|

Accepted: 28 May 2020

CLINICAL REPORT

A novel CACNA1A variant in a child with early stroke and
intractable epilepsy
Franciska J. Gudenkauf1
| Mahshid S. Azamian2
Anuranjita Nayak4 | Seema R. Lalani2
1

School of Medicine, Baylor College of
Medicine, Houston, TX, USA
2

Department of Molecular and Human
Genetics, Baylor College of Medicine,
Houston, TX, USA
3

Department of Radiology, Baylor College
of Medicine, Houston, TX, USA
4

Section of Pediatric Neurology and
Developmental Neuroscience, Department
of Pediatrics, Baylor College of Medicine,
Houston, TX, USA
Correspondence: Seema R. Lalani,
Department of Molecular and Human
Genetics, Baylor College of Medicine, One
Baylor Plaza, Houston, TX 77030, USA.
Email: [email-masked]

| Jill V. Hunter3 |

Abstract
Background: CACNA1A variants have been described in several disorders that encompass a wide range of neurologic phenotypes, including hemiplegic migraine,
ataxia, cognitive delay, and epilepsy. To date, ischemic stroke caused by a CACNA1A
variant has only been reported once in the literature.
Methods: We describe a 4-year-old female with recurrent ischemic strokes beginning at 6 weeks of age, intractable epilepsy, and significant global developmental
delay. Exome sequencing (ES) was completed for her evaluation.
Results: We found a novel de novo, likely pathogenic variant, p.Leu1692Gln in
CACNA1A by ES. The substitution affects a leucine residue that is highly conserved
in species from fish to primates.
Conclusion: We present the second case of recurrent ischemic strokes in a patient
with CACNA1A mutation. Our findings expand the phenotypic heterogeneity related to Cav2.1 (P/Q-type) calcium channel dysfunction and suggest consideration of
CACNA1A disorder in evaluation of pediatric strokes.
KEYWORDS

CACNA1A, epilepsy, stroke

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IN T RO D U C T ION

The CACNA1A gene (OMIM #601011) codes for the alpha-1
pore-forming subunit of the P/Q-type voltage-gated calcium channel, which is located in the neuronal membrane
(Currie, 2010; Luo et al., 2017). The Cav2.1 (P/Q-type)
channels are expressed in mammalian brain and are responsible for Ca2+ influx to modulate membrane excitability,
synaptic transmission, and calcium-dependent gene transcription (Takahashi & Momiyama, 1993; Westenbroek
et al., 1995). The alpha-1 subunit encoded by CACNA1A
contains four repeated domains (I–IV), each consisting of six

membrane-spanning segments (S1–S6) and a P-loop between
S5 and S6 (Currie, 2010); the four S4 segments constitute the
voltage sensor of the channel and the S5 and S6 segments
along with the P-loops form the pore lining (Figure 1a).
Pathogenic variants in CACNA1A can lead to a variety of
neurological symptoms and several well-described disorders (Byers, Beatty, Hahn, & Gospe, 2016; Luo et al., 2017).
Familial hemiplegic migraine type 1 (FHM1, OMIM
#141500), caused by gain-of-function variants in CACNA1A,
is an extreme type of migraine with aura that typically presents in the first or second decade of life with episodes of
headaches, sensory loss, visual disturbance, hemiparesis,

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC
Mol Genet Genomic Med. 2020;00:e1383.		
https://doi.org/10.1002/mgg3.1383

wileyonlinelibrary.com/journal/mgg3

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GUDENKAUF et al.

(a)

(b)

F I G U R E 1 Structure of the alpha-1 pore-forming subunit of the Cav2.1 (P/Q-type) voltage-gated calcium channel. (a) Secondary structure;
our patient's variant, p.Leu1692Gln, is located in the S5 segment of domain IV (red diamond), while the single previously reported strokeassociated variant, p.Arg1349Gln, is located in the S4 segment of domain III (yellow diamond). (b) Amino acid conservation across species; the
leucine residue (L) at 1692 codon is highly conserved across species. Our patient's variant (p.Leu1692Gln) substitutes a glutamine residue (Q)
instead

