagnostic strategies
Patients with adult-onset progressive ataxia are likely to have diagnostic genetic testing for common CAG trinucleotide expansion mutations in a small group of ataxia genes. As an example, when CAG expansion is seen in the CACNA1A gene, the diagnosis is SCA6. Case closed. But this study teaches us that genetic testing may not always be straightforward. CACNA1A is proving itself as an important gene in the health and disease of both young and adult brains. Our understanding to date is that CAG expansion mutation causes its adult progressive form, but researchers should look into other possible mutations in this gene when CAG is not the answer. CACNA1A is unlikely the only gene that behaves this way. This report opens our eyes to the subtleties of the role of genes and their mutations in brain health and disease.
Absence Seizure: A type of abnormal electrical brain activity (seizure) in which the person briefly loses consciousness and appears to stare into space. It is more common in children.
Conflict of Interest Statement
The author and editor declare no conflict of interest.
Citation of Article Reviewed
Stendel C, D’Adamo MC, Wiessner M, Dusl M, Cenciarini M, Belia S, Nematian-Ardestani E, Bauer P, Senderek J, Klopstock T, Pessia M. Association of A Novel Splice Site Mutation in P/Q-Type Calcium Channels with Childhood Epilepsy and Late-Onset Slowly Progressive Non-Episodic Cerebellar Ataxia. Int J Mol Sci. 2020 May 27;21(11):3810. doi: 10.3390/ijms21113810. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312673/