and cerebellar signs such as nystagmus or ataxia (Byers
et al., 2016; Jen, 2001). Episodic ataxia type 2 (EA2, OMIM
#108500) is usually due to loss-of-function variants that lead
to paroxysms of ataxia, vertigo, and nausea typically lasting
minutes to days (Spacey, 2003). Individuals with EA2 may
also experience migraines and hemiplegia like those with
FHM1 (Spacey, 2003). Abnormal trinucleotide repeat expansion in the CACNA1A gene causes spinocerebellar ataxia
type 6 (SCA6, OMIM #183086), which normally presents in
adulthood with progressive gait ataxia, incoordination, tremors, dysarthria, and nystagmus (Case y & Gomez, 1998).
Although these disorders are caused by different pathogenic variants, it is evident that phenotypic features are shared
among them (Byers et al., 2016). Even family members with
the same variant may exhibit variable expressivity anywhere
within, or even outside, the spectrum of symptoms associated
with these disorders (Byers et al., 2016). In addition to these
three disorders, CACNA1A variants have been associated
with epilepsy and several other neurologic manifestations, including global developmental delay, hypotonia, and cerebellar hypoplasia, highlighting the incredibly diverse variability
in phenotype resulting from genetic alterations in this gene
(Byers et al., 2016; Liu et al., 2018; Luo et al., 2017). Indeed,
with the commonplace use of molecular genetic testing, new
associations between CACNA1A variants and phenotypic
manifestations will surely continue to be revealed.
Here, we present the case of a 4-year-old female with a
history of recurrent ischemic strokes starting at 6 weeks of

age, intractable epilepsy, and significant global developmental delay who was found to have a novel likely pathogenic, de novo variant in CACNA1A (p.Leu1692Gln). To our
knowledge, there has only been one previously reported case
of ischemic stroke caused by CACNA1A mutation (p.Arg1349Gln) in a young girl with FHM1 (Knierim et al., 2011).
However, the particular variant in the CACNA1A gene identified in our patient has not yet been described.

2

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M ETHODS

2.1 | Editorial policies and ethical
considerations
The study was approved by the ethics committee at Baylor
College of Medicine. Informed consent was obtained from
the family for inclusion in the study.

2.2

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Case report

We describe a 4-year-5-month-old Hispanic female who was
born to non-consanguineous parents. Her early medical history was seemingly unremarkable until about 6 weeks of age,
when she presented with transient tonic stiffening of her left
upper extremity without any alteration in consciousness, in
the setting of fever. She then presented 2 weeks later with an

GUDENKAUF et al.

atypical febrile seizure involving her left hemibody, followed
by developmental regression with loss of visual tracking. Her
head circumference was noted to be normal at 2 months of
age (39 cm). Electroencephalogram (EEG) revealed corroborating epileptiform activity from the right centro-parietal
regions. Magnetic resonance imaging (MRI) showed multifocal restricted diffusion abnormality in the right anterior putamen, bilateral posterior limbs of the internal capsule, right
corticospinal tract, and splenium of the corpus callosum,
consistent with recent right putaminal infarction (Figure 2a).

  

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Magnetic resonance arteriography (MRA) and magnetic resonance venography (MRV) were normal. Hypercoagulability
workup was negative except for a transiently positive lupus
anticoagulant. Echocardiogram showed a small- to moderate-sized fenestrated secundum atrial septal defect versus
stretched patent foramen ovale (PFO). She was treated with
daily aspirin and discharged home on levetiracetam.
The patient presented again at 3.5 months of age with
fever and status epilepticus. EEG showed diffuse background slowing with periods of generalized suppression,

F I G U R E 2 Select brain imaging in a patient with p.Leu1692Gln CACNA1A variant, recurrent strokes, and intractable epilepsy. (a) MRI at
8 weeks of age; iso DWI and ADC maps demonstrating restricted diffusion-weighted imaging returned from the right anterior putamen, posterior
limbs of the internal capsule bilaterally, right corticospinal tract, and splenium of the corpus callosum, consistent with acute right putaminal
infarction and postictal changes. (b) H1 MRS short-TE multivoxel at 3.5 months of age and (c) H1 MRS long-TE single-voxel at 3.5 months of
age; placed in right basal ganglia, both demonstrating a relative paucity of NAA without evidence for lactate doublet. Appearance is consistent
with neuronal and axonal loss. (d) MRI at 5.5 months of age; axial T2-weighted and axial iso DWI and ADC maps through the plane of the basal
ganglia show increased T2 hyperintensity returned from the right basal ganglia with new restricted diffusion abnormality in the right-sided globus
pallidus. Appearances consistent with new right globus pallidus infarction within the preceding 7–10 days. There is bilateral but symmetric
underopercularization noted, together with mild right posterior plagiocephaly. ADC, apparent diffusion coefficient; DWI, diffusion-weighted
restriction; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA, N-acetylaspartate; TE, echo time

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focal voltage attenuation in the left hemispheric leads, and
multifocal epileptiform discharges. On brain imaging, there
was interval evolution of infarction in the right putamen
with resolution of restricted diffusion. Magnetic resonance
spectroscopy (MRS) at the time showed a relative paucity
of N-acetylaspartate without lactate doublet, consistent with
neuronal and axonal loss (Figure 2b,c). Around 4 months of
age, she was diagnosed with an apparently spontaneous right
internal jugular vein nonocclusive thrombus and was treated
with enoxaparin. Despite adequate anticoagulation, she presented at 5.5 months of age with increasing seizures and new
diffusion restriction on brain MRI involving the right globus
pallidus concerning for a new infarct (Figure 2d). She had
repeated hospitalizations due to frequent refractory status epilepticus, developed intractable epileptic encephalopathy, and
was implanted with a vagus nerve stimulator by age 8 months
due to medical refractoriness. Her seizure management,
complicated by apneic events, required repeated intubations,
eventually leading to tracheostomy. Brain MRI at 7 months of
age showed no new areas of diffusion restriction with interval
resolution of the previously noted changes. However, there
were prominent ventricles and sulci suggestive of diffuse cerebral volume loss. At 4 years and 5 months of age follow-up
visit, she was nonambulatory, nonverbal, and minimally interactive. She was gastrostomy tube-dependent. Her physical
exam revealed acquired microcephaly with head circumference of 46.7 cm (Z = −2.05), spasticity of the lower extremities, increased deep tendon reflexes, and axial hypotonia. Her
seizures had improved with her current treatment regimen
and no new neurologic deficits were reported.

2.3

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Diagnostic Workup

Extensive diagnostic workup was pursued throughout this
time, with the majority of studies resulting as either negative or inconclusive. Newborn screenings, comprehensive
chromosomal microarray, and mitochondrial DNA next generation sequencing results were all normal. Tests for inborn
errors of metabolism were nondiagnostic (e.g., acylcarnitine
profile, plasma amino acids, urine organic acids, and blood
lactate levels). Global Metabolomics Assisted Pathway
Screen and cerebrospinal fluid neurotransmitter studies were
normal. Cerebrospinal fluid infectious workup was negative,
as were laboratory tests for arginine:glycine amidinotransferase deficiency. Muscle biopsy was done at age 7 months,
which showed a paucity of mitochondria suggesting mitochondrial depletion. Electron transport chain study indicated
a reduction in several respiratory chain complex activities;
however, the findings did not satisfy a minor criterion of the
modified Walker criteria for the diagnosis of a respiratory
chain disorder. To obtain a definitive diagnosis, trio exome
sequencing was performed.

GUDENKAUF et al.

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RESULTS

Trio exome sequencing identified a heterozygous, likely
pathogenic de novo variant, c.5075T>A (p.Leu1692Gln)
in CACNA1A (NM_001127221.1; chr19:13346084). This
substitution (leucine to glutamine) affects a leucine residue that is highly conserved in species from fish to primates (Kent et al., 2002) and is predicted to be damaging
by in silico prediction programs (Figure 1b). This variant is not observed in gnomAD (Karczewski et al., 2020).
A heterozygous variant of unknown clinical significance,
c.5900G>A (p.Arg1967Gln) was also seen in CACNA1A
(NM_001127221.1; chr19:13325090), inherited from her
asymptomatic father. This variant was previously reported
in a cohort study for risk assessment in epilepsy (Klassen
et al., 2011), but has also been observed in gnomAD. It has
been classified as benign or likely benign in ClinVar by multiple submitters (Landrum et al., 2018).

4

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DISCUSSION

Here, we present a young child with early ischemic stroke,
intractable epilepsy, and significant global developmental delay due to a novel de novo variant, p.Leu1692Gln in
CACNA1A. As discussed, variants in this gene have been implicated in a wide range of neurologic phenotypes and welldescribed disorders, such as FHM1, EA2, and SCA6 (Byers
et al., 2016). In recent years, CACNA1A has become associated with a multitude of neurological phenotypes, including
congenital hypotonia, cerebellar hypoplasia, cognitive delay,
refractory epilepsy, and stroke (Klassen et al., 2011; Knierim
et al., 2011; Liu et al., 2018). To our knowledge, this is only the
second case of stroke described in a patient with a CACNA1A
variant. In 2011, Knierim et al. reported a 6-year-old female
with a diagnosis of FHM1 who presented with recurrent ischemic strokes after minor head trauma, associated with seizures and other neurologic symptoms, who was found to have
a novel p.Arg1349Gln variant in CACNA1A. This variant is
located in the helical region of the S4 segment in domain
III and was hypothesized to be a gain-of-function mutation,
whereas our patient's variant is in the helical region of the
S5 segment in domain IV (Knierim et al., 2011; The UniProt
Consortium, 2019; Figure 1a). FHM1 is a severe form of migraine with aura, which has been independently associated
with a risk for both stroke and epilepsy (Jen, 2001; Kurth,
Chabriat, & Bousser, 2012; Rogawaski, 2012). Migraine
with aura doubles the risk of ischemic stroke, likely due to
cortical spreading depression (CSD) which triggers headache and reduces cerebral blood flow to a level that induces
ischemia (Jolobe, 2012; Kurth et al., 2012). Specifically,
in FHM1, ion homeostasis is disrupted due to the calcium
channel defects, which increases neuronal excitability and

GUDENKAUF et al.

lowers the threshold for CSD (Kurth et al., 2012). In transgenic mouse models of FHM1, the calcium channels open
with smaller depolarizations and stay open for a long time,
thus, increasing neuronal excitability with glutamate release after continued presynaptic influx of calcium (Tottene
et al., 2005). It has also been shown that Cacna1a transgenic
mice required increased cerebral blood flow and suffered
stroke even with milder ischemia, developed larger infarcts,
and experienced more severe outcomes (Eikermann-Haerter
et al., 2012; Jolobe, 2012). Thus, the increased susceptibility to ischemia secondary to reduced cerebral blood flow
from CSD may explain the association between migraine and
stroke (Kurth et al., 2012). Additionally, the neuronal excitability that precedes CSD is implicated in seizure initiation
(Nye & Thadani, 2015; Rogawaski, 2012); further, epilepsy
can frequently present with peri-ictal migrainous headaches,
and migraine may trigger epilepsy, or even occur simultaneously. CSD is implicated as an important mechanism in all
three conditions––a mechanism disrupted by CACNA1A mutation (Nye & Thadani, 2015).
Our patient presented very young at 6 weeks of age with
stroke. Thus, it remains unknown if her phenotype would be
more similar to classic FHM1 if she had not had a stroke at
such a young age. The question also remains if this novel
variant predisposes to early infarcts after minor trauma/fever,
as our patient was febrile on both occasions when she presented at 6 and 8 weeks of age. Overall, her phenotype appears to be on the severe end of CACNA1A-related disease.
Yet, it is uncertain whether her clinical course stems from the
sequelae of stroke, the sequelae of refractory epilepsy, the
underlying novel CACNA1A variant, or, most likely, a combination of all of these. It also bears questioning whether the
stroke can be fully attributed to the underlying genetic variant, or to some comorbid process that has now complicated
her clinical course. It is interesting that similar to other metabolic strokes, such as seen in cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and mitochondrial encephalopathy, lactic
acidosis, and stroke-like episodes (MELAS), the distribution
of the infarcts in her does not correspond to vascular territories. Other thromboembolic possibilities were excluded by
her normal MRA and MRV studies. For the same reason,
the ASD versus PFO found on echocardiogram was unlikely
to be implicated in her stroke. Along with MRS lacking a
lactate peak, other workup was nondiagnostic for a mitochondrial disease. Coagulopathy was ruled out, which can
also predispose to arterial ischemic strokes (Felling, Sun,
Maxwell, Goldenberg, & Bernard, 2017). Thus, based on her
extensive nondiagnostic workup and a previously reported
individual with FHM1 and stroke related to CACNA1A variant (Knierim et al., 2011), we propose that the de novo variant in this gene in our patient is most likely the cause of her
recurrent strokes.

  

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While early recurrent strokes caused significant morbidity in our patient, the refractory epilepsy that developed
later resulted in more severe neurological sequelae. Our patient's initial MRI showed diffusion restriction in the right
anterior putamen and right corticospinal tract, with EEG revealing epileptiform activity from the right centro-parietal
regions; thus, it is conceivable that the seizure activity was
related to ischemia. However, repeat EEG at 3.5 months
after intractable seizures showed multifocal epileptiform
discharges and voltage attenuation in the left hemisphere,
despite all prior ischemic insults having affected the right
side; this may suggest the seizures are not fully attributable
to a history of stroke and instead may indicate progression
to epileptic encephalopathy. Further, seizures, epilepsy,
and epileptic encephalopathy all have been described as
part of the phenotypic spectrum of CACNA1A mutations
(Byers et al., 2016). In the previously described case of
stroke due to CACNA1A mutation, the affected patient also
presented with seizures (Knierim et al., 2011). Thus, it is
possible that our patient's epilepsy represents phenotypic
manifestations of her underlying variant, as opposed to
being fully caused by ischemic insults. Further, our patient
also manifested a p.Arg1967Gln variant of unknown clinical significance, which has been reported in a study evaluating risk assessment in epilepsy (Klassen et al., 2011), but
also previously classified as benign (Landrum et al., 2018).
It is unclear if this variant is also contributing to her phenotype. Additionally, our patient's final MRI at 7-months
showed diffuse cerebral volume loss, likely not fully attributable to stroke; this manifestation, as well as her acquired
microcephaly, may also be phenotypic of the variant, as
decreased brain volume such as cerebellar hypoplasia has
previously been reported (Luo et al., 2017).
In summary, we report a second patient with recurrent
strokes related to CACNA1A mutation. Our findings expand
the phenotypic heterogeneity related to Cav2.1 (P/Q-type)
calcium channel dysfunction and suggest consideration
of CACNA1A disorder in evaluation of pediatric strokes,
especially if the brain lesions do not conform to vascular
territories. While we postulate a gain-of-function mechanism for this Cav2.1 voltage-gated Ca2+ channel in causing
stroke in our patient, further studies are needed to understand the basis of stroke related to the p.Leu1692Gln variant and determine the specific impact of this variant on
CACNA1A function.
ACKNOWLEDGMENTS
We thank the patient and her family for their participation in
the study.
CONFLICT OF INTEREST
The authors declare no conflict of interest related to the
manuscript.

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AUTHOR CONTRIBUTIONS
F.J.G. and S.R.L. planned the report. M.S.A. consented and
enrolled the patient/family in the study. S.R.L., A.N., and
J.V.H. provided the clinical data. F.J.G. and J.V.H. created
the figures. F.J.G., S.R.L., and A.N. drafted the manuscript.
All coauthors read and approved the final manuscript as
submitted.
DATA AVAILABILIT Y STATEMENT
Variant was submitted to the National Center for
Biotechnology Information ClinVar database (https://www.
ncbi.nlm.nih.gov/clinv​ar/).
ORCID
Franciska J. Gudenkauf
https://orcid.
org/0000-0002-7463-8934
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How to cite this article: Gudenkauf FJ, Azamian MS,
Hunter JV, Nayak A, Lalani SR. A novel CACNA1A
variant in a child with early stroke and intractable
epilepsy. Mol Genet Genomic Med. 2020;00:e1383.
https://doi.org/10.1002/mgg3.1383